Intraoperative radiation therapy for brain metastasis in a pregnant patient: a case report.

We present the rare case of a 42-year-old woman with oligometastatic lung adenocarcinoma in her first trimester of pregnancy who was treated for brain metastases with metastasectomy and intraoperative radiation therapy (IORT) using the INTRABEAM® system (Zeiss AG, Jena, Germany). This case underscores the potential of IORT in optimizing cancer treatment while safeguarding fetal health in pregnant patients.

Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II.

Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664.

Phase II study of induction chemotherapy with docetaxel, cisplatin, 5-fluorouracil followed by radioimmunotherapy with cetuximab and intensity-modulated radiotherapy in combination with a carbon ion boost for locally advanced tumors of the oro-, hypopharynx and larynx.

PURPOSE: This phase II trial was designed to evaluate efficacy and safety of a highly intensified therapy in locally advanced squamous cell carcinoma of the oro-, hypopharynx and larynx. METHODS: In this prospective, mono-centric, open-label, non-randomized phase II trial the single treatment arm consisted of a combined induction chemotherapy with docetaxel, cisplatin, 5-fluorouracil, followed by bioradiation with the monoclonal antibody cetuximab, carbon ion boost (24Gy(RBE) in 8 fractions) and IMRT (50 Gy in 25 fractions). The trial was closed early due to slow accrual. RESULTS: Eight patients (median age 52.5 years) were enrolled into the trial. The median follow-up was 13 months and the 12-months locoregional tumor control, progression-free survival and overall survival rates were 100.0% each. Complete remission was achieved in 7 patients. The most commonly late radiation adverse event was xerostomia (85.7% at 12 months). Five serious adverse events with recovery were documented in 4 patients: mucositis grade 3 (n = 2), decreased lymphocyte count grade 4, febrile neutropenia grade 4 and hypersensitivity grade 3 to cetuximab (n = 1 each). Most symptom scales had their worst value at the last treatment day and recovered until the 4th follow-up visit. CONCLUSION: The study treatment was tolerable and promising. Reduced quality of life recovered for most aspects until the last follow-up visit.

Diffusion-weighted imaging in rectal carcinoma patients without and after chemoradiotherapy: a comparative study with histology.

Diffusion-weighted imaging (DWI) can be used to quantitatively assess functional parameters in rectal carcinoma that are relevant for prognosis and treatment response assessment. However, there is no consensus on the histopathological background underlying the findings derived from DWI. The aim of this study was to perform a comparison of DWI and histologic parameters in two groups of rectal carcinoma patients without (n=12) and after (n=9) neoadjuvant chemoradiotherapy (CRT). The intravoxel incoherent motion (IVIM) model was used to calculate the diffusion coefficient D and the perfusion fraction f in rectal carcinoma, the adjacent rectum and fat in the two patient groups. Immunohistological analysis was performed to assess the cellularity, vascular area fraction and vessel diameter for comparison and correlation. Out of 36 correlations between parameters from DWI and histology, four were found to be significant. In rectal carcinoma of patients without CRT, the diffusion D and the perfusion f correlated with the vascular area fraction, respectively, which could not be found in the group of patients who received CRT. Further correlations were found for the rectum and fat. Histological evaluation revealed significant differences between the tissues on the microscopic level concerning the cellular and vascular environment that influence diffusion and perfusion. In conclusion, DWI produces valuable biomarkers for diffusion and perfusion in rectal carcinoma and adjacent tissues that are highly dependent of the underlying cellular microenvironment influenced by structural and functional changes as well as the administered treatment, and consequently can be beyond histological ascertainability.

Review of clinical experience with ion beam radiotherapy.

The article describes both the early development of oncology as a core discipline at the University of Heidelberg Hospital and the first steps towards ion beam treatment, from the pilot project carried out in co-operation with the Gesellschaft für Schwerionenforschung Darmstadt to the initial start-up of clinical service at the Heidelberg Heavy Ion Centre (HIT). We present an overview, based on data published in the literature, of the available clinical evidence relating the use of ion beam therapy to treat major indications in active particle centres. A rationale for the use of particle therapy in each of these indications is given. In view of the limited availability of data, we discuss the necessity to conduct clinical trials. We also look forward towards the next activities to be undertaken at the HIT.

Whole-abdominal IMRT for advanced ovarian carcinoma: planning issues and feasibility.

