Robert Krempien

Concentration of Transforming Growth Factor Beta in Human Bone Tissue: Relationship to Age, Menopause, Bone Turnover, and Bone Volume

Transforming growth factor β (TGF‐β) is thought to play an important role in bone metabolism, but its relationship to human bone turnover and bone mass has not been examined yet. In this study, we measured the concentration of TGF‐β in 811 samples of male and female bone from four representative sites of the human skeleton and in the supernatants of 72 short‐term human bone marrow cultures from the iliac crest. The concentrations of TGF‐β1 and TGF‐β2 in the bone matrix were positively correlated with histomorphometric indices of bone resorption and bone formation and with serum levels of osteocalcin and bone‐specific alkaline phosphatase. We also observed a positive association between the release of TGF‐β in the bone marrow cultures and serum osteocalcin. Changes in the rate of cancellous or cortical bone remodeling with age or menopause were accompanied by corresponding changes in skeletal TGF‐β. In contrast, there was no significant relationship between the concentration of TGF‐β and bone volume at any skeletal site. In conclusion, our study supports the hypothesis that TGF‐β plays an important role in human bone remodeling, but fails to demonstrate an association between the skeletal concentration of TGF‐β and human bone mass.

Results of European pooled analysis of IORT-containing multimodality treatment for locally advanced rectal cancer: adjuvant chemotherapy prevents local recurrence rather than distant metastases

BACKGROUND The purpose of this study is to analyze the pooled results of multimodality treatment of locally advanced rectal cancer (LARC) in four major treatment centers with particular expertise in intraoperative radiotherapy (IORT). PATIENTS AND METHODS A total of 605 patients with LARC who underwent multimodality treatment up to 2005 were studied. The basic treatment principle was preoperative (chemo)radiotherapy, intended radical surgery, IORT and elective adjuvant chemotherapy (aCT). In uni- and multivariate analyses, risk factors for local recurrence (LR), distant metastases (DM) and overall survival (OS) were studied. RESULTS Chemoradiotherapy lead to more downstaging and complete remissions than radiotherapy alone (P < 0.001). In all, 42% of the patients received aCT, independent of tumor-node-metastasis stage or radicality of the resection. LR rate, DM rate and OS were 12.0%, 29.2% and 67.1%, respectively. Risk factors associated with LR were no downstaging, lymph node (LN) positivity, margin involvement and no postoperative chemotherapy. Male gender, preoperatively staged T4 disease, no downstaging, LN positivity and margin involvement were associated with a higher risk for DM. A risk model was created to determine a prognostic index for individual patients with LARC. CONCLUSIONS Overall oncological results after multimodality treatment of LARC are promising. Adding aCT to the treatment can possibly improve LR rates.

Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283]

BackgroundPancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR.Methods/designThe PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patients enrolment.DiscussionThe primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment).Secondary objectives are to determine the role and the mechanism of cetuximab in patients chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.

Open low-field magnetic resonance imaging in radiation therapy treatment planning

PURPOSE To evaluate the possibilities of an open low-field magnetic resonance imaging (MRI) scanner in external beam radiotherapy treatment (RT) planning. METHODS AND MATERIALS A custom-made flat tabletop was constructed for the open MR, which was compatible with standard therapy positioning devices. To assess and correct image distortion in low-field MRI, a custom-made phantom was constructed and a software algorithm was developed. A total of 243 patients (43 patients with non-small-cell lung cancer, 155 patients with prostate cancer, and 45 patients with brain tumors) received low-field MR imaging in addition to computed tomographic (CT) planning imaging between January 1998 and September 2001 before the start of the irradiation. RESULTS Open low-field MRI provided adequate images for RT planning in nearly 95% of the examined patients. The mean and the maximal distortions 15 cm around the isocenter were reduced from 2.5 mm to 0.9 mm and from 6.1 mm to 2.1 mm respectively. The MRI-assisted planning led to better discrimination of tumor extent in two-thirds of the patients and to an optimization in lung cancer RT planning in one-third of the patients. In prostate cancer planning, low-field MRI resulted in significant reduction (40%) of organ volume and clinical target volume (CTV) compared with CT and to a reduction of the mean percentage of rectal dose of 15%. In brain tumors, low-field MR image quality was superior compared with CT in 39/45 patients for planning purposes. CONCLUSIONS The data presented here show that low-field MRI is feasible in RT treatment planning when image correction regarding system-induced distortions is performed and by selecting MR imaging protocol parameters with the emphasis on adequate images for RT planning.

