Interdisciplinary management of meningioma involving the cavernous sinus

The thesis consists of two parts: an anatomical study of the complex anatomy of the cavernous sinus (CS) and its surrounding structures, and a rerospective clinical study involving 104 patients with CS meningioma who were treated at the University Hospital of Philipps University, Marburg. The aim of the anatomical study was to improve our surgical technique and results through better understanding of the complex anatomical relationships in the CS region. We used 3 skull base approaches commonly used to expose the CS to study this anatomy. Using 5 cadaver heads, each approach was performed 10 times in the same way as live surgery. The extent of exposure and the anatomical landmarks necessary to perform each approach were identified and documented. The second part of this thesis consists of a retrospective study of 104 patients harboring CS meningiomas, who were treated in the departments of Neurosurgery and Radiotherapy of Philipps University, Marburg, between 1997 and 2003. The clinical data, as well as the results and morbidity of treatment were documented analysed. Additionally, post treatment quality of life was assessed using one of the most widely used assessment instruments, which is the Medical Outcome Study Short Form 36 (SF-36). This questionnaire comprises 36 items, which measure patients’ responses in 8 different health domains. There were 80 females and 24 males with an average age of 56 years. The mean follow-up period was 40 months. The most common tumor origin was the medial sphenoid ridge and the petroclival region. Sixty-eight patients in this series underwent at least one surgical resection. Among the patients who were operated upon at our institute, the rate ot total resection was 59.5%.The most common post operative complication was new cranial nerves dysfunction, encountered in 45.9% of our patients but it was permanent in only 13.5% of cases. Seventy-nine patients received SRT either as unique treatment (36 cases) or after subtotal surgical resection (43 cases). The median target volume was 11.8 ml and the mean dose was 55.8 Gy.Apart from temporary local alopecia and local radiodermatitis, symptoms related to acute post-irradiation toxicity were generally uncommon and easily controlled by steroid medication. Late radiation toxicity was also uncommon. Local tumor control was achieved in all but 2 cases, and about 50% of patients showed tumor regression in follow-up according to our definition of tumor shrinkage and enlargement. Two mortalities occurred during the follow-up period: one surgically-treated patient died one year after surgery from an unrelated cause; and the other was treated by a combination of surgery and SRT and died from tumor progress 16 months after treatment. Questionnaires from a total of 96 patients were eligible for analysis. These patients were subdivided into 3 groups according to their treatment protocols. The first group included 22 patients who were surgically treated, the second group included 34 patients who were treated uniquely with fractionated stereotactic radiotherapy (SRT), and the third group included 40 patients who were treated with a combination of microsurgery and SRT. there was no statistically significant difference in all tested domains of post-treatment life quality between the three treatment protocols; however, patients of the second group had the best values in all but one domain. SRT seems to be an efficient and safe initial or adjuvant treatment for meningiomas involving the CS as proved by tumor control rates and long term life quality scores. On the other hand, surgery still plays an important role in the management of these tumors especially in the presence of optic compression, brain stem compression and large tumor volume. In certain cases, both modalities should be combined in order to optimize the management

Toward a physiological explanation of juvenile growth curves

Juvenile growth curves are generally sigmoid in shape: Growth is initially nearly exponential, but it slows to near zero as the animal approaches maturity. The drop‐off in growth rate is puzzling because, everything else being equal, selection favors growing as fast as possible. Existing theory posits sublinear scaling of resource acquisition with juvenile body mass and linear scaling of the requirement for maintenance, so the difference, fuel for growth, decreases as the juvenile increases in size. Experimental evidence, however, suggests that maintenance metabolism increases sublinearly not linearly with size. Here, we develop a new theory consistent with the experimental evidence. Our theory is based on the plausible assumption that there is a trade‐off in the capacity of capillaries to supply growing and developed cells. As the proportion of non‐growing cells increases, they take up more macromolecules from the capillaries, leaving fewer to support growing cells. The predicted growth curves are realistic and similar to those of previous models (Bertalanffy, Gompertz, and Logistic) but have the advantage of being derived from a plausible physiological model. We hope that our focus on resource delivery in capillaries will encourage new experimental work to identify the detailed physiological basis of the trade‐off underlying juvenile growth curves

Charakterisierung molekulargenetischer Prognosefaktoren auf dem kurzen Arm des Chromosoms 1 in humanen Meningeomen.

