Early time course of neointima formation and vascular remodelling following percutaneous coronary intervention and vascular brachytherapy of in-stent restenotic lesions as assessed by intravascular ultrasound analysis.

In-stent restenosis (ISR) represents the major limitation of stent implantation. Treatment, although of relative technical ease, is unsatisfactory due to a high incidence of recurrent restenosis. Vascular brachytherapy (VBT) has emerged as a powerful adjunct therapeutic modality to treat ISR. Inhibition of neointima formation has been regarded as the relevant mechanism of action. Yet, positive remodelling has been suspected as another contributing factor. Since only very few precise analyses of the extent, distribution and time course of the respective mechanims exist, the goal of the present study was to describe the changes of the vessel geometry at the target lesion and at the reference site following angioplasty and VBT of ISR in 42 patients by means of quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) before and after the index procedure and at the 3 and 6 month follow-up. By QCA the acute lumen gain measured 2.2+/-0.8 mm, the late lumen loss at 3 months was 0.1+/-0.5 mm and at 6 months 0.4+/-0.7 mm. By IVUS luminal cross-sectional area increased from 1.5+/-1.2 mm(2) to 7.9+/-1.9 mm(2) (p<0.001). The intima hyperplasia cross-sectional area at 3 months was only 0.2+/-1.0 mm(2) (p=0.191), but increased to 0.7+/-0.6 mm(2) (p<0.001) at 6 months resulting in a lumen cross-sectional area of 7.1+/-1.7 mm(2). Stent dimensions did not show any significant changes over time. The external elastic membrane cross-sectional area at 3 months increased by 1.3+/-1.9 mm(2) (p<0.001), and showed a further increase by 0.7+/-2.9 mm(2) at 6 months. Positive remodelling could be demonstrated also at the reference segment. In conclusion the absolute amount of intima hyperplasia during a 6-month follow-up period after VBT of ISR is low and most pronounced between the third and sixth month. Besides this, predominantly within the first 3 months of follow-up, significant positive remodelling could be demonstrated at the target lesion and at the reference site. Both observed effects may contribute to the preservation of the vessel lumen.

[Supratentorial primitive neuroectodermal tumor: a single center experience and comparison with the literature]. / Supratentorieller primitiver neuroektodermaler Tumor: Erfahrungen in einem Zentrum im Vergleich zur Literatur.

Supratentorial primitive neuroectodermal tumors (stPNETs) are malignant tumors. We saw within three years six children with stPNETs. In four of the six children radical resection could be achieved. All had craniospinal irradiation and chemotherapy according to the HIT-91 protocol. The two children with incomplete resection died due to tumor progression after 7 and 10 months. Two of the 4 children with complete tumor resection had local relapses 8 months after diagnosis and died after 14 and 18 months. One child had a diffuse meningeal relapse 12 months after diagnosis. Despite (high-dose) systemic chemotherapy and intraventricular mafosfamide, he died 21 months after diagnosis due to tumor although remission could be achieved. Only one child is still in remission 86 months after diagnosis.

[Clinical and angiographic one-year follow-up of vascular beta-brachytherapy for coronary lesions treated by a stent with a very high risk for restenosis]. / Klinischer und angiographischer Ein-Jahres-Verlauf nach vaskulärer Beta-Brachytherapie von Instent-Restenosen mit sehr hohem Rezidivrisiko.

BACKGROUND: Vascular brachytherapy (VBT) has been proven to reduce restenosis rate and unwanted cardiac events in several randomized trials. Long-term data on populations at high risk for re-interventions are few. The aim of this study was to assess the acute and one-year outcome of beta-radiation in coronary in-stent restenoses with a high likelihood of recurrence. METHODS: In 79 patients, VBT using 90Yttrium/Strontium or 32Phosphorus, was performed. Clinical and angiographic follow-up was carried out after 6 months and 1 year. RESULTS: 44.4 % of patients had three-vessel coronary artery disease and a high prevalence of cardiovascular risk factors and comorbidity. Mean lesion length was 36.8+/-18.9 mm. VBT was successful in all patients. Fractionation of VBT was necessary in 2,5 %. Acute gain of luminal diameter was 2.15+/-0.89 mm. During the hospital stay one acute myocardial infarction (AMI) not associated with VBT occurred. After 6 months loss of luminal diameter measured 0.39+/-0.47 mm, equaling a restenosis rate (RR) of 16.8 % (1 year: 0.60+/-0.56 mm, RR 33.5 %). 18.9 % of patients required revascularization of the target lesion (1 year: 29.5 %). After 6 months, all patients survived, three had an AMI after discontinuation of clopidogrel, one of them was asymptomatic (1 year: 1 cardiac death, 2 symptomatic AMI). CONCLUSION: Beta-VBT in patients at a high risk for recurrence after angioplasty is feasible and safe. Though the clinical and angiographic results at 1 year showed some impairment as opposed to the 6-months-follow-up, they nevertheless are largely superior to those patients from historic controls not treated with VBT.

