Prediction of AVM obliteration after stereotactic radiotherapy using radiobiological modelling

This study was carried out in order to derive the radiobiological parameters of the dose-response relation for the obliteration of arteriovenous malformation (AVM) following single fraction stereotactic radiotherapy. Furthermore, the accuracy by which the linear Poisson model predicts the probability of obliteration and how the haemorrhage history, location and volume of the AVM influence its radiosensitivity are investigated. The study patient material consists of 85 patients who received radiation for AVM therapy. Radiation-induced AVM obliterations were assessed on the basis of post-irradiation angiographies and other radiological findings. For each patient the dose delivered to the clinical target volume and the clinical treatment outcome were available. These data were used in a maximum likelihood analysis to calculate the best estimates of the parameters of the linear Poisson model. The uncertainties of these parameters were also calculated and their individual influence on the dose-response curve was studied. AVM radiosensitivity was assumed to be the same for all the patients. The radiobiological model used was proved suitable for predicting the treatment outcome pattern of the studied patient material. The radiobiological parameters of the model were calculated for different AVM locations, bleeding histories and AVM sizes. The range of parameter variability had considerable effect on the dose-response curve of AVM. The correlation between the dosimetric data and their corresponding clinical effect could be accurately modelled using the linear Poisson model. The derived response parameters can be introduced into the clinical routine with the calculated accuracy assuming the same methodology in target definition and delineation. The known volume dependence of AVM radiosensitivity was confirmed. Moreover, a trend relating AVM location with its radiosensitivity was observed.     

Ultrastructural localization of the 9-kilodalton vitamin D-dependent calcium-binding protein in the murine intraplacental yolk sac

The calcium-binding protein (CaBP) calbindin has been implicated in the molecular mechanism of placental calcium transfer. Previous light microscopic studies have identified CaBP in visceral (but not parietal) endodermal cells of the yolk sac with the most intense immunocytochemical signal observed in the intraplacental yolk sac. In the present studies, electron microscopy was used to study the localization of CaBP in placenta. Placentas of 17-day pregnant mice were fixed by perfusion in 0.5% glutaraldehyde, embedded in low-temperature Lowicryl K4M, and examined in thin section for specific labeling with a polyclonal antiserum. Antibody to CaBP was localized by using protein A-gold particles which were quantified for subcellular compartmentation by using a Videoplan computer system. A high signal for CaBP was found in the visceral endodermal cells of the intraplacental yolk sac. In these cells, gold particles indicating the location of CaBP were observed over 1) the cytoplasmic matrix where the average number of gold particles per micron 2 was 33; 2) the microvilli (17/micron 2); 3) the mitochondria (17/micron 2); and 4) the nucleus (43/micron 2). Sections from antigen-absorbed controls, by contrast, showed few gold particles: cytosol, 2/micron 2; microvilli, 5/micron 2; mitochondria, 5/micron 2; and nucleus, 4/micron 2. Electron-lucent profiles of the Golgi and endoplasmic reticulum contained no particles in the controls and a low particle count (4/micron 2) in the stained sections. Parietal endodermal cells of the intraplacental yolk sac showed a relatively low signal for CaBP compared with the visceral endodermal cells (5 particles/micron 2 vs. 39).(ABSTRACT TRUNCATED AT 250 WORDS)     

Metastases--with no end in sight. I. Clinical and experimental pathology

In the recent century research in cancer metastasis has greatly improved; nowadays it is a superior topic in cancer literature. Most of its problems result from alternate assumptions: The functional seed and soil and the hemomechanic hypothesis, after all putting two questions on account of metastasis being either a permanent likewise passive or a cascade phenomenon. In regard of metastasizing bronchial-, breast- and prostate carcinomas or multifocal tumors and most of rodent neoplasms a passive tumor cell transport might be a single effect, but the characteristic feature rather a step by step metastasizing cascade, implicating special organ localizations, and the fact, that metastasis distribution correlates with tumor biology, localization of the first metastasis and in manifold metastasizing tumors with typical organ patterns. From introduction of recent in vitro and cloning-techniques the metastasizing potency of tumors now becoming able to be defined by function of its genetic heterogeneity, developing metastasizing phenotypes respective neoplastic evolution by mutation, gene amplification, and epigenetic factors. On the other side having an unique xenobiotic metabolism metastasizing tumor cells are in accordance with the conception of their inherent "commonality".     

