Increased CD133 expression in bone marrow of myelodysplastic syndromes.

Fresh frozen bone marrow biopsies were evaluated immunohistochemically, applying monoclonal antibodies against CD31, CD34, VEGFR-2 and CD133, a novel marker identifying human endothelial progenitor cells (EPCs). Specimens of 51 patients diagnosed with MDS were compared with 16 AML and 18 controls. The percentage of CD34 expressing cells was increased and CD31 expression was decreased in advanced stages of MDS compared with normal BM. VEGFR-2 expression was also raised in MDS. Here we show for the first time that increased numbers of CD133 positive cells are present in the majority of MDS patients. Additionally, those cells occasionally seem to contribute to capillary forming units in bone marrow.

The patient positioning concept for the planned MedAustron centre.

Especially for ion therapy, efficiency in form of patient throughput is becoming increasingly important, and here, patient positioning in treatment room isocenter is a key aspect. In order to ascertain high quality nonetheless, we suggest an alternative to the rigidly installed couch paradigm in form of real-time patient positioning onhand a ceiling mounted infrared photogrammetric system giving positioning information to a novel treatment couch with 6 degrees of freedom integrated on a rolling platform. All MedAustron treatment planning rooms and even the planning CT are not forseen to have a rigidly installed treatment couch.

The status of MedAustron.

This paper describes the status of the design study of the Austrian Ion Therapy and Cancer-Research Centre Project MedAustron. This work was performed during the last two years by the MedAustron study group. The team was spread out over several research institutes and University clinics, with full-time members at the Medical University of Vienna, Innsbruck Medical University and Fotec, Wiener Neustadt in collaboration with the Medical University Graz, the Hospital of Wiener Neustadt, the Vienna University of Technology and the research institutes CERN, PSI, the Slovak University of Technology in Bratislava and the Jozef Stefan Institute, Ljubljana. The study group has also worked in cooperation with GSI, Darmstadt and the CNAO foundation, Milan. The agreed aim of this study was to investigate a conceptual design of an accelerator facility which provides optimum treatment conditions for high-precision active beam scanning of cancer tumours with both proton and carbon ions.

A simple and non-invasive vacuum mouthpiece-based head fixation system for high precision radiotherapy.

PURPOSE: To demonstrate why conventional non-invasive mouthpiece-based fixation has not achieved the expected accuracy and to suggest a solution of the problem. PATIENTS AND METHODS: The Vogele Bale Hohner (VBH) head holder is a non-invasive vacuum mouthpiece-based head fixation system. Feasibility and repositioning accuracy were evaluated by portal image analysis in 12 patients with cranial tumors intended for stereotactic procedures, fixated with the newest version (VBH HeadFix-ARC). RESULTS: Portal image analysis (8 patients evaluated in 2-D, 4 patients in 3-D) showed that even in routine external beam radiation therapy, treatment can be applied to within a mean 2-D and 3-D accuracy of under 2 mm (SD 0.92 mm and 1.2 mm, respectively) with cost and repositioning time per patient and patient comfort comparable to that of common thermoplastic masks. CONCLUSION: These preliminary results show that high repositioning accuracy does not rule out simple and quick application and patient comfort. Paramount, however, is tensionless repositioning via the vacuum mouthpiece.

Head and neck tumors: fractionated frameless stereotactic interstitial brachytherapy-initial experience.

The authors used a frameless stereotactic navigation system, the Vogele-Bale-Hohner head holder, and a targeting device to reproducibly position brachytherapy needles for fractionated interstitial brachytherapy in 12 patients with inoperable cancers of the head and neck. In all cases, deviations of the needle relative to the planned position were within 1-15 mm depending on the location of the tumor.

Oxygen tension in transplanted mouse osteosarcomas during fractionated high-LET- and low-LET radiotherapy--predictive aspects for choosing beam quality?