[Edge effect and late thrombosis -- inevitable complications of vascular brachytherapy?]. / Edge effect und späte Thrombose -- Notwendiges Ubel oder vermeidbare Nebenwirkung der intrakoronaren Brachytherapie?

Restenosis is the limiting entity after percutaneous coronary angioplasty. Vascular brachytherapy for the treatment of in-stent restenosis has been shown to reduce the repeat restenosis rate and the incidence of major adverse events in several randomized trials. Besides the beneficial effects, brachytherapy yielded some unwanted side effects. The development of new stenoses at the edges of the target lesion treated with radiation is termed edge effect. It occurs after afterloading brachytherapy as well as after implantation of radioactive stents. It is characterized by extensive intimal hyperplasia and negative remodeling. As contributing factors the axial dose fall-off, inherent to all radioactive sources, and the application of vessel wall trauma by angioplasty have been identified. The combination of both factors, by insufficient overlap of the radiation length over the injured vessel segment, has been referred to as geographic miss. It has been shown to be associated with a very high incidence of the edge effect. Avoidance of geographic miss is strongly recommended in vascular brachytherapy procedures. Late thrombosis after vascular brachytherapy is of multifactorial origin. It comprises platelet recruitment, fibrin deposition, disturbed vasomotion, non-healing dissection and stent malapposition predisposing to turbulent blood flow. The strongest predictors for late thrombosis are premature discontinuation of antiplatelet therapy and implantation of new stents during the brachytherapy procedure. With a consequent and prolonged antiplatelet therapy, the incidence of late thrombosis has been reduced to placebo levels. Edge effect and late thrombosis represent unwanted side effects of vascular brachytherapy. By means of a thorough treatment planning and prolonged antiplatelet therapy their incidences can be largely reduced. With regard to the very favorable net effect, they do not constitute relevant limitations of vascular brachytherapy.

External radiotherapy of thyroid cancer.

Differentiated thyroid cancer comprises papillary, mixed papillary-follicular and follicular adenocarcinomas. They are mostly hormone-sensitive and respond to thyroid-stimulating hormone (TSH) suppression. The standard treatment is total thyroidectomy, (131)I therapy and thyroid hormone suppression therapy. Adjuvant external radiotherapy is discussed controversially. Most authors recommend adjuvant external radiotherapy for extra-capsular tumor extension. Decision on an individual basis should be made for patients with lymph node involvement. In the case of incomplete surgical resection, external radiotherapy should be applied if second surgery is not possible. For medullary thyroid cancer, external beam radiotherapy seems to be beneficial for patients with surgically inaccessible disease, with microscopic residual or gross tumor after surgery, with recurrent locoregional disease, or with surgically unmanageable metastases. Patients suffering from anaplastic thyroid cancer should receive combined treatment consisting of extensive surgery, external irradiation with total doses up to 60 Gy, and chemotherapy. The combined treatment modality leads to higher local control rates and prolongs survival.

Conventional pituitary irradiation is effective in normalising plasma IGF-I in patients with acromegaly.

OBJECTIVE: For patients in whom acromegaly persists despite pituitary surgery, conventional pituitary irradiation represents an additional treatment option. A 30-60% cure rate is described in the literature, but these studies did not utilise strict rules of remission, such as "safe" GH levels <2.5 microg/l, and age-adjusted normal IGF-I levels. DESIGN AND METHODS: We report the outcome of 41 patients with acromegaly who received pituitary conventional external irradiation. The median follow-up time was 12.8 years (3.7-43.4 years) post-radiotherapy. RESULTS: The median pre-irradiation GH level was 31.0 microg/l (7.0-210 microg/l). Information on IGF-I levels was only available for 6 patients prior to therapy. Utilising strict rules of remission, one-third (14/41) of our patients had normal biochemical parameters, i.e. "safe" GH (0.5 microg/l (range 0.2-1.6 microg/l)) and normal age-adjusted IGF-I levels (multiple of upper limit of normal range (xULN); 0.45 (0.2-1.0)) at the end of the follow-up period. An additional 9 patients achieved normal levels with adjunctive drug therapy. Furthermore, disease activity was reduced in a considerable proportion of the 18 patients who did not achieve normal biochemical levels (GH: 3.6 microg/l (1.9-15.7 microg/l); xULN of IGF-I: 1.6 (0.9-2.6)). In retrospect, remission is unlikely in patients who had a GH level greater than 52 microg/l (mean+2 s.d. of cured patients) prior to radiotherapy. In addition to the 12 patients with pre-irradiation pituitary functional deficiency, another 11 patients developed symptoms of panhypopituitarism during the 3-year period following irradiation. Within a 6-year period, partial pituitary insufficiency was observed in a further 7 patients, thus necessitating hormone substitution treatment. CONCLUSION: Using strict rules of remission, in our cohort we found both a normalisation of IGF-I and safe GH levels in 34% of patients treated for acromegaly with conventional irradiation therapy.

Does additional brachytherapy improve the effect of external irradiation? A prospective, randomized study in central lung tumors.