Transplantation of autogenous perichondrial or periosteal grafts for treatment of deep hyalin-cartilage lesions

The problem in the treatment of deep hyalin cartilage defects is due to the minimal regeneration potential of this specific tissue. Several attempts were made to solve this difficulties experimentally and clinically. The proliferative potential of autogenous perichondrium/periost is well-known for decades. Perichondrium can be harvested from the lower ribs near to the sternum and periost from the adjacent bone (mostly proximal tibia). Experimentally and clinically, it has been shown that both types of tissue bear the potential to form hyalin-like cartilage under in vitro and in vivo conditions. Furthermore, regarding the biomechanical data (shear modulus) and the biochemical data (content of type II collagen) the newly grown tissue resembles normal hyalin cartilage. In addition, it has been shown that the transplant fixation with fibrin glue is sufficient in order to allow early postoperative treatment with continuous passive motion which is known to stimulate cartilaginuous regeneration. Despite the satisfying experimental and clinical results further examinations are needed in order to evaluate the optimal surgical technique and postoperative regimen regarding the CPM-criteria. In addition, application of growth-factor might further improve this biological kind of treatment which has to be analysed.     

Complete loss of functional smooth muscle cells precedes vascular remodeling in rat aorta allografts

BACKGROUND: The functional consequences of vascular remodeling in rat aorta allografts were studied at different times after transplantation (Tx). METHODS: At days 1, 3, 7, 14, 28, and 56 after Tx, rat aorta allografts (Dark Agouti [DA]-to-Lewis) were mounted as isolated organs, and their contractile properties tested with phenylephrine, KCl, or endothelin-1. Controls were native DA-aortae and DA-syngeneic grafts. Changes in alpha smooth muscle actin and morphology were assessed by immunoblotting and histology. RESULTS: PostTx syngeneic grafts presented similar functional and morphological properties to native aortae. In allografts, no morphological changes was detected at day 7 after Tx, but phenylephrine-induced vasoconstriction was reduced by 60%. Signs of medial smooth muscle cell (SMC) loss and adventitial inflammation were observed at day 14 after Tx, without neointima formation. A complete loss of contractile property was observed at day 28 after Tx in association with a 75% decrease in alpha-SMC actin, severe adventitial inflammation, and reduced medial cellularity. At this time, neointima was restricted to both edges of allografts. At day 56 after Tx, allografts were also not functional and exhibited neointima on their entire length. All these changes were prevented by treating recipients with cyclosporine (7.5 mg/kg/day). CONCLUSION: These results indicate that, after Tx, the contractile property of rat aorta allografts is altered before manifest vascular remodeling. Because this can be prevented by cyclosporine, it most likely reflects an acute rejection of SMC. These results also show that vascular graft dysfunction can be used to monitor the development of rejection in the rat aorta allograft model.     

Einfluß des operationstraumas auf die NK-zell-aktivität beim ösophaguskarizinom nach transmediastinaler dissektion vs. transthorakaler en-bloc-resektion

Zusammenfassung Um den Einfluß des chirurgischen Traumas beim Ösophaguskarzinom auf das zelluläre Immunsystem zu erfassen, wurden perioperativ in einer prospektiven Studie die Aktivität der natürlichen Killerzellen sowie die Serumkonzentrationen von Interleukin-2, Interleukin-6 un TNF- bei transmediastinaler Dissektion (n=12) vs. transthorakaler En-bloc-Resektion (n=10) der Speiserörhre im Vergleich zu einer Kontrollgruppe mit thorakoabdominalen chirurgischen Eingriffen bei nicht maligner Grunderkrankung erfaßt. Die Bestimmung der NK-Zell-Aktivität erfolgte präoperativ sowie am 4. und 10. Tag postoperativ durch einen standardisierten Europiumchlorid-release-Assay unter Verwendung von K-562-Targetzellen, die Lymphokine Interleukin-2, Interleukin-6 und TNF- wurden zusätzlich am 1. und 7. Tag postoperativ mit stadardisierten ELISA-Assays bestimmt.In unserem Patientengut sank die NK-Zellaktivität am 4. postoperrativen Tag sowohl in der Kontrollgrupe al auch bei beiden Operations verfahren zur Speiseröhrenresektion signifikant (p<0,05) zum Ausgangswert: in der Kontrollgruppe durchschnittlich um 45%, nach transmediastinaler Speriseröhrendissektion (1-Höhlen-Eingriff) durchschnittlich um 34%, nauch transthorakaler En-bloc-Resektion (2-Höhlen-Eingriff) im Mittel um 63% zum präoperativen Wert. Die transthorakale En-bloc-Resektion der Speiseröhre führte durch das größere chirurgische Trauma zu einer stäkeren Abnahme der zytotoxischen Aktivität der natürlichen Killerzellen. Eine Suppression der immunologischen Tumorabwehr insbesondere in der vulnerablen perioperativen Phase kann damit indirekt das Risiko der Manifestation von hämatogene Metastasen auf dem Boden einer intraoperativen Tumorzelldissemination u. a. bedingt durch Tumormanipulation begünstigen und damit prognostisch relevant werden.

