Oliver Koelbl

Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma

This multicenter study aimed to identify prognostic factors in patients with brain metastases from malignant melanoma (BM‐MM).

INFLUENCE OF PATIENT POSITIONING ON DOSE-VOLUME HISTOGRAM AND NORMAL TISSUE COMPLICATION PROBABILITY FOR SMALL BOWEL AND BLADDER IN PATIENTS RECEIVING PELVIC IRRADIATION: A PROSPECTIVE STUDY USING A 3D PLANNING SYSTEM AND A RADIOBIOLOGICAL MODEL

PURPOSEnA prospective study was undertaken to evaluate the influence of patient positioning (prone position using a belly board vs. supine position) on the dose-volume histograms (DVHs) of organs of risk, and to analyze its possible clinical relevance using radiobiological models.nnnMETHODS AND MATERIALSnFrom November 1996 to August 1997 a computed tomography (CT) scan was done in the prone position using a belly board and in supine position in 20 consecutive patients receiving postoperative pelvic irradiation because of rectal cancer. Using a three-dimensional (3D) planning system (Helax, TMS) the DVH for small bowel, bladder, a standard planning target volume (PTV) of postoperative irradiation of rectal cancer, the intersection of volume of PTV and small bowel (PTV intersection V(SB), respectively, of PTV and bladder (PTV intersection V(B)) were defined in each axial CT slice. The normal tissue complication probability (NTCP) was determined by the radiobiological model of Lyman and Kutcher using the tolerance data of Emami. For evaluation of late toxicity alpha/beta ratio was 2.5; for evaluation of acute toxicity, it was 10. Total dose was 50.4 Gy (1.8 Gy/fraction) (ICRU 50).nnnRESULTSnUsing the prone position compared to the supine position, the median volume of PTV intersection V(B) was reduced by 18.5 cm3 (62%). Median dose (related to the reference dose) to the bladder was 44.5% (22.4 Gy) in prone and 66.05% (33.3 Gy) in supine position (p<0.001). Median V(B) within the 90% (45.4 Gy), 80% (40.3 Gy), 60% (30.2 Gy), and 40% (20.2 Gy) isodose was significantly lower in the prone position when compared to the supine position. Using the radiobiological models, however, there was no difference of NTCP between prone position or supine position. In the prone position, median volume of PTV intersection V(SB) was reduced by 32.5 cm3 (54%). The median dose to small bowel was 30.85% (15.4 Gy) in the prone position and 47.35% (23.9Gy) in the supine position (p<0.001). Significant differences between prone and supine position were found for median V(SB) within the 90% (45.4 Gy), 80% (40.3 Gy), 60% (30.2 Gy), and 40% (20.2 Gy) isodose. According to the method of Lyman, median NTCP of small bowel was significant lower in prone than in supine position.nnnCONCLUSIONnThe prone position with a standard belly board should be the standard positioning technique for patients receiving adjuvant postoperative radiation therapy following surgery of rectal cancer. Both irradiated volume and total dose to the organs of risk can be reduced significantly. As a consequence of this, radiation induced toxicity will be minimized.

p53 and Ki-67 as predictive markers for radiosensitivity in squamous cell carcinoma of the oral cavity? an immunohistochemical and clinicopathologic study.

PURPOSEnPreviously published data relating the expression of p53 and Ki-67 to radiation response in head and neck cancer are conflicting. This may be due to differences in patient selection and treatment modalities. In this study of a homogenous population of patients with oral cavity cancer, Ki-67 and p53 indices were correlated with histopathologically assessed tumor regression after preoperative radiochemotherapy and longterm outcome.nnnMETHODS AND MATERIALSnEighty-eight patients with squamous cell carcinoma of the oral cavity and treated between September 1985 and November 1995 by preoperative radiochemotherapy and definitive surgery were included in this analysis. By immunohistochemistry (IHC) the pre-irradiation expression of p53 and of Ki-67 were analyzed and correlated with the histopathologically proven tumor regression, overall survival and local control.nnnRESULTSnThe overall 2- and 5-year survival rates were 76.5% and 63%, the locoregional control rates were 84% and 79%, respectively. After preoperative radiochemotherapy 29 patients (33%) showed complete tumor regression (ypT(0) classification). Survival and local control rates were significantly higher for patients showing ypT(0) classification than ypT(1-4) classification (p < 0.01). This effect was independent of pretreatment tumor classification in multivariate analysis. Pre-irradiation p53 status and Ki-67 index had no influence on tumor regression and clinical outcome in these patients.nnnCONCLUSIONnComplete tumor regression after preoperative treatment is related to an improved outcome in combined modality treatment of oral cavity cancer. The presented study could not demonstrate an influence of p53 and Ki-67 status as detected by immunohistochemical staining on survival, local control, or tumor regression after radiochemotherapy.