PURPOSE: The lower OER of high-LET radiations, compared to conventional (low-LET) radiations, has often been put forward as an argument for using high-LET radiotherapy in the management of hypoxic tumours. Among the different neutron beams used in therapy, the reactor fission neutrons have the lowest OER. The aim of the present study is to follow the variations of tumour oxygenation status during fractionated irradiation with different radiation qualities. Little information is available so far after fractionated high-LET irradiation. In addition, the RBE of reactor fission neutrons for effects on tumours and on normal tissues are compared. MATERIAL AND METHODS: Murine OTS 64-osteosarcomas were transplanted in 102 balb-C mice and irradiated by 36 Gy of photons in fractions of 3 Gy five times a week (group P-36/3) or by 12 Gy of reactor fission neutrons in fractions of 2 Gy two times a week (group N-12/2). Irradiations started at a tumor volume of 500 to 600 mm3. A third group received no radiotherapy, but all investigations (group CG). Tumor volume and tumor oxygenation were measured once a week under therapy and during three weeks after therapy. For in vivo-evaluation of oxygen status a computerized polarographic needle electrode system (KIMOC pO2 histograph, Eppendorf) was used. The median pO2 and the hypoxic fraction (pO2 values < 5 mm Hg) of single tumors and of total groups were calculated from pooled histograms and from row data as well. RESULTS: In correlation with the increase of tumor volume, from day 1 to day 42 of follow-up the median pO2 decreased from 20 mm to 8 mm Hg and the hypoxic fraction increased from 7% to 31%. After fractionated photon therapy a growth delay of three weeks was observed. Six weeks after beginning of the irradiation the median tumor volume had been doubled again. After fission neutron therapy growth delay continued until the end of the follow-up period. In both of the irradiated groups a significant decrease of median pO2 values and an increase of the hypoxic fraction were observed under radiotherapy. Hypoxia was more intensive after neutrons with a decrease of the median pO2 from 20 mm Hg to 1 mm Hg vs. 10 mm Hg after photon therapy and with an increase of the hypoxic fraction from 7% to 78% vs. 36% respectively. Two weeks after the end of therapy the median pO2 and the hypoxic fraction of both treated groups reached the levels prior to irradiation indicating a complete reoxygenation. CONCLUSION: During fractionated irradiation of murine osteosarcomas with photons and reactor fission neutrons, a marked hypoxia was observed for both radiation qualities, but hypoxia was more intense during fractionated neutron irradiation. After irradiation, a complete reoxygenation occurred in both groups independently of the degree of hypoxia observed during the treatment. The RBE of reactor fission neutrons, after fractionated irradiation, was much higher for effects on murine osteosarcomas compared to their RBE observed for normal tissues in previous experiments. Present data are in agreement with our clinical observations on more than 300 patients treated with reactor fission neutrons for advanced and hypoxic tumours with various histologies.

New drugs for BNCT: an experimental approach.

New kinds of boron-containing drugs were developed and tested in several murine tumor models. The boron-containing ether lipid B-Et-11-OMe was injected in mammary carcinoma (AT17) and osteosarcoma (OTS-64) bearing mice. Furthermore boron-substituted ferrocenium derivatives were tested. Two were excessively toxic; the third could be investigated. Boron accumulation and time-dependent biodistribution were determined using alpha-particle sensitive films and inductively coupled plasma-atomic emission pectrometry (ICP-AES) and -mass spectrometry (ICP-MS) of tumors, organs and tissues. Additionally, a new method of boron detection by NMR is in preparation.

A challenge for high-precision radiation therapy: the case for hadrons.

Developments in Hadron therapy, i.e., fast neutrons, protons, pions, heavy ions and boron neutron capture therapy are reviewed. For each type of particle, operational and closed facilities are listed as well as planned new facilities. Improvements in clinical results have always been linked to technological developments and better physical selectivity of the irradiation. Exploring the benefit of further improvement in dose localization expected from protons and conformal therapy is the challenge for the coming years. The radiobiological rationale for high-LET radiation in cancer treatment, proposed in the fifties, is still valid and has not been contradicted by recent radiobiological findings. This justifies the planning of a therapy facility where protons and heavy ions (carbon ions) could be applied, under optimal physical and technical conditions. Appropriate selection between low- and high-LET radiation for a particular tumor is indeed a radiobiological problem, independent of technical development.

Palliative radiotherapy of malignant melanoma with reactor fission neutron therapy (RENT): a prospective study.