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Influence of surgical trauma on natural killer cell activity in esophageal carcinoma following transmediastinal dissection compareed with transthoracic en bloc resection

In order to assess the impact of surgical trauma involved in the therapy of esophageal carcinoma on the cellular immune system, a perspective study was performed involving perioperative hematological parameters. The activity of natural killer cells and the serum concentrations of interleuin-2, interleukin-6 and TNF- were measured in 12 cases of transmediastinal dissection and 10 cases of transthioracic en bloc esophageal resection and compared to values of a control group of thoracic and abdominal surgical patients with non-malignant maladies. Natural killer cells assume a central role in the non-specific immunological response in tumor patients. Their main function is the destruction of tumor cells via cytotoxic activities amplified by the release of interleukin-2 and TNF-. Natural killer cell activity was measured prior to surgery and on postoperative days 4 and 10 using a standardized europium chloride release assay, utilizing K 562 target cells. Lymphokines interleukin-2, interleukin-6, and THF- were also measured on postoperative days 1 and 7 using standardized ELISA assays. The activity of natural killer cells in our patient group sank significantly (P<0.05) on postoperative day 4 and likewise in the control group and both study groups, activity sank to the original values. In the control groups, natural killer cell activity averaged 45% of preoperative values, in comparison with an average of 63% following transmediastinal esophageal carcinoma resection (one cavity procedure), and transthoracic en bloc resection patients only reached 61% of preoperative values, transmediastinal dissection patients assumed 75%, and 77% was achieved by control group members. Transthoracic en bloc resection of the esophagus led to a more extreme reduction in cytotoxic cellular activity owing to the greater surgical trauma. Suppression of the immunological tumor resistance, especially in the vulnerable perisurgical pahse, can have an indirect negative effect on the manifestation risk of hematogenic metastases owing to intraoperative tumor cell dissemination resulting from tumor manipulation and may thus be prognostically relevant.

     

Inhibition of leukocyte migration by extracts of malignant prostatic tissue and correlation of degree of in vitro sensitization to clinical responsiveness in prostatic cancer patients

In an attempt to evaluate the degree of in vitro cellular sensitization to tumor and its relationship to clinical responsiveness, direct leukocyte migration tests were carried out in patients with varying degrees of adenocarcinoma of the prostate employing pooled allogeneic extracts of normal, benign, and malignant prostatic tissue as a source of antigen. Cell-mediated immunity to presumably common prostatic tumor associated antigens was observed. The degree of sensitization of clinically significant specific reactivity of the patients' leukocytes to malignant prostatic tissue was greatest in patients with localized disease, low-grade tumor, and clinically inactive disease than in patients with advanced disease, high-grade tumor, and clinically active disease. Evaluation of the possible correlation of specific reactivity to malignant prostatic tissue as a prognostic index of clinical responsiveness revealed a positive correlation with the degree of sensitization in 3 (43 per cent) of 7 patients. Correlation in 4 patients was questionable because of observations of "stimulation" of migration rather than inhibition, suggested by some to be reflective of weak sensitization to tumor. Evaluation of a larger patient population as well as a prospective study of the relationship of the degree of sensitization and clinical responsiveness will be necessary before any definitive conclusions may be drawn regarding the present observations.     

