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Biomedical subjects

F Lohr

Publications and source records attributed to F Lohr.

At least 37 records · Page 2Linked to original sources

Conformal three-dimensional photon radiotherapy for paranasal sinus tumors.

BACKGROUND: Tumors in the nasal cavity and paranasal sinus are difficult to treat with radiotherapy. Usually, in addition to a two- or three-field photon technique, an interorbital electron field is required. This may result, however, in severe over- or underdosage, the latter being especially detrimental when occurring in the main tumor bulk. METHODS AND RESULTS: We present a conformal three-dimensional treatment technique that provides sufficient interorbital dose with photons only while sparing the eyes, optic nerves and chiasm, and may be considered for selected tumors in this region.

Dose-Response Relationship, Radiation↗

Fractionated stereotactic conformal radiation therapy of brain stem gliomas: outcome and prognostic factors.

BACKGROUND AND PURPOSE: Evaluation of outcome and prognostic factors in patients with brain stem glioma (BSG) following fractionated stereotactic radiotherapy (FSRT). MATERIALS AND METHODS: Between 1990 and 1997, we treated 41 patients with FSRT in a phase I/II trial. Median age was 24 years. Out of 36 patients with histologically proven glioma, ten had a partial tumour resection. Histology revealed low grade gliomas in 30 patients and anaplastic gliomas in six patients. A mean total dose of 54 Gy was given in daily fractions of 1.8 Gy. Median follow-up was 12 months. RESULTS: Three patients died during FSRT. Neurological improvement was achieved in 19/38 patients. Reduction of tumour size was reported in 12/38, in 16 patients the lesion was unchanged, ten showed progression. Median time to progression was 23 months, median overall survival 40 months with an actuarial survival of 83% at 1 year, 55% at 3 years and 33% at 5 years. In 20 of 22 patients with recurrence progression was inside the target volume. Significant prognostic factors for survival were clinical and radiological response 6 weeks after FSRT. Treatment toxicity was mild. Ototoxicity occurred in one patient. CONCLUSIONS: FSRT is a feasible treatment modality for BSG with tolerable toxicity. The risk of marginal failure is low.

Adolescent↗

Noninvasive patient fixation for extracranial stereotactic radiotherapy.

PURPOSE: To evaluate the setup accuracy that can be achieved with a novel noninvasive patient fixation technique based on a body cast attached to a recently developed stereotactic body frame during fractionated extracranial stereotactic radiotherapy. METHODS AND MATERIALS: Thirty-one CT studies (> or = 20 slices, thickness: 3 mm) from 5 patients who were immobilized in a body cast attached to a stereotactic body frame for treatment of paramedullary tumors in the thoracic or lumbar spine were evaluated with respect to setup accuracy. The immobilization device consisted of a custom-made wrap-around body cast that extended from the neck to the thighs and a separate head mask, both made from Scotchcast. Each CT study was performed immediately before or after every second or third actual treatment fraction without repositioning the patient between CT and treatment. The stereotactic localization system was mounted and the isocenter as initially located stereotactically was marked with fiducials for each CT study. Deviation of the treated isocenter as compared to the planned position was measured in all three dimensions. RESULTS: The immobilization device can be easily handled, attached to and removed from the stereotactic frame and thus enables treatment of multiple patients with the same stereotactic frame each day. Mean patient movements of 1.6 mm+/-1.2 mm (laterolateral [LL]), 1.4 mm+/-1.0 mm (anterior-posterior [AP]), 2.3 mm+/-1.3 mm (transversal vectorial error [VE]) and < slice thickness = 3 mm (craniocaudal [CC]) were recorded for the targets in the thoracic spine and 1.4 mm+/-1.0 mm (LL), 1.2 mm+/-0.7 mm (AP), 1.8 mm+/-1.2 mm (VE), and < 3 mm (CC) for the lumbar spine. The worst case deviation was 3.9 mm for the first patient with the target in the thoracic spine (in the LL direction). Combining those numbers (mean transversal VE for both locations and maximum CC error of 3 mm), the mean three-dimensional vectorial patient movement and thus the mean overall accuracy can be safely estimated to be < or = 3.6 mm. CONCLUSION: The presented combination of a body cast and head mask system in a rigid stereotactic body frame ensures reliable noninvasive patient fixation for fractionated extracranial stereotactic radiotherapy and may enable dose escalation for less radioresponsive tumors that are near the spinal cord or otherwise critically located while minimizing the risk of late sequelae.

