Elisabeth Weiss

Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis

Inflammatory diseases of the CNS, such as MS and its animal model EAE, are characterized by infiltration of activated lymphocytes and phagocytes into the CNS. Within the CNS, activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurologic deficit. TLRs recognize microbes and are pivotal mediators of innate immunity. Within the CNS, augmented TLR expression during EAE is observed, even in the absence of any apparent microbial involvement. To determine the functional relevance of this phenomenon during sterile autoimmunity, we studied the role of different TLRs as well as their common signaling adaptor MyD88 in the development of EAE. We found that MyD88 mice were completely EAE resistant. Surprisingly, this protection is partly due to engagement of the CpG receptor TLR9. Restricting the MyD88 or TLR9 mutation to host radio-resistant cells, including the cells within the CNS, revealed that engagement of radio-resistant cells modulated the disease course and histopathological changes. Our data clearly demonstrate that both TLR9 and MyD88 are essential modulators of the autoimmune process during the effector phase of disease and suggest that endogenous danger signals modulate the disease pathogenesis.

Dexamethasone treatment in patients with brain metastases and primary brain tumors: do the benefits outweigh the side-effects?

In order to minimize neurological symptoms and treatment-related side-effects, patients with primary or secondary brain tumors receive dexamethasone. The goal of this study was to analyze dosage and duration of dexamethasone intake and to compare the advantages and disadvantages of this medication during the course of radiation therapy (RT). Data from 138 consecutive patients were therefore analyzed retrospectively. During the course of therapy, the dosage of dexamethasone was evaluated, as were the indications for and duration of this treatment, its side-effects and any clinical changes reported during dexamethasone intake. The dosage of dexamethasone was higher at the outset and during RT (median 7–12xa0mg/day) than at the end of RT (median 1–6xa0mg/day). The average duration of dexamethasone intake was 23xa0weeks for patients with primary, and 7xa0weeks for patients with secondary brain tumors. The most frequent side-effects were a rise in serum glucose level, peripheral edema, psychiatric disorders, and Cushings syndrome. Life-threatening complications remained rare. Initially, dexamethasone led to good clinical improvement with few side-effects of RT, whereas by the end of RT the symptom relief was slight and toxicity increased. In a group of 13 patients who received no dexamethasone during RT, 12 showed neither RT-related side-effects nor of neurological impairment. Dexamethasone effectively minimizes neurological symptoms and RT-related side-effects in patients with primary and secondary brain tumors. Nevertheless, the side-effects of dexamethasone itself increase over time. For this reason, a generalized dose scheme should not be used. Instead, dosage should be adapted to each patients individual needs. Future prospective studies will have to determine whether dexamethasone is advantageous on balance or not.

Conformal radiotherapy planning of cervix carcinoma: differences in the delineation of the clinical target volume. A comparison between gynaecologic and radiation oncologists.

PURPOSEnTo assess uncertainties in the definition of the clinical target volume (CTV) for patients scheduled for primary radiotherapy of cervix carcinoma.nnnMETHODS AND MATERIALSnSeven physicians (five radiation oncologists and two gynaecologists) independently contoured the CTVs for three patients. All observers were provided with the same clinical information. CTVs were entered directly in the treatment planning system. Differences were analysed qualitatively and quantitatively.nnnRESULTSnThe qualitative analysis revealed a good agreement by all observers on anatomical structures identified to be at risk for tumour spread. Quantitatively, however, a large interobserver variability was found. The ratio between largest and smallest volumes ranged between 3.6 and 4.9 for all observers (3.6-4.9 for the radiation oncologists, 1.3-2.8 for the gynaecologists). The median three-dimensional difference in gravity centres ranged between 10.9 and 26.3mm for the respective patients. The ratio of common volumes to encompassing volumes ranged between 0.11 and 0.13 for the radiation oncologists, and between 0.30 and 0.57 for the gynaecologists.nnnCONCLUSIONSnAlthough there was a good consistency in outlined anatomical structures, for the radiation therapy of carcinomas of the uterine cervix a large interobserver variability in CTV delineation concerning the magnitude and relative location of volumes was observed. Compared to other factors, e.g. set-up and organ motion, interobserver variability in CTV definition seems to have the highest impact on the geometrical accuracy in the radiotherapy of this tumour entity.