Meningeome, zumeist benigne Neoplasien des ZNS, stellen bis heute in manchen Fällen eine diagnostische und therapeutische Herausforderung dar: Zum einen ist für die kleine Gruppe der atypischen und anaplastischen Tumoren das Grading aufgrund histopathologischer Marker trotz revidierter WHO-Klassifikation schwierig. Zum anderen ist die Rezidivhäufigkeit auch benigner Tumorvarianten ein Problem. Sichere klinische und histopathologische Diagnosekriterien von prädiktivem Wert für Rezidivhäufigkeit und maligne Transformation sind bisher nicht bekannt. Deshalb haben Prognosefaktoren auf molekularer Ebene in letzter Zeit zunehmend an Bedeutung gewonnen. Als häufigste chromosomale Veränderung bei Meningeomen wurde die Monosomie 22 oder Teildeletion eines Chromosoms 22 entdeckt. Dabei scheint es sich um den primären Schritt zur Tumorentstehung zu handeln. Der zusätzliche Verlust genomischer Sequenzen auf 1p (LOH) scheint sich signifikant häufiger in atypischen und anaplastischen Meningeomen zu finden und wird deshalb als Prognosefaktor für malignes Wachstumsverhalten diskutiert. Ziel der vorliegenden Studie war die Expressionsanalyse 1p-spezifischer Transkripte, um funktionelle Konsequenzen von 1p-Deletionen in der Tumorprogression zu untersuchen und daraus diagnostische Marker zur besseren prognostischen Einschätzung zu gewinnen. Zur Validierung der m-RNA-Expression ergänzten eine Analyse der genomischen Ebene mit ausgewählten Mikrosatelliten-Markern und eine Proteinexpressionsanalyse die Untersuchung. Eine zusätzliche immunhistochemische Untersuchung der ALPL-Aktivität diente dazu, die molekulargenetischen Ergebnisse mit Hilfe einer leicht zugänglichen praktisch-diagnostischen Methode zu überprüfen. Die Ergebnisse der Transkriptionsanalyse zeigten Expressionsdefizite als Hinweis auf genomische Veränderungen gehäuft im Bereich der Gene ALPL, RAB3B und GADD45. Es konnten Zielbereiche der Deletion, aber kein einzelnes Zielgen definiert werden. Die deutliche Konzentration der Transkriptionsdefizite in den WHO II- und III-Tumoren bestätigte die von anderen Autoren beschriebene Progressionsassoziation der 1p-Alterationen in Meningeomen. Die Mikrosatellitenanalyse mit 1p-spezifischen Markern unterstützte den Verlust genomischer Sequenzen in diesem Bereich mit zunehmendem Malignitätsgrad. Die gute Korrelation der ALPL-Expression mit der Transkriptionsanalyse bestärkte die Hypothese genomischer Veränderungen des für ALPL kodierenden Gens im Rahmen der Tumorprogression. Die immunhistochemische Bestätigung eines progressionsassoziierten ALPL-Verlustes unterstützt die Erfassung eines molekulargenetischen Prognosefaktors mit Hilfe einer der Routinediagnostik leicht zugänglichen Methode. Dagegen ergaben sich für RAB3B divergente Ergebnisse, die auf komplexe Regulationsmechanismen hinweisen könnten. Die in der Studie nachgewiesenen 1p-spezifischen Transkriptionsdefizite werfen bei Annahme eines intakten Allels die Frage auf, welche molekularen Mechanismen zur vollständigen funktionellen Inaktivierung des Gens führen könnten. Eine mögliche Erklärung liefert Knudson’s „two-hit“-Modell, die jedoch in Meningeomen bisher nicht bewiesen werden konnte. Wahrscheinlicher ist ein komplexer Prozess, der morphologische, funktionelle und regulatorische Alterationen auf mehreren Ebenen beinhaltet. Die prädiktive Bedeutung von 1p-Deletionen bei Meningeomen konnte in dieser Studie bestätigt werden. Wenn es gelänge, diese Erkenntnis im klinischen Alltag nutzbar zu machen, könnten insbesondere rezidivgefährdete Meningeompatienten davon profitieren