Image fusion of CT and MRI data enables improved target volume definition in 3D-brachytherapy treatment planning

PURPOSE To integrate MRI into CT-based 3D-brachytherapy treatment planning using a software system for image registration and fusion. METHODS AND MATERIALS Sixteen patients with recurrent head-and-neck cancer, vulvar cancer, liposarcoma, and cervical cancer were treated with interstitial (n=12) and endocavitary (n=4) brachytherapy. CT and MRI scans were performed after implantation and prior to treatment planning. Image registration to integrate the CT and MR information into a single geometric framework was performed using a software algorithm based on mutual information. Conventional 3D-brachytherapy planning based on CT-information alone was compared to brachytherapy planning based on fused CT and MRI data. The accuracy of the image fusion was measured using predefined corresponding landmarks in the CT and MRI data. RESULTS The presented automated algorithm proved to be robust and reliable (mean registration error 1.8 mm, range 0.8-4.1 mm, SD 0.9 mm). Tumor visualization was difficult using CT alone in all cases. Brachytherapy treatment planning based on fused CT and MRI data enabled better definition of target volume and risk structures as compared to treatment planning based on CT alone. CONCLUSIONS Image registration and fusion is feasible for afterloading brachytherapy treatment planning. Treatment planning based on fused CT and MRI data resulted in improved target volume and risk structure definition.

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy

BACKGROUND AND PURPOSE To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. MATERIALS AND METHODS A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. RESULTS After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort. CONCLUSIONS Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases.

Electromagnetically navigated brachytherapy as a new treatment option for peripheral pulmonary tumors.

Purpose:This technical note describes the principles of navigated brachytherapy for treatment of peripheral non-small cell lung cancer (NSCLC).Material and Methods:In a prospective feasibility trial a first patient with medically inoperable NSCLC in the right upper lobe was treated with external-beam radiotherapy (50 Gy) and navigated endoluminal brachytherapy (15 Gy). Navigated bronchoscopy was performed with an electromagnetic navigation system for localization of a microsensor mounted on the tip of a dedicated catheter placed within the working channel of a bronchoscope. The probe can be actively guided by a steering mechanism to targeted lesions in the periphery of the lung. After successful localization of the NSCLC, endobronchial ultrasound (EBUS) was performed to confirm the exact position in the center of the lesion. A 6-F brachytherapy catheter was placed within the tumor. Primary 3-D-planned brachytherapy was performed on chest CTs acquired with the inserted catheter. High-dose-rate brachytherapy (370 GBq iridium-192) was applied as a boost three times a week (single dose 5 Gy) and provided highly conformal irradiations of the NSCLC including the draining bronchovascular bundle.Results:The brachytherapy catheter was tolerated well during treatment (5 days) and alimentation was possible without any problems. Repeated CTs showed stable positioning of the catheter. During follow-up (12 months), endoluminal ultrasound and CT demonstrated a partial remission while histology showed a complete remission of the tumor.Conclusion:Navigated brachytherapy for peripheral pulmonary tumors not amenable to conventional bronchoscopy is feasible.Ziel:Diese technische Mitteilung beschreibt die Grundlagen einer navigierten Brachytherapie zur Therapie von peripheren, nichtkleinzelligen Bronchialkarzinomen (NSCLC).Material und Methodik:Im Rahmen einer prospektiven Machbarkeitsstudie wurde ein Patient mit einem aus internistischen Gründen inoperablen NSCLC im rechten Oberlappen mit einer Teletherapie (50 Gy) und einer navigierten Brachytherapie behandelt (15 Gy). Die navigierte Bronchoskopie wurde mit einem elektromagnetischen Navigationssystem durchgeführt. Dieses System erlaubte eine Echtzeitdarstellung eines Mikrosensors, der an der Spitze eines speziellen Navigationskatheters angebracht und in den Arbeitskanal des Bronchoskops eingeschoben wurde. Der Navigationskatheter kann aktiv mit Hilfe eines Lenkungssystems zu peripheren Lungentumoren geführt werden. Nach erfolgreicher Ansteuerung des NSCLC wurde ein endobronchialer Ultraschall (EBUS) zur Bestätigung einer zentralen Positionierung im Tumor durchgeführt (Abbildungen 1 und 2). Im Anschluss wurde ein konventioneller 6-F-Bronchuskatheter im Tumor platziert. Auf der Basis eines Planungs-CT, das mit liegendem Brachytherapiekatheter gefahren wurde, erfolgte eine primäre 3-D-geplante Brachytherapie. Die High-Dose-Rate-Brachytherapy (370 GBq Iridium-192) wurde als Boostbestrahlung appliziert (3 × 5 Gy/Woche) und erlaubte eine hochkonformale Bestrahlung des peripheren NSCLC und des zuführenden bronchovaskulären Bündels (Abbildungen 3 und 4).Ergebnisse:Der Brachytherapiekatheter wurde während der Behandlung gut toleriert und erlaubte eine problemlose Ernährung des Patienten. Wiederholte CT-Untersuchungen zeigten eine stabile Lage des Katheters. In der Nachsorge (12 Monate) zeigten EBUS und CT eine partielle und die histologische Untersuchung eine komplette Remission des Tumors.Schlussfolgerung:Eine navigierte Brachytherapie zur Therapie peripherer NSCLCs, die nicht mit einer konventionellen Bronchoskopie erreicht werden können, ist durchführbar.