Effect of Pentoxifylline and Tocopherol on Radiation Proctitis/Enteritis

Background and Purpose:Chronic radiation proctitis/enteritis is a relevant complication of pelvic irradiation, which is still mainly treated by supportive measures only. There is some evidence that the combined treatment with pentoxifylline and tocopherol might alter the pathogenesis of radiation-induced fibrosis. In a retrospective analysis the clinical benefit of the treatment with pentoxifylline/tocopherol on radiation-induced proctitis/enteritis was evaluated, compared to supportive care only.Patients and Methods:Of 30 patients with radiation-induced proctitis/enteritis grade I–II according to the RTOG/EORTC toxicity criteria, 21 were treated with pentoxifylline and tocopherol. Depending on physician’s decision nine patients received symptomatic treatment only.Results:With pentoxifylline/tocopherol treatment 15/21 patients (71%) experienced a relief of their symptoms. A reduction from grade I/II to grade 0 toxicity was observed in seven and from grade II to grade I toxicity in eight patients. No improvement was seen in six patients. The median time to improvement with pentoxifylline and tocopherol treatment was 28 weeks. In three of nine patients who were treated supportively only, deterioration of symptoms occurred. Three patients experienced no amelioration, and three patients with grade I toxicity experienced a spontaneous relief of their symptoms (33%).Conclusion:The combination treatment with pentoxifylline and tocopherol seems to have a benefit in patients with grade I–II radiation-induced proctitis/enteritis. The optimal schedule of treatment duration is not yet clear. From the observations made in this study it is assumed the treatment should be given for 6–12 months at least. A prospective phase II study should be undertaken to evaluate optimal treatment duration.Hintergrund und Ziel:Die strahleninduzierte chronische Proktitis/Enteritis ist eine relevante Komplikation nach Beckenbestrahlungen, die hauptsächlich symptomatisch therapiert wird. Die kombinierte Behandlung mit Pentoxifyllin und Tocopherol könnte die Pathogenese der strahleninduzierten Fibrose beeinflussen. In einer retrospektiven Analyse wurde der klinische Nutzen dieser Kombinationstherapie bei strahleninduzierter Proktitis/Enteritis ausgewertet und mit alleiniger symptomatischer Behandlung verglichen.Patienten und Methodik:Von 30 Patienten mit einer strahleninduzierten Proktitis/Enteritis Grad I–II nach den Kriterien der RTOG/EORTC wurden 21 mit Pentoxifyllin und Tocopherol behandelt. In Abhängigkeit von der ärztlichen Entscheidung wurden neun Patienten nur symptomatisch behandelt (Tabelle 1).Ergebnisse:15/21 Patienten (71%) unter Therapie mit Pentoxifyllin und Tocopherol erlebten eine Verbesserung ihrer Symptome (Tabelle 3, Abbildung 1). Eine Reduktion von Grad I/II zu Grad 0 trat bei sieben, von Grad II zu I bei acht Patienten auf. Keine Verbesserung konnte bei sechs Patienten erreicht werden. Die mittlere Zeit bis zur Verbesserung der Symptome unter Therapie mit Pentoxifyllin und Tocopherol betrug 28 Wochen (7 Monate) (Abbildung 3). Drei der neun symptomatisch therapierten Patienten erlitten eine Symptomverschlechterung. Drei Patienten erlebten keine Befundänderung, und drei Patienten mit Grad-I-Toxizität erfuhren eine spontane Verbesserung ihrer Symptome (33%) (Tabelle 4).Schlussfolgerung:Die Kombinationstherapie aus Pentoxifyllin und Tocopherol scheint einen Nutzen bei der strahleninduzierten Proktitis/Enteritis Grad I–II zu haben (Abbildung 2). Die optimale Behandlungsdauer ist nicht bekannt. Nach den Ergebnissen dieser Studie ist anzunehmen, dass die Medikamente mindestens 6–12 Monate gegeben werden sollten. Eine prospektive Phase- II-Studie sollte durchgeführt werden, um die optimale Behandlungsdauer zu evaluieren.