Density-Dependence as a Size-Independent Regulatory Mechanism

The growth function of populations is central in biomathematics. The main dogma is the existence of density dependence mechanisms, which can be modelled with distinct functional forms that depend on the size of the population. One important class of regulatory functions is the $\theta$-logistic, which generalises the logistic equation. Using this model as a motivation, this paper introduces a simple dynamical reformulation that generalises many growth functions. The reformulation consists of two equations, one for population size, and one for the growth rate. Furthermore, the model shows that although population is density-dependent, the dynamics of the growth rate does not depend either on population size, nor on the carrying capacity. Actually, the growth equation is uncoupled from the population size equation, and the model has only two parameters, a Malthusian parameter $\rho$ and a competition coefficient $\theta$. Distinct sign combinations of these parameters reproduce not only the family of $\theta$-logistics, but also the van Bertalanffy, Gompertz and Potential Growth equations, among other possibilities. It is also shown that, except for two critical points, there is a general size-scaling relation that includes those appearing in the most important allometric theories, including the recently proposed Metabolic Theory of Ecology. With this model, several issues of general interest are discussed such as the growth of animal population, extinctions, cell growth and allometry, and the effect of environment over a population.Comment: 41 Pages, 5 figures Submitted to JT

Complex Systems Science: Dreams of Universality, Reality of Interdisciplinarity

Using a large database (~ 215 000 records) of relevant articles, we empirically study the "complex systems" field and its claims to find universal principles applying to systems in general. The study of references shared by the papers allows us to obtain a global point of view on the structure of this highly interdisciplinary field. We show that its overall coherence does not arise from a universal theory but instead from computational techniques and fruitful adaptations of the idea of self-organization to specific systems. We also find that communication between different disciplines goes through specific "trading zones", ie sub-communities that create an interface around specific tools (a DNA microchip) or concepts (a network).Comment: Journal of the American Society for Information Science and Technology (2012) 10.1002/asi.2264

Motor-evoked potentials (MEP) during brainstem surgery to preserve corticospinal function

Background: Brainstem surgery bears a risk of damage to the corticospinal tract (CST). Motor-evoked potentials (MEPs) are used intraoperatively to monitor CST function in order to detect CST damage at a reversible stage and thus impede permanent neurological deficits. While the method of MEP is generally accepted, warning criteria in the context of brainstem surgery still have to be agreed on. Method: We analyzed 104 consecutive patients who underwent microsurgical resection of lesions affecting the brainstem. Motor grade was documented prior to surgery, early postoperatively and at discharge. A baseline MEP stimulation intensity threshold was defined and intraoperative testing aimed to keep MEP response amplitude constant. MEPs were considered deteriorated and the surgical team was notified whenever the threshold was elevated by ≥20mA or MEP response fell under 50%. Findings: On the first postoperative day, 18 patients experienced new paresis that resolved by discharge in 11. MEPs deteriorated in 39 patients, and 16 of these showed new postoperative paresis, indicating a 41% risk of new paresis. In the remaining 2/18 patients, intraoperative MEPs were stable, although new paresis appeared postoperatively. In one of these patients, intraoperative hemorrhage caused postoperative swelling, and the new motor deficit persisted until discharge. Of all 104 patients, 7 deteriorated in motor grade at discharge, 92 remained unchanged, and 5 patients have improved. Conclusions: Adjustment of surgical strategy contributed to good motor outcome in 33/39 patients. MEP monitoring may help significantly to prevent motor deficits during demanding neurosurgical procedures on the brainste

Predictive models of glucose control : roles for glucose-sensing neurones

© 2014 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.Peer reviewedPublisher PD

The Implications of Interactions for Science and Philosophy

Reductionism has dominated science and philosophy for centuries. Complexity has recently shown that interactions---which reductionism neglects---are relevant for understanding phenomena. When interactions are considered, reductionism becomes limited in several aspects. In this paper, I argue that interactions imply non-reductionism, non-materialism, non-predictability, non-Platonism, and non-nihilism. As alternatives to each of these, holism, informism, adaptation, contextuality, and meaningfulness are put forward, respectively. A worldview that includes interactions not only describes better our world, but can help to solve many open scientific, philosophical, and social problems caused by implications of reductionism.Comment: 12 pages, 2 figure