Casts, Surgical↗

Acute central nervous system (CNS) toxicity of total body irradiation (TBI) measured using neuropsychological testing of attention functions.

PURPOSE: The purpose of this study was to investigate acute normal tissue damage of low irradiation doses to the healthy, adult central nervous system (CNS) using neuropsychological testing of attention functions. METHODS AND MATERIALS: Neuropsychological testing (IQ, attention [modified Trail-Making Test A, Digit Symbol Test, D2 Test, Wiener Determination Machine]) was used to examine 40 patients (43 +/- 10 years) before and immediately after the first fraction (1.2 Gy) of hyperfractionated total body irradiation (TBI) at the University of Heidelberg. The patients received antiemetic premedication. Test results are given as mean percentiles +/- standard deviation, with 50 +/- 34 being normal. Thirty-eight control patients (53 +/- 15 years) were studied to quantify the influence of hospitalization, stress, and repeated testing. RESULTS: The patients showed normal baseline test results (IQ = 101 +/- 14, attention = 54 +/- 28) and no decrease in test results after 1.2 Gy TBI. Attention functions improved (66 +/- 25) corresponding to a practice effect of repeated testing that was seen in the control group, although alternate versions of the tests were used (IQ = 104 +/- 10, attention before = 42 +/- 29, attention after = 52 +/- 31). CONCLUSION: Our data show no deterioration of neuropsychologic test results acutely after 1.2 Gy whole body exposure in adult patients without CNS disease receiving antiemetic medication.

Adult↗

Assessment of neuropsychological changes in patients with arteriovenous malformation (AVM) after radiosurgery.

PURPOSE: The purpose of this study was to investigate neuropsychological effects of radiosurgery in patients with cerebral arteriovenous malformation (AVM), with special focus on attention and memory. This report describes the study setup and presents the first results during a follow-up of up to 1 year. MATERIALS AND METHODS: Seventy-nine patients were studied before, acutely after radiosurgery, and during the regular follow-up (subacute phase: Weeks 6-12, chronic phase: Months 6-12). Radiosurgery was performed using a modified linear accelerator (minimum doses to the target volume: 15-22 Gy, median 20 Gy). Estimated whole brain dose was 0.5 to 2 Gy. Neuropsychological testing included assessment of general intelligence (Wechsler Adult Intelligence Scale), attention (modified Trail-Making Test A, Digit Symbol Test, D2 Test, Wiener Determination Machine) and memory (Rey Auditory Verbal Learning Test, Benton Visual Retention Test). During follow-up, alternate test versions were used. Neuropsychological deficits were defined as a test score of at least one standard deviation (SD) below the mean of the normal distribution. RESULTS: The pretherapeutic evaluation revealed marked deviations from the normal population; 24% had deficits in intelligence (range 23-31% in different subtests), attention (35%, 23-59%) and memory (48%, 31-61%). The overall percentage of aberrant results was reduced by 12% (memory) to 14% (attention) in the chronic phase up to 12 months after therapy. The improvement in test scores was significant (p < 0.05) in 3 of 4 subtests of attention functions. CONCLUSIONS: The acute tolerance of radiosurgery seems to be very good in these patients, showing no relevant increase in number of patients with neuropsychological deficits. Although the long-term follow-up needs to be further increased, our data indicate a tendency to slight improvement in the overall neuropsychological performance of AVM patients in the chronic phase after radiosurgery.

Adult↗

X-ray induced changes in immunostaining of proliferating cell nuclear antigen (PCNA) in V79 hamster fibroblasts.