To study the efficacy and safety of relatively low-dosed reactor fission neutron therapy (RENT) at the research reactor of the Technical University Munich, we treated 33 superficial lesions of 20 patients with advanced malignant melanoma by neutron beam alone (n = 22), mixed neutron/electron beam (n = 5), or by neutron beam after incomplete surgery (n = 6). Median tumor volume was 17.0 cm3. Median dose for neutron beam alone was 8.0 Gy and for mixed beam 3.0 Gy n + 45.3 Gy e-. Local tumor response, local control time, survival and treatment related toxicity were followed prospectively over a time period of 52 months. Overall response rate (CR;PR) after neutron beam alone and mixed beam therapy was 64% (CR: 36%) and 100% (CR: 60%), respectively. Observed differences between complete (CR) and incomplete (PR, NC) responding lesions were as follows: median tumor volume: 2.0 vs. 51.5 cm3, local control time: 13.3 vs. 3.7 months, median survival: 19.8 vs. 9.0 months. No severe acute or late sequelae could be observed. In conclusion, low-dosed RENT is an effective and well tolerated palliative treatment of superficial malignant melanoma utilizing the biologic advantage of diminished cellular repair capacity. Because melanoma lesions of small size (< or = 6 cm3) tend to respond completely, neutron beam should be performed at an early stage.

[First experiences with computer-assisted frameless stereotactic interstitial brachytherapy (CASIB)]. / Erste Erfahrungen mit computerunterstützter stereotaktischer interstitieller Brachytherapie.

PURPOSE: To reach an optimal treatment result and to avoid damage to critical structures a homogeneous dose distribution in the tumor volume with a rapid decreasing dose to the surrounding structures is necessary. Fractionated interstitial brachytherapy of tumors in the ENT region employing needles depends on exact localization of the target volume during all fractions. Therefore reproducibility of positioning of the needle(s) plays an important role. MATERIAL AND METHODS: We used the ISG Viewing Wand system in combination with the Vogele-Bale-Hohner (VBH) head holder and a new targeting device. Point of entrance, pathway, and target point of the needle were planned and insertion of the needle simulated in advance. To date we have treated 7 patients with inoperable tumors in the ENT region. The actual position of the needle in the control CT was compared to the planned position. RESULTS: The accuracy of positioning of the needle depended on the location of the tumor. In a patient with a recurrent retroorbital adenocarcinoma the mean accuracy was 1 mm. Due to soft tissue displacement in the neck region and the resulting necessity to readjust the targeting device the needle was placed with a mean deviation of 15 mm between the planned and the actual position. CONCLUSIONS: Computer-assisted frameless stereotactic interstitial brachytherapy allows for precise, reproducible and preplanned insertion of hollow needles into target structures closely adherent to the surrounding tissue, thus avoiding damage of neighbouring structures. This technique is of great advantage in treating deeply seated tumors which are fixed to bony structures, especially at the skull base. Inaccuracy in the neck region caused by soft tissue shift requires improvement of the immobilization in this region.

European results of neutron therapy in soft tissue sarcomas.

The purpose of this publication is to review the data of European neutron therapy facilities in the treatment of soft tissue sarcoma. In the past locally advanced soft tissue sarcoma was a common indication for neutron therapy in several European centers. Data from 1171 patients treated at 11 centers were analysed on the basis of published data or personal communication. Neutron therapy was of benefit especially for patients with primary radiotherapy of inoperable tumors, and with macroscopic disease after surgery. Local control was about 50% in these patients. These results are superior to those from photon therapy from the literature. Results for postoperative neutron therapy after R0- and R1-resection are similar to those from photon therapy. The incidence of late side effects was considerably high in some neutron series. This is influenced by the treatment of most patients with first-generation machines of limited technical standard, and that in most cases large treatment volumes were irradiated.

Neutron therapy in malignant salivary gland tumors: results at European centers.