The relationship between belly board position and patient anatomy and its influence on dose -volume histogram of small bowel for postoperative radiotherapy of rectal cancer

The influence of three different belly board (BB) positions in radiotherapy of rectal cancer on the dose-volume histogram of the small bowel (SB) were analysed for 20 patients. Placing the lower border of the BB opening near the lumbosacral junction, both the volume of SB within the pelvis and the volume of SB within all tested dose levels were lower compared to its position near the symphysis or the lumbosacral junction.

The influence of heterotopic ossification on functional status of hip joint following total hip arthroplasty

Purpose:The functional failure induced by heterotopic ossification (HO) following total hip arthroplasty (THA) was analyzed and correlated to the radiologic failure.Patients and Methods:From July 1997 to July 2001, 315 patients (345 hips) received THA indicated by a hypertrophic osteoarthritis of higher degree (Kellgren grade III, IV). All patients were irradiated prophylactically for prevention of HO on the evening before surgery with a 7-Gy single fraction. The patients’ median age was 66.3 years. Radiologic failure was assessed by comparison of pre- and postoperative hip X-rays (immediately and 6 months after surgery). Analysis of radiographs was performed according to the Brooker Score. Clinical failure was appraised by measurement of passive range of motion (ROM) of the hip joint with a standard goniometer. The t-test was used for statistical analysis.Results:281 patients (81.5%) did not develop HO. HO of Brooker grade I or II was found in 58 patients (16.8%). Six patients (1.7%) developed HO Brooker grade III or IV. There was a significant negative correlation between the degree of radiologic and clinical failure. ROM differed significantly between patients with HO Brooker grade 0, I, II and patients with HO Brooker grade III, IV. Comparing the pre- and postoperative ROM, all patients with Brooker grade 0, I and II showed a significant improvement of flexion, internal and external rotation, abduction and adduction movement. Patients with HO Brooker grade III and IV showed no improvement of ROM in the postoperative follow-up.Conclusion:The development of HO following THA influences the physical function of the hip joint dependent on the degree of ossification. HO of lower degree (Brooker I, II) does not influence the clinical outcome, whereas HO of higher degree (Brooker III, IV) reduces the function of hip arthroplasty. Therefore, the purpose of a prophylactic therapy must be to reduce HO of higher degree.Ziel:Der Einfluss heterotoper Ossifikationen (HO) nach Totalendoprothese des Hüftgelenks (TEP) auf die Gelenkbeweglichkeit wird untersucht.Patienten und Methodik:Von Juli 1997 bis Juli 2001 erhielten 315 Patienten (345 Hüften) eine TEP. Als Operationsindikation lag bei allen Patienten eine höhergradige Koxarthrose vor (Kellgren III, IV). Die Patienten wurden am Vorabend der Operation mit einer Einzeldosis von 7 Gy als Ossifikationsprophylaxe bestrahlt. Das mediane Alter der Patienten betrug 66,3 Jahre. Die Klassifikation der HO wurde anhand prä- und postoperativer Röntgenaufnahmen (am Operationstag bzw. 6 Monate nach Operation) nach dem Brooker-Score durchgeführt. Folgende präoperative und in der Nachsorge erhobene Beweglichkeitsparameter (ROM) wurden in Abhängigkeit von der HO-Entwicklung miteinander verglichen: Flexion, Außen- und Innenrotation, Ab- und Adduktion. Der t-Test für gepaarte Stichproben wurde für die statistische Analyse verwendet.Ergebnisse:281 Patienten (81,5%) entwickelten keine HO, 58 Patienten (16,8%) HO Grad I/II und sechs Patienten (1,7%) HO Grad III/IV. Die erhobenen ROM unterschieden sich signifikant bei den Patienten, die keine oder niedriggradige HO (Brooker I, II) entwickelt hatten, und denen, die höhergradige HO (Brooker III, IV) aufwiesen. Die Patienten mit HO Brooker 0, I und II zeigten im Gegensatz zu den Patienten mit HO Brooker III und IV postoperativ eine signifikante Verbesserung der Werte für Flexion, Innen- und Außenrotation, Ab- und Adduktion.Schlussfolgerung:Die Entstehung von HO nach TEP beeinflusst in Abhängigkeit von deren Ausmaß die postoperative Hüftbeweglichkeit. Dabei sind HO Grad I und II nicht, Grad III und IV von großer klinischer Relevanz. Daher muss eine prophylaktische Therapie insbesondere darauf abzielen, die Inzidenz höhergradiger HO zu reduzieren.