BACKGROUND: Proliferating cell nuclear antigen (PCNA) ist a 36 kD protein that is involved in DNA-replication and -repair. For V79 hamster cells, a mutated p53 and a so-called "adaptive response", an improved radiation tolerance after pre-irradiation with low X-ray doses hours before definitive irradiation with higher doses have been reported. To better understand the role of PCNA after photon irradiation in vivo, using flow cytometry, we studied the immunochemical PCNA-staining in V79 cells after irradiation with 6-MeV photons with and without serum depletion and with and without low-dose pre-irradiation under different growth conditions. MATERIAL AND METHODS: Using V79 hamster cells, BrdUrd incorporation, total and DNA-bound PCNA were measured for exponential cells and for confluent cells at different times (up to 14 days) after reaching confluence. Cells were either grown with medium containing 10% fetal calf serum (FCS) or 0.5% FCS. Six days after reaching confluence, cells were irradiated with 1 Gy (and 8 Gy for non-serum-depleted cells) (6-MV photons, 2 Gy/min). Then, immunochemical PCNA-staining was measured by flow cytometry at 0, 30, 60 and 120 min after irradiation. For studying the adaptive response, exponentially growing cells and cells that were 6 days in confluence were pretreated with 0.01 Gy, reincubated for 5 h and then definitively treated with 1 Gy and harvested and processed as described above. RESULTS: Four days after reaching confluence, DNA-bound PCNA and BrdUrd content were reduced to a minimum of < 15% positive cells while total PCNA remained essentially unchanged. After irradiation with 1 Gy 6 days after reaching confluence, cells grown with 10% FCS showed a moderate but distinct transient increase in DNA-bound PCNA at 30 min after irradiation. After irradiation with 8 Gy, there was no clear increase at 30 min but a more distinct decrease at 60 min, implying that the increase might occur earlier in the time course at higher doses. Total cellular PCNA and BrdUrd uptake were constant during the first 2 hours after irradiation. In cells that were kept with serum depleted medium for 6 days after reaching confluence, total PCNA was reduced and no changes in either DNA-bound PCNA or BrdUrd-uptake were observed after irradiation. When cells were primed with a dose of 0.01 Gy 5 h before subsequent treatment with 1 Gy, neither for exponentially growing cells nor for those in confluence a significant difference in the detected amount of PCNA (total and DNA-bound) or BrdUrd was observed when compared to cells treated without a priming dose. CONCLUSIONS: The moderate X-ray induced DNA association of PCNA is indicative for ongoing DNA repair but appears to require serum stimuli. However, this p53-independent pathway involving PCNA does not seem to be the most relevant for survival in these rodent cells that tolerate much residual damage. Furthermore, no adaptive response for DNA-association of PCNA could be detected in V79 cells.

Animals↗

Lethal pulmonary toxicity after autologous bone marrow transplantation/peripheral blood stem cell transplantation for hematological malignancies.

BACKGROUND AND PURPOSE: Retrospective evaluation of the incidence of lethal pulmonary complications (LPC) with special emphasis on interstitial pneumonia (IP) in a large group of patients homogeneously treated with hyperfractionated total body irradiation (HTBI) before autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PBSCT) for hematological malignancy. The factors influencing IP are discussed. MATERIALS AND METHODS: Of 260 patients (maximum follow-up 137 months) that were treated with ABMT or PBSCT for hematological neoplasms between 1982 and 1994, 209 patients received HTBI and could be evaluated with respect to lethal pulmonary complications and especially lethal interstitial pneumonia. For most patients (n = 155), the HTBI dose was 14.4 Gy (lung dose 9-9.5 Gy) given in 12 fractions over 4 days. Twenty-one patients received a total dose of > or =15 Gy with pulmonary doses of 9-10.5 Gy. RESULTS: The actuarial overall 5-year survival for all 209 patients evaluated was 44 +/- 4%, enabling valid evaluation with respect to lethal pulmonary toxicity. The actuarial incidence of all LPC during the first year was calculated as being 8 +/- 2%. The actuarial incidence of lethal IP is certainly lower and was estimated to be between 3 and 5% for all patients. The overall treatment-related mortality was 12% in 188 patients that received a total dose of <15 Gy and 24% among the patients treated with a total dose of > or =15 Gy. CONCLUSION: ABMT/PBSCT, like other transplant modalities without significant graft versus host disease (GvHD), has a low transplant-related mortality, a very small rate of overall LPC and a low incidence of lethal IP after HTBI. Doses up to 14.4 Gy with lung doses of 9-9.5 Gy can be administered safely. For total doses of > or =15 Gy with lung doses of 9-10.5 Gy, the risk of serious transplant-related complications cannot yet be finally assessed but such higher doses should be considered with caution because of the possibility of increasing toxicity in organs other than the lung.

Adolescent↗

Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases.