INTRODUCTION: Despite enormous efforts to improve therapeutic strategies for patients with advanced ovarian carcinoma, outcome remains poor even with the advent cisplatinum-based chemotherapy regimen or taxanes with over 70% of patients developing local failure. Several trials were able to establish the potential benefit of adjuvant whole abdominal RT (WAI) though at the cost of sometimes marked side-effects. New technologies like IMRT have the potential of sparing normal tissues thus also potentially limiting treatment-related toxicity, hence a phase I trial was initiated to evaluate potential clinical benefit of WAI with IMRT. We intended to demonstrate that whole-abdominal IMRT is feasible and can be used in a routine clinical setting. METHODS: A water-equivalent phantom containing OARs was created simulating organ shape of the upper abdomen to investigate the necessary number of beams for the upper abdominal target irrespective of the number of segments and hence treatment times. We prescribed a total dose of 30 Gy in 1.5 Gy fractions to the median of the target. IMRT treatment plans for three patients with advanced ovarian cancer were created using 2 isocentres and between 12 and 14 beams while restricting the number of segments so as to restrict treatment times to less than 45 min. Dose to OARs such as kidneys and liver was strictly limited even below established maxima. RESULTS: In the phantom plans, no clear indication as to the optimum number of beams could be shown though there seems to be a slight trend toward a higher number of beams yielding better results. Examples demonstrating clinically inacceptable dose distributions for plans using only 9 beams. Acceptable treatment plans for real patients could be achieved using 12-14 beams and 2 isocentres. Treatment plans consisted of 264-286 segments resulting in an overall treatment time of approximately 37-45 min. Mean doses to the kidneys could be limited to 29.3% [23.1-33.2%] (right), and 26.8% [21-30.4%] (left). 50% of the liver received less than 72.4% [61-83%]. CONCLUSION: IMRT for whole abdominal irradiation in patients with advanced ovarian carcinoma is applicable and feasible though treatment planning is complex and time-consuming. There is a significant reduction of dose to critical organs by using IMRT while maintaining target volume coverage.

[What is the impact of new radiotherapy techniques?]. / Was leisten die neuen Bestrahlungstechniken?

Radiation oncology, along with surgery and chemotherapy, is one of the cornerstones in the treatment of head and neck tumors. Within the last years, this field has experienced a remarkable evolution of new technical possibilities. New imaging modalities have been introduced into radiation planning and into linear accelerators themselves. In addition, new techniques enable the tailor-made conformation of radiation beams and dose distributions to complex tumor geometries. At the same time, organs at risk can be spared, and long-term toxicities are considerably reduced. This report presents the new techniques in radiation oncology and describes the effects on new treatment options and patients' quality of life.

Inverse planned stereotactic intensity modulated radiotherapy (IMRT) in the treatment of incompletely and completely resected adenoid cystic carcinomas of the head and neck: initial clinical results and toxicity of treatment.

BACKGROUND: Presenting the initial clinical results in the treatment of complex shaped adenoid cystic carcinomas (ACC) of the head and neck region by inverse planned stereotactic IMRT. MATERIALS: 25 patients with huge ACC in different areas of the head and neck were treated. At the time of radiotherapy two patients already suffered from distant metastases. A complete resection of the tumor was possible in only 4 patients. The remaining patients were incompletely resected (R2: 20; R1: 1). 21 patients received an integrated boost IMRT (IBRT), which allow the use of different single doses for different target volumes in one fraction. All patients were treated after inverse treatment planning and stereotactic target point localization. RESULTS: The mean follow-up was 22.8 months (91-1490 days). According to Kaplan Meier the three year overall survival rate was 72%. 4 patients died caused by a systemic progression of the disease. The three-year recurrence free survival was according to Kaplan Meier in this group of patients 38%. 3 patients developed an in-field recurrence and 3 patient showed a metastasis in an adjacent lymph node of the head and neck region. One patient with an in-field recurrence and a patient with the lymph node recurrence could be re-treated by radiotherapy. Both patients are now controlled. Acute side effects >Grade II did only appear so far in a small number of patients. CONCLUSION: The inverse planned stereotactic IMRT is feasible in the treatment of ACC. By using IMRT, high control rates and low side effects could by achieved. Further evaluation concerning the long term follow-up is needed. Due to the technical advantage of IMRT this treatment modality should be used if a particle therapy is not available.

Treatment of non-small cell lung cancer with intensity-modulated radiation therapy in combination with cetuximab: the NEAR protocol (NCT00115518).