Preoperative Irradiation for Prevention of Heterotopic Ossification Following Prosthetic Total Hip Replacement

Background:The effectiveness of pre- or postoperative radiotherapynfor prevention of heterotopic ossification (HO) following totalnhip replacement (THR) has already been demonstrated in the past.nThereby, in most studies using preoperative radiotherapynpatients were irradiated < 6 h before surgery. The purpose ofnthis prospective study was to analyze the effectiveness ofnpreoperative irradiation on the evening before surgery and tonidentify risk factors for HO in a homogeneous collective ofnpatients.Patients and Methods:From July 1997 to July 2001, 416 patients (462 hips; 235nmales, 227 females) received preoperative radiotherapy of thenhip on the evening before surgery with a 7-Gy single fraction.nThe patients’ median age was 67.1 years. The most frequentnindication for radiotherapy was hypertrophic osteoarthritis (383nhips, 82.9%). Treatment results were assessed by comparison ofnpre- and postoperative hip X-rays (immediately and 6 monthsnafter surgery). The analysis of radiographs was performednaccording to the Brooker score.Results:The overall incidence of HO was 18.1% (n = 84), Brookernscore 1 12.3% (n = 57), score 2 3.9% (n = 18), score 3 1.5% (n =n7), and score 4 0.4% (n = 2). Sex, body height, hypertrophicnosteoarthritis of higher degree, size of the femoral componentnof the prosthesis, previous ipsi- or contralateral HO, and shortncourse of nonsteroidal anti-inflammatory drug (diclofenac)ntherapy significantly influenced the HO rate in univariatenanalysis. In multivariate analysis, an interdependence ofnprosthesis size, sex and patient’s height was found. From thesenthree variables, only prosthesis size was statisticallynsignificant in multivariate analysis. The cumulative dose ofndiclofenac (≤ 300 mg or > 300 mg) within the first 7npostoperative days and previous ipsi- or contralateral HOninfluenced the incidence of HO in multivariate analysis.Conclusion:Preoperative radiotherapy on the evening before surgery isnan effective treatment modality to reduce overall (Brooker 1–4)nand clinically relevant, severe HOs (Brooker 3–4), and includesnseveral advantages compared to postoperative irradiation.nPrevious ipsi- and contralateral HOs were identified as highnrisk factors for HO in this study. In patients with these risknfactors, the incidence of HO increased.Hintergrund:Die Wirksamkeit einer prä- oder postoperativen Radiationzur Vermeidung heterotoper Ossifikationen (HO) nachntotalendoprothetischem Hüftgelenkersatz (TEP) wurde in dernVergangenheit bereits gezeigt. Dabei wurde in den meistennStudien einer präoperativen Radiatio die Bestrahlung im Zeitraumnvon 6 h vor der Operation durchgeführt. Ziel dieser Arbeit warnes, die Wirksamkeit einer präoperativen Bestrahlung am Abend vorndem Operationstag in einem homogenen Patientenkollektiv zunüberprüfen.Patienten und Methodik:Von 07/1997 bis 07/2001 wurde bei 416 Patienten (462nHüften; 235 Männer, 227 Frauen) eine präoperativenEinzeitbestrahlung der Hüfte mit einer Dosis von 7 Gyndurchgeführt. Das mediane Alter der Patienten betrug 67,1 Jahre.nDie häufigste Indikation für die prophylaktische Bestrahlung warneine hypertrophe Osteoarthritis (383 Hüften, 82,9%). DasnTherapieergebnis wurde anhand von Röntgenbildern unmittelbarnpostoperativ und 6 Monate nach Operation gemäß dem Brooker-nScore beurteilt.Ergebnisse:Die HO-Inzidenz betrug 18,1% (n = 84), Brooker-Grad 1n12,3% (n = 57), Grad 2 3,9% (n = 18), Grad 3 1,5% (n = 7) andnGrad 4 0,4% (n = 2). Geschlecht, Körpergröße, Ausmaß dernOsteoarthritis, Größe des Prothesenschafts, vorherige ipsi- odernkontralaterale HO und die zusätzliche Gabe von nichtsteroidalennAntiphlogistika (Diclofenac) hatten in der univariaten Analysensignifikanten Einfluss auf die HO-Rate. Es fand sich einenKorrelation von Geschlecht, Körpergröße und Schaftgröße, so dassnin der multivariaten Analyse nur noch die Schaftgröße einenSignifikanz aufwies. Die kumulative Diclofenacdosis (≤ 300 mgnbzw. > 300 mg) und vorherige ipsi- oder kontralaterale HOnbehielten auch in der multivariaten Analyse ihren signifikantennEinfluss auf die HO-Rate.Schlussfolgerung:Eine präoperative Bestrahlung am Vorabend der Operationnstellt eine effektive Behandlung zur Vermeidung von HO nach TEPndar und hat gegenüber einer postoperativen Bestrahlung Vorteile.nInsbesondere vorherige ipsi- und kontralaterale HO stellennHochrisikofaktoren für die Entstehung von HO auch nachnBestrahlung dar.