PURPOSE: Evaluation of the treatment outcome after radiosurgery (RS) alone or in combination with whole-brain radiotherapy (WBRT) with special attention to prescribed dose and its influence on local control and survival. PATIENTS AND METHODS: Between September 1984 and January 1997, 236 patients with 311 brain metastases treated with radiosurgery met the following inclusion criteria: one to three brain metastases per patient; no previous WBRT; and Kamofsky performance status (KPS) > or = 50%. One hundred fifty-eight patients treated only with RS received a median dose of 20 Gy prescribed to the 80% isodose line; 78 patients received RS with a median dose of 15 Gy/80% and an additional course of WBRT. RESULTS: For the entire series, overall median survival was 5.5 months, with control of CNS disease achieved in 92% of the treated brain metastases; the results were not significantly different between patients treated by RS with or without WBRT. However, in patients without evidence of extracranial disease, median survival was increased for patients who received WBRT (15.4 vs 8.3 months; P=.08). Additionally, there was a suggestion that increased doses for patients treated with RS only resulted in improved outcome. Four lesions were suspicious for radiation necrosis by magnetic resonance imaging (MRI); in one of the four lesions, radiation necrosis was confirmed histologically. The incidence of transient low-grade toxicity was 18%; symptoms could be treated by the temporary administration of steroids. CONCLUSION: RS is an effective, noninvasive means of controlling brain metastases when used alone or in combination with WBRT. There is a trend for superior local control and especially in patients without extracranial disease for superior survival when RS is used in conjunction with WBRT. Randomized trials would seem to be warranted, comparing the benefit of RS with or without additional WBRT.

Brain Neoplasms↗

Differential sensitivity of three sublines of the rat Dunning prostate tumor system R3327 to radiation and/or local tumor hyperthermia.

To better understand the relationship of the growth characteristics of tumor tissues and their response to ionizing radiation alone and in combination with local tumor hyperthermia, we compared three different tumor sublines of the Dunning rat prostate carcinoma R3327. This report includes results obtained with the anaplastic AT1 subline (volume doubling time 5.2 days), the moderately differentiated mucin-secreting HI subline (volume doubling time about 9 days) and the well-differentiated, hormone-dependent H subline (volume doubling time about 17 days). The effects of single doses of photons (10 to 40 Gy) with and without local tumor hyperthermia (35 min immersion at 43.5 degrees C) were quantified by growth delay. The time to reach five times the volume at the time of treatment after 30 Gy alone was found to be 56.0, 134.9 and 184.0 days for the R3327-AT1, HI and H tumors, respectively. The R3327-H tumor was more radiosensitive than the AT1 or HI subline. Five of nine R3327-H tumors were controlled locally with a single dose of photons (40 Gy). Local tumor hyperthermia alone induced growth delay in both differentiated tumors, while the anaplastic tumor subline did not respond. Combined treatment modalities with heat applied directly after irradiation revealed isoeffective thermal enhancement ratios for 30 Gy which decreased from 1.59 for the AT1 tumor and 1.42 for the HI tumor to 1.23 in the well-differentiated subline R3327-H.

Animals↗

Predictive value of the flow cytometric PCNA assay (proliferating cell nuclear antigen) in head and neck tumors after accelerated-hyperfractionated radiochemotherapy.

PURPOSE: Proliferation of tumor cells during radiotherapy may limit tumor control, especially in rapidly proliferating tumors such as head and neck carcinomas. We present a flow cytometric method for detection of PCNA in solid head and neck tumors and how these data correlate with outcome. METHODS AND MATERIALS: Pretherapeutic biopsies of 20 inoperable patients with Stage IV squamous cell carcinoma were examined. Biparametric flow cytometry was done after anti-PCNA (PC10) and propidium iodine staining were performed. PCNA index (percentage PCNA positive cells), DNA index, and S phase fraction (SPF, euploid tumors only) were determined. The therapy consisted of an accelerated-hyperfractionated radiochemotherapy (66 Gy/5 weeks, concomitant boost of 1.6 Gy/day in weeks 4+5, Carboplatin 5 x 70 mg/m2 in weeks 1+5). The median follow-up time was 30 months. RESULTS: Fourteen patients suffered from disease progession and 12 died. Median actuarial, cause-specific survival, and disease-free survival (DFS) times were 17 and 9 months, respectively. PCNA indices ranged from 4 to 70% (median 9%); there were 7 aneuploid and 13 euploid tumors. SPF ranged from 4 to 14.5% (median 10.5%). Neither SPF nor ploidy had a significant influence on outcome. Patients were divided according to PCNA index in higher (n = 10) and lower (n = 10) than the median. Survival and DFS were 13 and 6 months for the group >9% and 20 and 15 months for the group <9%. The difference in DFS was significant (p = 0.03, log rank test). CONCLUSION: These results fall in line with other studies showing the influence of pretherapeutic proliferation on outcome after radiotherapy. Although the moderately accelerated therapy regimen certainly reduces the influence of proliferation on outcome, patients with faster proliferating tumors still have a worse outcome. DFS is the more relevant endpoint in this study because of effective salvage therapies, which influence survival.