BACKGROUND: Even today, treatment of Stage III NSCLC still poses a serious challenge. So far, surgical resection is the treatment of choice. Patients whose tumour is not resectable or who are unfit to undergo surgery are usually referred to a combined radio-chemotherapy. However, combined radio-chemotherapeutic treatment is also associated with sometimes marked side effects but has been shown to be more efficient than radiation therapy alone. Nevertheless, there is a significant subset of patients whose overall condition does not permit administration of chemotherapy in a combined-modality treatment. It could be demonstrated though, that NSCLCs often exhibit over-expression of EGF-receptors hence providing an excellent target for the monoclonal EGFR-antagonist cetuximab (Erbitux) which has already been shown to be effective in colorectal as well as head-and-neck tumours with comparatively mild side-effects. METHODS/DESIGN: The NEAR trial is a prospective phase II feasibility study combining a monoclonal EGF-receptor antibody with loco-regional irradiation in patients with stage III NSCLC. This trial aims at testing the combination's efficacy and rate of development of distant metastases with an accrual of 30 patients. Patients receive weekly infusions of cetuximab (Erbitux) plus loco-regional radiation therapy as intensity-modulated radiation therapy. After conclusion of radiation treatment patients continue to receive weekly cetuximab for 13 more cycles. DISCUSSION: The primary objective of the NEAR trial is to evaluate toxicities and feasibility of the combined treatment with cetuximab (Erbitux) and IMRT loco-regional irradiation. Secondary objectives are remission rates, 3-year-survival and local/systemic progression-free survival.

Influence of intra-fractional breathing movement in step-and-shoot IMRT.

Efforts have been made to extend the application of intensity-modulated radiotherapy to a variety of organs. One of the unanswered questions is whether breathing-induced organ motion may lead to a relevant over- or underdosage, e.g., in treatment plans for the irradiation of lung cancer. Theoretical considerations have been made concerning the different kinds of IMRT but there is still a lack of experimental data. We examined 18 points in a fraction of a clinical treatment plan of a NSCLC delivered in static IMRT with a new phantom and nine ionization chambers. Measurements were performed at a speed of 12 and 16 breathing cycles per minute. The dose differences between static points and moving target points ranged between -2.4% and +5.5% (mean: +0.2%, median: -0.1%) when moving with 12 cycles min(-1) and between -3.6% and +5.0% (mean: -0.4%, median: -0.6%) when moving with 16 cycles min(-1). All differences of measurements with and without movements were below 5%, with one exception. In conclusion, our results underline that at least in static IMRT breathing effects (concerning target dose coverage) due to interplay effects between collimator leaf movement and target movement are of secondary importance and will not reduce the clinical value of IMRT in the step-and-shoot technique for irradiation of thoracic targets.

[Late radiation changes after small volume radiosurgery of the rat brain. Measuring local cerebral blood flow and histopathological studies]. / Strahlenspätveränderungen nach kleinvolumiger radiochirurgischer Bestrahlung des Rattenhirns. Messung des lokalen zerebralen Blutflusses und histopathologische Untersuchungen.

BACKGROUND: The goal of this study was to investigate late effects following stereotactic single fraction and small volume irradiation on cerebral blood flow and histologic alterations in the rat brain parenchyma. MATERIAL AND METHODS: 66 Copenhagen rats, separated into eleven groups of six animals each received single doses of 20, 30, 40, 50 and 100 Gy using a 15 MV linear accelerator. Six rats served as controls. Two cylindrical collimators of 2 mm and 3 mm aperture were used. The diameters of the spherical 80% isodose were 3.7 and 4.7 mm, respectively (Table 1). Irradiation was applied to a predefined area in the right frontal lobe. 19 months after irradiation local cerebral blood flow (LCBF) was measured by the autoradiographic method in one animal of each dose group between 20 and 50 Gy. 9 and 19 months after irradiation, half of the animals of each group were sacrificed for brain histology. All animals irradiated with 100 Gy were sacrificed 7 months after irradiation. RESULTS: An increase of local cerebral blood flow was measured in brain structures within the 80% isodose in animals irradiated with 50 Gy (Figure 3) compared to the contralateral hemisphere. Measurements close to necrotic areas showed a strong decrease of local cerebral blood flow (Figure 1). A volume increase of the irradiated hemisphere was seen after 19 months (Figure 2). The histologic examination after 19 months showed necrotic areas in the 30-50 Gy groups (Figure 4b) but not in the 20 Gy groups (Figure 4c). The animals who received 100 Gy demonstrated brain necrosis within 9 months after irradiation (Figure 4a). At both points in time the groups irradiated with the 3-mm collimator showed more pronounced histomorphologic and functional changes compared to the groups irradiated with the 2-mm collimator. CONCLUSION: Alterations of the local cerebral blood flow were measured as a late effect after single dose irradiation. The alterations of the local cerebral blood flow could be explained by the histomorphologic changes of the blood vessels. Using a semi-quantitative classification a dose, time and volume dependence for the endpoint radionecrosis was seen.

