Impact of SBRT fractionation in hypoxia dose painting - Accounting for heterogeneous and dynamic tumor oxygenation

Purpose Tumor hypoxia, often found in nonsmall cell lung cancer (NSCLC), implies an increased resistance to radiotherapy. Pretreatment assessment of tumor oxygenation is, therefore, warranted in these patients, as functional imaging of hypoxia could be used as a basis for dose painting. This study aimed at investigating the feasibility of using a method for calculating the dose required in hypoxic subvolumes segmented on F-18-HX4 positron emission tomography (PET) imaging of NSCLC. Methods Positron emission tomography imaging data based on the hypoxia tracer F-18-HX4 of 19 NSCLC patients were included in the study. Normalized tracer uptake was converted to oxygen partial pressure (pO(2)) and hypoxic target volumes (HTVs) were segmented using a threshold of 10 mmHg. Uniform doses required to overcome the hypoxic resistance in the target volumes were calculated based on a previously proposed method taking into account the effect of interfraction reoxygenation, for fractionation schedules ranging from extremely hypofractionated stereotactic body radiotherapy (SBRT) to conventionally fractionated radiotherapy. Results Gross target volumes ranged between 6.2 and 859.6 cm(3), and the hypoxic fraction <10 mmHg between 1.2% and 72.4%. The calculated doses for overcoming the resistance of cells in the HTVs were comparable to those currently prescribed in clinical practice as well as those previously tested in feasibility studies on dose escalation in NSCLC. Depending on the size of the HTV and the distribution of pO(2), HTV doses were calculated as 43.6-48.4 Gy for a three-fraction schedule, 51.7-57.6 Gy for five fractions, and 59.5-66.4 Gy for eight fractions. For patients in whom the HTV pO(2) distribution was more favorable, a lower dose was required despite a bigger volume. Tumor control probability was lower for single-fraction schedules, while higher levels of tumor control probability were found for schedules employing several fractions. Conclusions The method to account for heterogeneous and dynamic hypoxia in target volume segmentation and dose prescription based on F-18-HX4-PET imaging appears feasible in NSCLC patients. The distribution of oxygen partial pressure within HTV could impact the required prescribed dose more than the size of the volume

Intratumoural and peripheral blood lymphocyte subsets in patients with metastatic renal cell carcinoma undergoing interleukin-2 based immunotherapy: association to objective response and survival

The aim of the present study was to analyse lymphocyte subsets in consecutive peripheral blood samples and consecutive tumour tissue core needle biopsies performed before and during interleukin-2 based immunotherapy, and to correlate the findings with objective response and survival. Twenty-six patients with metastatic renal cell carcinoma were treated with low dose s.c. interleukin-2, interferon-α and histamine. A total of 250 blood samples and 62 core needle biopsies from 23 and 19 of these patients, respectively, were analysed. After 2 weeks of treatment, a significant positive correlation between absolute number of peripheral blood lymphocytes (P=0.028), CD3 (P=0.017), CD57 (P=0.041) and objective response was demonstrated. There was no correlation between any peripheral blood leukocyte subsets and survival. Cytotoxicity of peripheral blood mononuclear cells was not correlated to objective response or survival. Within the tumour tissue at baseline, a significant positive correlation between CD4 (P=0.027), CD8 (P=0.028), CD57 (P=0.007) and objective response was demonstrated. After one month of immunotherapy, a significant positive correlation between intratumoral CD3 (P=0.026), CD8 (P=0.015), CD57 (P=0.009) and objective response was demonstrated. A significant positive correlation between intratumoral baseline CD4 (P=0.047), baseline CD57 (P=0.035), CD3 at one month (P=0.049) and survival was demonstrated. These data provide novel in vivo evidence of the possible contribution of lymphocyte subsets in the tumour reduction in responding patients during interleukin-2 based immunotherapy. Confirmation of the results requires further studies including a larger number of patients

Bmp4 Is Essential for the Formation of the Vestibular Apparatus that Detects Angular Head Movements

Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-β), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 (Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification

A systematic overview of radiation therapy effects in skeletal metastases

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for skeletal metastases is based on data from 16 randomized trials. Moreover, data from 20 prospective studies, 5 retrospective studies and 22 other articles were used. A total of 63 scientific articles are included, involving 8051 patients. The results were compared with those of a similar overview from 1996 including 13054 patients. The conclusions reached can be summarized as follows: Irradiation of skeletal metastases is, with few exceptions, a palliative treatment. There is strong evidence that radiotherapy of skeletal metastases gives an overall (complete and partial pain relief) in more than 80% of patients. There is strong evidence that the duration of pain relief in at least 50% of patients lasts for greater than or equal to6 months. There is convincing evidence that pain relief, in terms of degree and duration, does not depend on the fractionation schedules applied. Irrespective of the fractionation schedule used at irradiation, the number of later complications, such as spinal cord compression or pathological fractures, at the index fields are low. There are some data showing that the difference in cost between single and multifraction treatment is small. However, these data do not permit any firm conclusions to be drawn. Several reports indicate that early diagnosis and early therapy of spinal cord compression are the two most important predictors of a favourable clinical outcome after radiotherapy. However, no controlled studies have been undertaken. When the diagnosis of spinal cord compression is late, a favourable outcome might depend on the radio-responsiveness of the tumour. The documentation is weak and no conclusions can be drawn. There is some evidence that a small proportion of totally paralytic patients can regain walking function after radiotherapy. There is strong evidence that the radionuclides Sr-89 and Sm-153 are efficient when they are used as a systemic treatment of generalized bone pain due to metastasis from carcinomas of the prostate and breast. Overall bone pain relief occurs in about 60-80% of patients with a median response duration of 2-4 months. There is strong evidence that intravenous treatment with bisphosphonates in patients with myeloma and osteolytic bone metastasis due to carcinoma of the breast significantly decreases the number of skeleton-related events and bone pain