Radiation-induced reduction of BMP-induced proteoglycan synthesis in an embryonal mesenchymal tissue equivalent using the chicken "limb bud" test.

Purpose: Heterotopic ossification (HO) is a common complication following total hip replacement. Clinical studies showed the effectiveness of irradiation for prevention of heterotopic ossification. The mechanism of radiotherapy responsible for the reduction of heterotopic ossification is unclear. The purpose of this study was to find a suitable cell system, which can reproduce in-vitro data resulting from clinical in-vivo studies. The establishment of such a cell model allows detailed analyses of the mechanism of radiotherapy.nn Method: The chicken limb bud test was used as an in-vitro model. The cells acquired by the limb bud test were irradiated with different doses (0 Gy, 3 Gy, 7 Gy, 10 Gy, 20 Gy). Irradiation was set either 1 hour before, or 1 or 3 days after BMP-2 incubation. The synthesis of proteoglycans (PGS) upon treatment with bone morphogenetic protein (BMP)-2 was measured in cells incubated with BMP-2 for 4 days followed by 35SO42− labeling for 6 hours. Labeled proteoglycans were precipitated using Alcian blue and measured in a raytest radio-TLC analyzer. The incubation with BMP-2 was defined to correlate the in-vivo stimulus meaning the operation.nn Results: The proteoglycan synthesis was significantly reduced by irradiation 1 hour before or 1 day after BMP-2 incubation, if the dosage was at least 7 Gy. Higher doses than 7 Gy did not lead to lower proteoglycan levels. There was only a trend for a reduction of proteoglycan synthesis by 3 Gy irradiation, but no significant difference compared to the non-irradiated control. An irradiation 3 days after BMP-2 incubation had no effect on proteoglycan.nn Conclusion: A dose and time dependent effect of radiation on BMP-2-induced proteoglycan synthesis was observed. Therefore the results of clinical in-vivo studies were reproduced exactly by the limb bud test. We established an in-vitro cell model to analyze the mechanism of the prevention of heterotopic ossification by radiotherapy on cellular or sub-cellular level.Hintergrund: Heterotope Ossifikationen stellen eine häufige postoperative Komplikation nach Hüftgelenksoperationen dar. In klinischen Studien konnte gezeigt werden, dass eine Bestrahlung des Operationsbereichs Ossifikationen verhindern kann. Dabei ist der genaue Wirkmechanismus der ionisierenden Strahlen unbekannt. Ziel dieser Untersuchung war es, ein geeignetes Zellsystem zu finden, welches die aus der klinischen Beobachtung gewonnenen Kenntnisse in vitro reproduzieren lässt, um damit ein Modell zu haben, den Wirkungsmechanismus der Bestrahlung analysieren zu können.nn Material and Methode: Als In-vitro-Organmodell wurde der Limb-Bud-Test gewählt. Die dabei gewonnenen embryonalen mesenchymalen Zellen wurden mit unterschiedlichen Bestrahlungsdosen (0 Gy, 3 Gy, 7 Gy, 10 Gy, 20 Gy) zu unterschiedlichen Zeitpunkten bestrahlt (1 Stunde vor, 1 und 3 Tage nach Zugabe von Bone Morphogenetic Protein [BMP]-2). Die Zellen wurden 4 Tage mit BMP-2 und anschließend für 6 Stunden mit 35SO42− inkubiert. Die so markierten Proteoglykane wurden mittels Alcian-Blau gefällt und in einem Raytest-Radio-TLC-Analyzer gemessen. Die Inkubation der Zellsuspension mit BMP-2 entsprach dabei der in vivo als Ossifikationsreiz geltenden Operation.nn Ergebnisse: Die 1 Stunde vor oder 1 Tag nach BMP-2-Zugabe bestrahlten Zellsuspensionen zeigten eine deutliche Abnahme der Proteoglykansyntheserate (PGS), sobald die Bestrahlungsdosis mindestens 7 Gy betrug. Eine Steigerung der Dosis bis zu 20 Gy führte nicht zu einem weiteren Abfall der Proteoglykansyntheserate. Für eine Dosis von 3 Gy fand sich lediglich ein Trend zu einer reduzierten Proteoglykansynthese, ohne dass der Unterschied zur unbestrahlten Kontrollgruppe signifikant gewesen wäre. Eine Bestrahlung 3 Tage nach BMP-2-Zugabe hatte keinen Einfluss auf die Proteoglykansyntheserate.nn Schlussfolgerung: Der Limb-Bud-Test erlaubt es, die Ergebnisse der klinischen Studien in vitro zu reproduzieren. Man hat damit ein Zellmodell zur Verfügung, das es erlaubt, auf zellulärer und subzellulärer Ebene den Wirkungsmechanismus der ionisierenden Strahlen bei der Verhinderung ektoper Ossifikationen zu untersuchen.