Delayed vascular injury after single high-dose irradiation in the rat brain: histologic immunohistochemical, and angiographic studies.

PURPOSE: To investigate structural and functional changes in rats after focal brain irradiation by using histologic, immunohistochemical, and angiographic methods. MATERIALS AND METHODS: Sixty rats were irradiated stereotactically with photons from a 15-MeV linear accelerator. Two collimators and single doses ranging from 20 to 100 Gy were used to treat stereotactically defined areas of 3.7- and 4.7-mm cross section (80% isodose) in the right frontal lobe. The dose-response relationship for the end-point necrosis at 19 months revealed a mean tolerance dose (D50) of 34.2 Gy (standard errors: +4.1, -3.7 Gy). Histologic, immunohistochemical, and angiographic examinations were performed to evaluate delayed radiation effects. RESULTS: All animals irradiated with 100 Gy developed radiation necrosis after 9 months. Microangiography and immunohistochemical fluorescence staining of the endothelial cells revealed dose-dependent vascular dilatation and rarefaction. Animals irradiated with 20-50 Gy showed no morphologic changes after 9 months. With irradiation of 30-50 Gy, histologic vascular changes that increased with dose were found after 19 months. At that time, no changes were detected after irradiation with 20 Gy with both field sizes and after irradiation with 30 Gy and the 2-mm collimator. Radiation-induced functional disturbances of the brain vasculature could be demonstrated by extravasation of contrast medium by using a microangiographic technique. CONCLUSION: The observed effect had a definite dependence on dose, volume, and time after treatment.

[Hereditary Parkinson disease: report of 3 families with dominant autosomal inheritance]. / Hereditärer Morbus Parkinson: Bericht über drei Familien mit autosomal-dominantem Erbgang.

We have studied three families who ancestors immigrated to North America from contiguous regions of northern Germany and southern Denmark. The pedigrees contain 77,206 and 376 individuals spanning 6, 7 and 8 generations with 7,7 and 11 affected members, respectively. Autosomal dominant inheritance pattern is present in two families and probable in the third. Typical L-dopa-responsive parkinsonism with bradykinesia, rigidity, resting tremor, and impaired postural reflexes uniformly develop in affected individuals from all three families. Further research on these three families, including genetic, pathologic and clinical examinations is planned.

D-Amino acids of the amino acid pool and occurrence of racemase and D-amino acid oxidase activities in Escherichia coli B.

Less than 20% of the amino acid content of the amino acid pool of Escherichia coli B exists in the D-form. Alanine, glutamic acid, and valine were shown by gas- chromatography to be partially in the D-form. Only D-alanine was formed by racemization in the crude extract of this organism. Alanine racemase was easily released from the membranes or vesicles but D-alanine oxidase activity remained firmly bound to the membrane. Most protein amino acids stimulated proline uptake into the vesicles, and the oxidative deamination activities were verified by the proline uptake stimulating amino acids. It is concluded that the obligatory pathway of L-amino acid--D-amino acid--oxo acid which exists in the oxidation of L-alanine does not exist with other L-amino acids. It is likely that other D-amino acids in the pool are formed in the presence of D-amino acid oxidase or D-amino acid aminotransferase.

[Electroencephalographic findings and occurence of seizures after surgery of the Gasserian ganglion]. / EEG-Befunde und epileptische Anfälle nach Operationen am Ganglion Gasseri

The results of EEG investigations after Spiller-Frazier's operation for trigeminal neuralgia in 112 patients are reported. Follow-up EEGs were recorded within 1-8 years after surgery; two to three follow-up tracings were available in 53 patients. Two distinct phases of EEG alterations were noted: 1) The immediate postoperative phase characterized by bilateral delta waves of maximal distribution in the frontal-precentral area and in the temporal area on the side of surgery. Such alterations are supposedly due to postoperative edema or associated metabolic disturbances. 2) Several months after surgery focal abnormalities of the temporal lobe develop, which consist of high amplitude alpha-, beta- or theta-waves, sharp waves, spikes and occasional stypical spike-and-wave complexes. These abnormalities are reflected on the contralateral side in approximately one third of the case. Repeated EEGs confirmed the consistency of degree and location of these findings with the exception of a less constant incidence of spikes and sharp waves. Severity of EEG abnormalities and incidence of potentially epileptogenic discharges increases with age. In spite of the precarious location of such focal abnormalities in the temporal lobe only 3 of 112 patients (2.7%) reported seizures with temporal lobe features. The age of the three patients was below the average age of 59.1 years. Seizures occurred sporadically beginning approximately 2 years after surgery. The low incidence of seizures may in our opinion be due to the advanced age of most patients.