PURPOSE: Endobronchial brachytherapy has become more widely used to increase the total local dose of irradiation ("boost") applied for the treatment of lung cancer. Apart from treatment for local stenosis, endobronchial brachytherapy in combination with external irradiation (EI) has the potential to improve local tumor control and perhaps prolong survival, but the real benefit has not been proven yet. To evaluate the possible effects of external irradiation with an additional boost of high dose rate (HDR) brachytherapy, we conducted a prospective randomized study. METHODS AND MATERIALS: Design-two groups were compared: Group 1 was treated with external radiotherapy alone (planned dose 60 Gy); Group 2 received an additional boost of HDR brachytherapy of scheduled 4.8 Gy each (at 10 mm from the source axis) before and after external irradiation. Patients-98 patients with advanced inoperable lung cancer were included in the study, 42 in Group 1 and 56 in Group 2. Both groups were comparable with respect to age, sex, tumor stage, Karnofsky performance status (KPS), and histology. RESULTS: A mean total external irradiation dose of 50.5 +/- 14.1 Gy in Group 1 and 50 +/- 12.5 Gy in Group 2 was applied. Group 2 received an additional dose of 7.44 +/- 2.6 Gy (at 10 mm depth) through brachytherapy. The median survival time in both groups was comparable (28 weeks and 27 weeks, respectively). In patients with squamous cell carcinoma (68 patients) Group 2 showed an advantage in median survival with borderline significance (40 vs. 33 weeks, p = 0.09). Group 2 showed also a better local tumor control in all patients; patients with squamous cell carcinoma had a significantly longer period of local tumor control. Fatal hemoptysis was the cause of death in 6 (14.2%) patients in Group 1 and 11 (18.9%) in Group 2 (p = 0.53). CONCLUSIONS: High dose rate brachytherapy in patients with inoperable lung cancer increased local control in our randomized study when used in combination with external irradiation. Survival time was also longer, but with no clear statistical significance. This applied especially to patients with squamous cell carcinomas. There was no statistically significant difference in the incidence of fatal hemoptysis between the two groups.

Palliative endobronchial brachytherapy for central lung tumors. A prospective, randomized comparison of two fractionation schedules.

AIM OF THE STUDY: Remote high dose rate brachytherapy is an effective local treatment modality for central lung tumors and has the potential to improve survival time. Optimal dose and fractionation schemes have not been identified yet. We conducted a prospective randomized study to compare two treatment schedules in terms of survival time, local tumor control, and possible complications. DESIGN: Group 1 received 4 brachytherapies with a dose of 3.8 Gy (at a 10-mm depth) on a weekly basis, and group 2 received 2 treatments with 7.2 Gy (at a 10-mm depth) at a 3-week interval. At a depth of 5 mm, the calculated doses would be 8 and 15 Gy. This study is still ongoing. Here we report interim results. PATIENTS: Ninety-three patients with advanced cancer were included in the study; 44 were in group 1 and 49, in group 2. Both groups were comparable regarding age, sex, tumor stage, Karnofsky performance status, and histologic findings. INTERVENTIONS: A mean total irradiation dose of 13.4 +/- 5.2 Gy for group 1 and 13.7 +/- 4.4 for group 2 were applied (calculated at 10 mm from the source axis, equivalent to 27.9 Gy in group 1 and 28.5 Gy in group 2 at a 5-mm depth). RESULTS: The 1-year survival rate was 11.4% in group 1 and 20.4% in group 2. No significant difference in survival time was found, but mean survival was longer in group 2 (49 weeks) than in group 1 (26 weeks). Local control after 3 months was comparable in both groups. Fatal hemoptysis occurred at a similar rate in group 1 (22.2%) and in group 2 (21.1%). CONCLUSION: High-dose rate brachytherapy with 2 x 7.2 Gy with a 3-week interval is equivalent to a 4 x 3.8-Gy regimen on a weekly basis. The shorter treatment schedule is more convenient for patients, does not cause more side effects, and provides an equal local tumor control.

[Current status of therapy of CNS metastases of germ cell tumors]. / Derzeitiger Stand der Therapie von ZNS-Metastasen bei Keimzelltumoren.

The incidence of CNS metastases in germ cell tumors is 2-5% and in very advanced disease over 20%. We report on 37 patients in whom CNS metastases were diagnosed with the CAT scanner. Twenty-nine patients were subsequently treated. In 19 cases, treatment consisted of radiotherapy, 1 patient was only operated on, and in 9 cases patients received combined surgery and radiotherapy. Two patients had seminomatous germ cell tumors, 27 patients non-seminomatous tumors. HCG levels were high in 11 cases. In 31 patients the disease was in the advanced stages; in 6 the disease was at the early stage. If there was just a solitary tumor, operation was the preferred mode of treatment. Radiotherapy consisted of 50 GY whole-brain irradiation, with a tumor saturation up to 60 GY. In 2 cases we suspected radiogenic necrosis. There were no other severe side effects. Of the 37 patients, 4 obtained a long-term cure (observation time 34-90 months). Therapy must take all methods of treatment into consideration and should only be carried out in fully equipped medical centers. Only then can we hope to obtain long-term cures in individuals with this usually fatal disease.