TRANSCRANIAL SONOGRAPHY: INTEGRATION INTO TARGET VOLUME DEFINITION FOR GLIOBLASTOMA MULTIFORME

PURPOSEnRecent studies indicate that transcranial sonography (TCS) reliably displays the extension of malignant brain tumors. The effect of integrating TCS into radiotherapy planning for glioblastoma multiforme (GBM) was investigated herein.nnnMETHODS AND MATERIALSnThirteen patients subtotally resected for GBM underwent TCS during radiotherapy planning and were conventionally treated (54 to 60 Gy). Gross tumor volumes (GTVs) and stereotactic boost planning target volumes (PTVs, 3-mm margin) were created, based on contrast enhancement on computed tomography (CT) only (PTV(CT)) or the combined CT and TCS information (PTV(CT+TCS)). Noncoplonar conformal treatment plans for both PTVs were compared. Tumor progression patterns and preoperative magnetic resonance imaging (MRI) were related to both PTVs.nnnRESULTSnA sufficient temporal bone window for TCS was present in 11 of 13 patients. GTVs as defined by TCS were considerably larger than the respective CT volumes: Of the composite GTV(CT+TCS) (median volume 42 ml), 23%, 13%, and 66% (medians) were covered by the overlap of both methods, CT only and TCS only, respectively. Median sizes of PTV(CT) and PTV(CT+TCS) were 34 and 74 ml, respectively. Addition of TCS to CT information led to a median increase of the volume irradiated within the 80% isodose by 32 ml (median factor 1.51). PTV(CT+TCS) volume was at median 24% of a conventional MRI(T2)-based PTV. Of eight progressions analyzed, three and six occurred inside the 80% isodose of the plans for PTV(CT) and for PTV(CT+TCS), respectively.nnnCONCLUSIONnAddition of TCS tumor volume to the contrast-enhancing CT volume in postoperative radiotherapy planning for GBM increases the treated volume by a median factor of 1.5. Since a high frequency of marginal recurrences is reported from dose-escalation trials of this disease, TCS may complement established methods in PTV definition.