Interfractional and intrafractional accuracy during radiotherapy of gynecologic carcinomas: a comprehensive evaluation using the ExacTrac system

PURPOSEnTo evaluate positioning uncertainties with an infrared body marker-based positioning system (ExacTrac) compared with conventional laser positioning in patients treated for gynecologic carcinomas, and to investigate patient movement during therapy.nnnMATERIALS AND METHODSnTen patients were positioned both with a conventional laser system and with the ExacTrac system. Positioning accuracy was evaluated using repeated electronic portal images. Average displacements and overall, systematic, and random errors were calculated and compared for the two positioning methods. Further, inter- and intrafractional patient movement including time trends in positioning displacements, respiratory amplitudes, and breathing frequencies were analyzed by online documentation of body marker movement with the ExacTrac system.nnnRESULTSnAverage displacements ranged between -3.6 and 6.7 mm for the three coordinates. Mean systematic and random errors ranged from 1.6 to 3.7 mm and 2.2 to 3.7 mm, respectively, with no significant differences between conventional and ExacTrac positioning (p > 0.07). The main breathing direction was from dorsocaudal to anterocranial in 9 of 10 patients. The mean 3D breathing amplitude in the pelvis was 2.4 mm (0.49-6.96 mm). Significant interfractional and intrafractional time trends were observed concerning breathing amplitudes and positioning displacements.nnnCONCLUSIONSnThe observed displacements did not vary significantly between the two evaluated positioning systems. The analysis of registered body marker positions revealed a wide variation in respiratory frequencies, breathing amplitudes, and patient displacements with interfractional and intrafractional time trends. Systems that allow the measurement of each patients motion characteristics are a necessary requirement for all efforts at individually tailored radiation therapy.

Primary intraspinal primitive neuroectodermal tumor: report of two cases and review of the literature.

AbstractBackground. Primary intraspinal primitive neuroectodermal tumor (PNET) is a very rare tumor entity. The optimal therapeutic approach is not known yet. We report on two women with primary intraspinal PNETs and review the literature. We describe the typical course of the disease, compare our patients to the other 17 cases reported until today, and discuss therapeutic options.nPatients and method. Case A: In a 49-Year-old woman with an intraspinal PNET at L2, laminectomy and a gross tumor removal was accomplished. Postoperative radiation was performed from T12 to L3 to a dose of 50.4Gy. Subsequently she was treated with chemotherapy containing vincristine, cisplatinum and lomustine. Case B: A 29-Year-old woman presented with intramedullary PNET lesions at T1–3 and T10–11. Due to the multifocal location, she received a primary craniospinal axis irradiation to a dose of 35.2Gy plus a boost to the tumor region to a total dose of 53.2Gy.nResults. Both patients developed multilocular intraspinal relapses with meningeosis neoplastica 17 and 6 months from radiation therapy and underwent palliative chemotherapy. Case A died 23 months, case B 17 months after primary diagnosis.nConclusion. Despite modern treatment with microsurgery, irradiation and chemotherapy in primary intraspinal PNETs, local relapse or dissemination in most cases lead to death within a few months. An improvement of treatment outcome can only be achieved by intensification through multidisciplinary treatment.

Treatment of primary malignant rhabdoid tumor of the brain : Report of three cases and review of the literature

PURPOSEnPrimary malignant rhabdoid tumor (MRT) of the central nervous system is an extremely aggressive tumor predominantly related to early childhood, with characteristic histopathological findings but unclear histogenesis. Owing to its low incidence, little knowledge exists concerning the best therapeutic strategy.nnnMETHODS AND MATERIALSnThree children of our hospital with MRT of the brain underwent a maximum tumor resection followed by multidrug chemotherapy and radiation therapy to the craniospinal axis.nnnRESULTSnRelapse was disseminated along the spinal subarachnoid spaces in one child and occurred at the primary tumor site in the other two patients. Maximum survival was 15 months from diagnosis.nnnCONCLUSIONnA review of patients reported in the literature and a comparison to our patients reveals a high propensity to early local relapse and meningeal dissemination. In the absence of more effective therapeutic options, we recommend multidisciplinary treatment of patients in good general condition and with resectable disease. In particular, following radiation therapy, tumor remissions and delay of tumor regrowth have been observed.