Diagnostic imaging in the management of craniosynostoses

Craniosynostoses are the most frequent craniofacial malformations. However, with a prevalence of 3–6 cases per 10,000 live births they are amongst the rarely seen diseases and their definite diagnosis thus poses a challenge to the physician. When an abnormal calvarial configuration is detected, a radiological evaluation is necessary to characterize the deformity and to guide the corrective surgical procedure. The demand for clear diagnostic criteria is justified by the severity of the disease and the possible consequences of delayed diagnosis. In addition to the clinical signs (deformation of the head), conventional skull X-rays show typical radiological alterations and are used for basic diagnostics. Diagnostic tests that may be performed to confirm the diagnosis and assess the extent of the problem, include computed tomography (CT), 3D-CT, magnetic resonance imaging (MRI) scans, and ultrasonography. In the present review we will describe the most important clinical and radiological characteristics of craniosynostosis by means of clinical, radiological and operative situs examples.

Inversely Planned Intensity Modulated Radiotherapy of the Breast Including the Internal Mammary Chain: A Plan Comparison Study

The aim of this paper is to evaluate the benefit of inversely planned intensity modulated radiotherapy (IMRT) in the adjuvant irradiation of breast cancer when internal mammary lymph nodes are included in the treatment volume. 20 patients treated with 3D-planned conventional radiotherapy (CRT) following breast conserving surgery were included in the study. We chose 10 patients with left-sided and 10 patients with right-sided tumors. All treatment volumes included the internal mammary chain. For plan comparison to the applied CRT plan an inverse IMRT-plan in ‘step-and-shoot’-technique was calculated. For all patients IMRT resulted in an improved conformity of dose distribution to the target volume compared to CRT (mean COIN95: 0.798 vs. 0.514 with COIN95 = C1* C2 (C1= fraction of CTV that is covered by > 95% of the prescribed dose and C2 = volume of CTV that is covered by > 95% of the prescribed dose/total volume that is covered by > 95% of the prescribed dose). In all cases with matching adjacent beams, the homogeneity in the target volume was improved. The volume of the ipsilateral lung irradiated with a dose higher than 20 Gy was reduced with IMRT from 24.6% to 13.1% compared to CRT. For left-sided target volume the heart volume with a dose higher than 30 Gy was reduced from 6.2% to 0.2%. The presented plan comparison study for irradiation of the breast and the parasternal lymph nodes showed a substantial improvement of the dose distribution by inversely planned IMRT compared to CRT. This is visible for the target volume, the ipsilateral lung and, in case of left-sided target volume, the heart. Despite an increase in integral dose to the entire normal tissue, the application of IMRT might be clinically advantageous in cases where no satisfying dose distribution can be obtained by CRT.

Results of chest wall reirradiation using pulsed-dose-rate (PDR) brachytherapy molds for breast cancer local recurrences

PURPOSE We report in a retrospective study on the effect and toxicity of chest wall reirradiation using pulsed-dose-rate (PDR) afterloading molds. METHODS AND MATERIALS Between 1993 and 1999, a total of 58 patients were treated. All patients presented with locally recurrent breast cancer (31 patients had concomitant distant metastases) after mastectomy and a previously completed course of radiation therapy (median, 54 Gy; range, 36-70). Indication for reirradiation was a progressive macroscopic skin recurrence in 30 cases and an incomplete surgical resection in 28 patients. Standard treatment consisted of a split course with two fractions of 20 Gy (interval, 31 days). The reference dose was prescribed to the skin surface at 5 mm distance from the source. PDR brachytherapy (37 GBq, (192)Ir) was carried out after geometric distance optimization with 0.5-1 Gy/pulse/h. The irradiated median area was 423 cm(2) (range, 100-919). The median follow-up was 18 months (range, 7-84). RESULTS The actuarial 1-, 2- and 3-year local recurrence-free survival rates in patients treated for macroscopic disease (microscopic disease in parenthesis) were 89% (96%), 81% (85%), and 75% (71%). Local control was obtained in 24/30 (22/28) patients. Twenty-nine of the 34 patients (85%) who deceased during follow-up were locally controlled. 9/58 patients experienced Grade III acute toxicity, 35/58 patients Grade III (29/58 telangiectasia, 6/58 contracture), and 4/58 Grade IV late toxicity (RTOG/EORTC). CONCLUSION Reirradiation of the chest wall using PDR brachytherapy molds is effective and provides a high local control rate with acceptable toxicity.