Malignant salivary gland tumors are relatively rare and account for only 3%-4% of all head and neck cancers. Especially in adenoid cystic carcinoma, the incidence of local recurrence and distant metastases is influenced by the perineural spread of tumor. In advanced salivary gland tumors, surgery alone has a high incidence of local failure. The results of conventional radiotherapy are suboptimal in inoperable or not completely resected salivary gland tumors and in recurrent disease. The pooled data of some international series for low linear energy transfer radiation show a local control of only 28%. Especially in advanced salivary gland tumors, neutron therapy can improve local control. In Europe at least 570 patients with salivary gland tumors have been treated with neutrons alone or with combined modalities. The clinical data of different centers in Europe and the United States result in a similar local control rate of 67% in gross disease. An analysis of different European series shows on average a complication rate of 10.6% for severe radiation-related morbidity. Modern neutron machines and the use of three-dimensional treatment planning systems are now available in a few institutions and may further reduce side effects.

The role of fast neutrons in the treatment of squamous cell carcinomas of the head and neck: The European experience.

After the first European stet on neutron therapy of head and neck cancer, published by Catterall and Bewley, revealed significant advantages of neutrons over photons in 134 randomized patients, the subsequent phase II and phase III studies led to controversial results. Figures for local tumor control varied from 26-76% after 2 years to 19% after 10 years and for survival from 16-46% after 2 years to 14% after 10 years. Results of all studies were consistent with showing an increased incidence of severe late effects. Eligibility criteria with regard to the tumor stage, history, and previous therapies of relapses varied from study to study. Also, physical treatment parameters, such as neutron energy, LET and OER, neutron and photon doses for one fraction and for the total radiotherapy were rather different. The benefit of neutron therapy in comparison with photons was low or non-existent when smaller tumor stages, such as primaries T2 or lymph nodes N1 were included into the trial. It increased when only T4 tumors, recurrences or tumors persisting after conventional radiotherapy were treated and when the percentage of fixed lymph nodes increased. There was only one European study in which patients suffering form lymph node metastases of the neck had, in contrast to American data (Griffin et al. 1978), a worse prognosis after neutrons than after photon therapy (Duncan et al. 1987b). In our own phase II study on reactor neutron therapy of 100 patients suffering from relapses and persistent tumors, not yet published, 3-year survival of 21% and 3-year local control of 32% were obtained. Although this was not a randomized study, during this period all patients with equivalent tumors treated by photon therapy alone died within 2 years. In conclusion there is no general indication for neutron therapy in squamous cell carcinoma of the head and neck, but there is a benefit of neutrons in palliative treatment of recurrences, necrotic and hypoxic primaries and lymph nodes.

Chlorine and sodium perfusion and electrolyte balance in human tissue and tumours before and during neutron and photon radiotherapy.

Radiotherapy with nuclear reactor fission neutrons was applied in 49 cases of pretreated patients with superficial metastases or relapses from primary carcinoma. Measurements of the decay rates of the radiation-induced radioactivity of 49Ca, 38Cl and 24Na in the irradiated tissue resulted in values for the simultaneous local kinetics of chlorine and sodium, and in approximate data on the electrolyte masses. The electrolytes were present in non-exchangeable and exchangeable compartments of soft tissue. Exchange times of the intravascular to extravascular turnover and the frequencies of the exchange fractions were determined for a series of irradiations. The results have been interpreted in terms of the mean electrolyte exchange rates, of a standardized functional blood flow, and of the supply capacity of the vascular system. In the average of all cases, the regional perfusion was reduced by about 30% by irradiation up to 14 Gy (equivalent photon dose = 45 Gy) connected with an increase in the non-exchangeable fractions. After fractionated doses higher than 14 Gy, functional blood flow and supply capacity increased to 120%, and fixed electrolytes were removed from the irradiated tissue. Data on electrolyte kinetics and vascularity are compared with the literature.

Oxygen tensions in rodent tumors after irradiation with neutrons.

We started investigations on intratumoral oxygen tension after irradiations with reactor fission neutrons using the Eppendorf-pO2 Histograph. Isotransplanted AT17-mammary carcinomas on C3H-mice and osteosarcomas OTS-64 on balb C-mice received 2 or 6 Gy neutrons single dose. Before and at certain points of time after treatment the pO2 values were evaluated. Some tumors with initially low median pO2 values showed a short-lasting increase between 2 and 24 h after irradiation. In those tumors with relatively high pretherapeutic pO2 values the pO2 decreased to the range of hypoxia. A third group of tumors showed no marked changes after irradiation. No tumor stopped growth during the observation period.