Concurrent low-dose cisplatin and thoracic radiotherapy in patients with inoperable stage III non-small cell lung cancer: a phase II trial with special reference to the hemoglobin level as prognostic parameter

PurposeTo evaluate the efficacy of concurrent radiochemotherapy in patients with stage III non-small cell lung cancer (NSCLC), and to examine the effect of hemoglobin levels on survival of those patients. The negative impact of anemia on survival has been noticed for other cancer sites including the head and neck, and the uterine cervix, but it has been rarely described in NSCLC cancer patients treated with radiotherapy.MethodsFrom April 1995 through March 2002, 56 patients with inoperable stage III non-small lung cancer were treated with radiotherapy consisting of 60xa0Gy (50xa0Gy+10xa0Gy boost) given in 30 fractions of 2xa0Gy daily, 5 days a week, over a period of 6 weeks, and concurrent low-dose daily chemotherapy (CHT) consisting of 6xa0mg/m2 of cisplatin given Mondays–Fridays during weeks 1–2 and 5–6. All patients had stage III disease and ages ranged from 39 to 81 years old (median 63.9 years).ResultsThe 2-year and 3-year survival rates were 34% and 16%, respectively. Patients with a pretreatment hemoglobin level superior or equal to 11.6xa0g/dl had a 2-year survival rate of 52% as compared to 15.5% for patients with a pretreatment hemoglobin level inferior to 11.6xa0g/dl (p=0.0075). Patients with higher KI (>70%) showed better survival rates than those with lower KI. Surprisingly, patients in stage IIIA did not survive significantly longer than those in stage IIIB. Hematological toxicity (grade ≥2) prevailed (25%), followed by esophageal (5.4%) and bronchopulmonary (2%) toxicity. Only three patients experienced acute grade 3 hematological toxicity. Because of acute toxic effects, irradiation was interrupted in 8 patients (14.3%) for 7–13 days (median 7.5 days). Late high-grade (≥3) toxicity was not found. No grade 4 toxicity or treatment-related deaths were observed during this study.ConclusionOur data show that concurrent radiotherapy with daily low dose cisplatin is well tolerated, and shows survival rates comparable to more aggressive treatment regimens. A combination of this chemotherapy with accelerated hyperfractionated radiotherapy might improve the results in the future. Furthermore, we could show that the hemoglobin levels prior to therapy have an influence on the prognosis, where lower levels were associated with worse outcome. Further trials should consider supplementation with erythropoietin.

Does the standardized helmet technique lead to adequate coverage of the cribriform plate? An analysis of current practice with respect to the ICRU 50 report

PURPOSEnTo investigate whether the standardized helmet technique adequately covers the cribriform plate.nnnMETHODS AND MATERIALSnFor 11 patients with acute leukemia or primary intracerebral neoplasms undergoing irradiation with the standardized helmet technique, three-dimensional isodose distributions were evaluated with special respect to the dose to the cribriform plate and the ocular lenses.nnnRESULTSnThe average dose received by 95% of the cribriform plate with the standardized helmet technique was 85% of the prescribed dose. To enclose the cribriform plate by the 95% isodose (according to the ICRU 50 report) with a 10-mm safety margin allowing for deviations during treatment planning and delivery, the eye block had to be moved in the ventrocaudal direction with an average vector length of 13.6 mm. Consequently, the mean dose received by 5% of the lenses rose from 18% to 91% of the prescribed total dose.nnnCONCLUSIONnSufficient lens shielding is usually not compatible with safe irradiation of the frontobasis by the standardized helmet technique.

Rhabdoid tumors of the central nervous system.

Abstractu2002Rhabdoid tumors of the central nervous system are rare malignancies with a still almost uniformly fatal outcome. There is still no proven curative therapy available. We report our experience with nine patients with central nervous system rhabdoid tumors. Gross complete surgical removal of the tumor was achieved in six patients. Seven patients received intensive chemotherapy. Four of these were treated in addition with both neuroaxis radiotherapy and a local boost directed to the tumor region, while two patients received local radiotherapy only. The therapy was reasonably well tolerated in most cases. Despite the aggressive therapy, eight of the nine patients died from progressive tumor disease, and one patient died from hemorrhagic brain stem lesions of unknown etiology. The mean survival time was 10 months after diagnosis. Conventional treatment, although aggressive, cannot change the fatal prognosis of central nervous system rhabdoid tumors. As these neoplasms are so rare, a coordinated register would probably be a good idea, offering a means of learning more about the tumor’s biology and possible strategies of treatment.