Adult↗

Simulation of 3D-treatment plans in head and neck tumors aided by matching of digitally reconstructed radiographs (DRR) and on-line distortion corrected simulator images.

BACKGROUND AND PURPOSE: Simulation of 3D-treatment plans for head and neck malignancy is difficult due to complex anatomy. Therefore, CT-simulation and stereotactic techniques are becoming more common in the treatment preparation, overcoming the need for simulation. However, if simulation is still performed, it is an important step in the treatment preparation/execution chain, since simulation errors, if not detected immediately, can compromise the success of treatment. A recently developed PC-based system for on-line image matching and comparison of digitally reconstructed radiographs (DRR) and distortion corrected simulator monitor images that enables instant correction of field placement errors during the simulation process was evaluated. The range of field placement errors with non-computer aided simulation is reported. MATERIALS AND METHODS: For 14 patients either a primary 3D-treatment plan or a 3D-boost plan after initial treatment with opposing laterals for head and neck malignancy with a coplanar or non-coplanar two- or three-field technique was simulated. After determining the robustness of the matching process and the accuracy of field placement error detection with phantom measurements, DRRs were generated from the treatment planning CT-dataset of each patient and were interactively matched with on-line simulator images that had undergone correction for geometrical distortion, using a landmark algorithm. Translational field placement errors in all three planes as well as in-plane rotational errors were studied and were corrected immediately. RESULTS: The interactive matching process is very robust with a tolerance of <2 mm when suitable anatomical landmarks are chosen. The accuracy for detection of translational errors in phantom measurements was <1 mm and for in-plane rotational errors the accuracy had a maximum of only 1.5 degrees. For patient simulation, the mean absolute distance of the planned versus simulated isocenter was 6.4 +/- 3.9 mm. The in-plane rotational error in both planes was <3 degrees with one exception. Three large field placement errors (two patients with 11.5 and 16.0 mm distances of the planned versus simulated isocenter, respectively and one patient with a 7 degree rotational error) were detected and, as with the smaller errors, were immediately corrected. CONCLUSION: On-line image matching of treatment planning CT-derived DRRs and distortion corrected treatment simulator images is a precise and reliable method to reduce field placement errors in the simulation of complex 3D-treatment plans for head and neck malignancy and thus enhances accuracy in the first step of the treatment preparation/execution chain. However, out-of-plane rotational errors could not be assessed and assumedly they are comparatively small since due to rigid fixation, detected in-plane errors were small.

Computer Simulation↗

Migration patterns in pulsed-field electrophoresis of DNA restriction fragments from log-phase mammalian cells after irradiation and incubation for repair.

An assay system was developed to detect changes of restriction fragment profiles obtained after pulsed-field gel electrophoresis (PFGE) for DNA from mammalian cells that were irradiated and incubated for repair. DNA was prepared from irradiated log-phase human melanoma cells (MRI 221) after incubation for repair (6 h) and was digested with the rare-cutting restriction enzyme NotI (RE) prior to PFGE separation. DNA-fragment size distributions were compared to the respective PFGE profiles from unirradiated controls. After doses of 5 and 10 Gy (plus a 6-h incubation for repair), the relative amount of DNA retained in the plug during PFGE was increased. For higher doses (30 and 60 Gy), this phenomenon was superimposed by the residual fragmentation (25-30% of the initial breakage of 0.42 dsb/100 Mbp/Gy). Since irradiated cells accumulated in S phase during incubation for repair, a correction for the reduced electrophoretic migration of DNA from S-phase cells was necessary, and a 0.5% increase in DNA retention per 1% S-phase increment was found. However, the % retention for the 5 Gy plus repair sample was significantly higher than for the S-phase adjusted control (p < 0.01). Radiation induced DNA-protein crosslinks cannot account for the observed phenomenon because of the extensive proteolysis in DNA preparation, and also a loss of restriction enzyme recognition sites appear to be an unlikely explanation from simple quantitative considerations. Based on the recent observation of misrejoining during dsb repair, it is proposed that the incorrect joining of DNA ends also causes a more random distribution of replicating DNA in restriction fragments derived from cells in S phase after incubation for repair. This process would necessarily increase the proportion of DNA unable to migrate in PFGE.