Adenosine receptor activation by adenine nucleotides requires conversion of the nucleotides to adenosine

Summary Adenine nucleotides cause adenosine receptor-mediated increases in cyclic AMP in the VA13 human fibroblast line. Levels of adenosine accumulated in the medium are insufficient to account for the responses to adenine nucleotides. Since rapid conversion of the nucleotides to adenosine by 5-nucleotidase in the vicinity of the receptor might account for the responses, six experimental methods were developed to distinguish between local conversion and direct action of the nucleotides. Results of all six methods favored local conversion. (1) 5-Nucleotidase inhibitors blocked the accumulations of cyclic AMP elicited by AMP, ADP, and ATP, but did not affect the response to adenosine. The most potent inhibitor of both conversion of AMP and response to AMP was ,-methylene-ADP (APCP). (2) Adenosine deaminase blocked the responses to AMP, ADP, ATP, and adenosine-containing coenzymes. (3) Theophylline, a specific competitive adenosine antagonist, was an insurmountable inhibitor of the increases in cyclic AMP caused by AMP, ADP, and ATP. The insurmountability was presumably due to substrate sataration of the converting enzyme 5-nucleotidase. (4) Although ADP and ATP had partial agonist-like dose-response curves, they did not inhibit the response to adenosine. (5) Nine cell lines which responded to adenosine were tested for response to AMP. Cell lines with high levels of 5-nucleotidase had large responses to AMP, those with intermediate levels of 5-nucleotidase had large or intermediate responses to AMP, and those with low 5-nucleotidase levels did not respond to AMP. (6) Inhibition of the uptake of labelled adenosine was used as an indicator of unlabelled adenosine concentrations near the cell membrane. Unlabelled AMP inhibited uptake nearly as effectively as unlabelled adenosine. APCP reversed the inhibition by AMP but not the inhibition by adenosine.The adenosine receptor is concluded to be an enity distinct from adenine nucleotide receptors.Submitted in partial fulfillment of the requirements for the degree Doctor of Philosophy in Neurosciences, University of California, San Diego. Supported by NIMH DA-00265 and PHS RR 05665. The author has been a NSF Graduate Fellow. An abstract of this material has been published (Bruns 1977)     

Krebsmedizin zwischen Qualität und Kostendiskussion

The statutory health insurance system in Germany is one of the oldest healthcare systems worldwide. Originating from the social legislation of Otto von Bismarck, this system is controlled by a self-governing body of health insurance companies and healthcare providers, who jointly decide which medical measures are refunded and to what extent. Due to increasing healthcare expenditure, even and especially in oncology, the call for a public debate on prioritization of healthcare services and the allocation of resources is getting louder. The answers to these questions are closely linked to the debate on quality in healthcare, how it can be measured and how much society is willing to pay for higher quality. This article discusses the role of the National Cancer Plan in this context. It also shows the benefits that cancer centers as intersectoral networks can bring to cancer treatment and which possibilities certification provides to achieve improvements in the quality of healthcare.     

A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors

Every fourth patient submitted to epilepsy surgery suffers from a brain tumor. Microscopically, these neoplasms present with a wide-ranging spectrum of glial or glio-neuronal tumor subtypes. Gangliogliomas (GG) and dysembryoplastic neuroepithelial tumors (DNTs) are the most frequently recognized entities accounting for 65 % of 1,551 tumors collected at the European Epilepsy Brain Bank (n = 5,842 epilepsy surgery samples). These tumors often present with early seizure onset at a mean age of 16.5 years, with 77 % of neoplasms affecting the temporal lobe. Relapse and malignant progression are rare events in this particular group of brain tumors. Surgical resection should be regarded, therefore, also as important treatment strategy to prevent epilepsy progression as well as seizure- and medication-related comorbidities. The characteristic clinical presentation and broad histopathological spectrum of these highly epileptogenic brain tumors will herein be classified as “long-term epilepsy associated tumors—LEATs”. LEATs differ from most other brain tumors by early onset of spontaneous seizures, and conceptually are regarded as developmental tumors to explain their pleomorphic microscopic appearance and frequent association with Focal Cortical Dysplasia Type IIIb. However, the broad neuropathologic spectrum and lack of reliable histopathological signatures make these tumors difficult to classify using the WHO system of brain tumors. As another consequence from poor agreement in published LEAT series, molecular diagnostic data remain ambiguous. Availability of surgical tissue specimens from patients which have been well characterized during their presurgical evaluation should open the possibility to systematically address the origin and epileptogenicity of LEATs, and will be further discussed herein. As a conclusion, the authors propose a novel A–B–C terminology of epileptogenic brain tumors (“epileptomas”) which hopefully promote the discussion between neuropathologists, neurooncologists and epileptologists. It must be our future mission to achieve international consensus for the clinico-pathological classification of LEATs that would also involve World Health Organization (WHO) and the International League against Epilepsy (ILAE).