DNA Repair↗

[Blood volume changes after the radiotherapy of the central nervous system].

BACKGROUND: The pathogenesis of late delayed radiation damage in normal brain tissue is most likely due to damage to the vascular endothelium. The mitotic activity of gliomas was shown to correlate with the tumor induced angiogenesis. Dynamic susceptibility contrast MR imaging (DSC MRI) allows the measurement of the cerebral hemodynamics based on the indicator dilution theory. We describe theory and technique of the method and present our experience with blood volume measurements after irradiation of the CNS. METHODS: We established a double slice technique on a standard 1.5 T MR system without hardware modifications, which allows an absolute quantification of the blood volume in regions of interest (ROI) within the brain. Fifty-five T2* weighted double slice images were acquired before, during and after bolus injection of Gd-DTPA (0.1 mmol/kg in 5 sec.) using a SD FLASH sequence (simultaneous dual fast low angle shot, TR/TE1/TE2 31/16/25, flip angle 10 degrees). Concentration-time curves were calculated from the measured signal-time curves. Blood volume values in tissue were normalised and calculated in absolute values (ml/100 g) based on the knowledge of the arterial input function (AIF), which was measured in the brain supplying arteries. The whole procedure requires only 2 to 3 minutes, the time for post processing is about 15 to 20 minutes. RESULTS: Blood volume parameter images of representative cases demonstrate the blood volume changes after radiotherapy. A reduction in blood volume could be observed in normal brain tissue and low-grade gliomas, while recurrent tumors were accompanied by a local increase in blood volume. CONCLUSIONS: Radiation induced blood volume changes in the CNS can be measured using dynamic susceptibility contrast MR imaging. The measurements in normal brain tissue allow a functional in-vivo analysis of late delayed radiation reactions of the CNS. The definite value of intratumoral blood volume measurements for determination of the therapeutic success and for differentiation of recurrences versus radionecroses remains to be clarified in further studies.

Adult↗

Comparison of proliferating cell nuclear antigen (PCNA) staining and BrdUrd-labelling index under different proliferative conditions in vitro by flow cytometry.

PC10 is a monoclonal antibody against proliferating cell nuclear antigen (PCNA). The staining pattern in immunochemistry depends on fixation and detergent extraction treatment. The aim of this study was to validate the flow cytometric PCNA assay against Bromodeoxyuridine-labelling index (BrdUrd-LI) under different proliferative conditions in vitro. Expression of PCNA in methanol fixed cells with, and without, prior detergent extraction with EDTA/Triton was compared to BrdUrd-labelling index in NIH-3T3 fibroblasts and human Caski tumour cells in exponential phase and under confluent conditions. Serum stimulation and serum starvation conditions were studied. The results for BrdUrd-LI and PCNA-index after extraction showed good correlation for 3T3 fibroblasts and for Caski cells, with some differences for serum withdrawn Caski cells. There was no correlation between the number of cells that were positive for PCNA without extraction and BrdUrd-LI. Spheroid cells with G1-DNA-content showed an almost synchronous recruitment and progression through the cell cycle after trypsination and replating. Tightly bound PCNA paralleled this synchronicity whereas total PCNA did not change significantly. The results demonstrate that immunochemical detection of non-extractable PCNA-index gives similar results as compared with BrdUrd-labelling index under different proliferative conditions in vitro for different monolayer cell lines, whereas without extraction PCNA does not correlate with BrdUrd-LI in these fast growing cell lines due to its long half-life. PCNA expression parallels the progression through the cell cycle in V79 spheroids, a primitive model of tumour growth.

Animals↗