The effects of ultra-high dose rate proton irradiation on growth delay in the treatment of human tumor xenografts in nude mice.

The new technology of laser-driven ion acceleration (LDA) has shown the potential for driving highly brilliant particle beams. Laser-driven ion acceleration differs from conventional proton sources by its ultra-high dose rate, whose radiobiological impact should be investigated thoroughly before adopting current clinical dose concepts. The growth of human FaDu tumors transplanted onto the hind leg of nude mice was measured sonographically. Tumors were irradiated with 20 Gy of 23 MeV protons at pulsed mode with single pulses of 1 ns duration or continuous mode (∼100 ms) in comparison to controls and to a dose-response curve for 6 MV photons. Tumor growth delay and the relative biological effectiveness (RBE) were calculated for all irradiation modes. The mean target dose reconstructed from Gafchromic films was 17.4 ± 0.8 Gy for the pulsed and 19.7 ± 1.1 Gy for the continuous irradiation mode. The mean tumor growth delay was 34 ± 6 days for pulsed, 35 ± 6 days for continuous protons, and 31 ± 7 days for photons 20 ± 1.2 Gy, resulting in RBEs of 1.22 ± 0.19 for pulsed and 1.10 ± 0.18 for continuous protons, respectively. In summary, protons were found to be significantly more effective in reducing the tumor volume than photons (P < 0.05). Together with the results of previous in vitro experiments, the in vivo data reveal no evidence for a substantially different radiobiology that is associated with the ultra-high dose rate of protons that might be generated from advanced laser technology in the future.

Induction and repair of DNA double-strand breaks assessed by gamma-H2AX foci after irradiation with pulsed or continuous proton beams.

In particle tumor therapy including beam scanning at accelerators, the dose per voxel is delivered within about 100 ms. In contrast, the new technology of laser plasma acceleration will produce ultimately shorter particle packages that deliver the dose within a nanosecond. Here, possible differences for relative biological effectiveness in creating DNA double-strand breaks in pulsed or continuous irradiation mode are studied. HeLa cells were irradiated with 1 or 5 Gy of 20-MeV protons at the Munich tandem accelerator, either at continuous mode (100 ms), or applying a single pulse of 1-ns duration. Cells were fixed 1 h after 1-Gy irradiation and 24 h after 5-Gy irradiation, respectively. A dose-effect curve based on five doses of X-rays was taken as reference. The total number of phosphorylated histone H2AX (gamma-H2AX) foci per cell was determined using a custom-made software macro for gamma-H2AX foci counting. For 1 h after 1-Gy 20-MeV proton exposures, values for the relative biological effectiveness (RBE) of 0.97 ± 0.19 for pulsed and 1.13 ± 0.21 for continuous irradiations were obtained in the first experiment 1.13 ± 0.09 and 1.16 ± 0.09 in the second experiment. After 5 Gy and 24 h, RBE values of 0.99 ± 0.29 and 0.91 ± 0.23 were calculated, respectively. Based on the gamma-H2AX foci numbers obtained, no significant differences in RBE between pulsed and continuous proton irradiation in HeLa cells were detected. These results are well in line with our data on micronucleus induction in HeLa cells.

The effectiveness of 20 mev protons at nanosecond pulse lengths in producing chromosome aberrations in human-hamster hybrid cells.

Laser accelerated radiotherapy is a potential cancer treatment with proton and carbon-ion beams that is currently under development. Ultra-fast high-energy laser pulses will accelerate ion beams that deliver their dose to a patient in a "pulsed mode" that is expected to differ from conventional irradiation by increasing the dose delivery rate to a tissue voxel by approximately 8 orders of magnitude. In two independently performed experiments at the ion microprobe SNAKE of the 14 MV Munich tandem accelerator, A(L) cells were exposed either to protons with 1-ns pulse durations or to protons applied over 150 ms in continuous irradiation mode. A slightly but consistently lower aberration yield was observed for the pulsed compared to the continuous mode of proton irradiation. This difference was not statistically significant when each aberration type was analyzed separately (P values between 0.61 and 0.85 in experiment I and P values between 0.32 and 0.64 in experiment II). However, excluding the total aberrations, which were not analyzed as independent radiation-induced effects, the mean ratio of the yields of dicentrics, centric rings and excess acentrics scored together showed (with 95% CI) a significant difference of 0.90 (0.81; 0.98) between the pulsed and the continuous irradiation modes. A similar tendency was also determined for the corresponding RBE values relative to 70 kV X rays. Since the different findings for the comparisons of individual chromosome aberration types and combined comparisons could be explained by different sample sizes with the consequence that the individual comparisons had less statistical power to identify a difference, it can be concluded that 20 MeV protons may be slightly less effective in the pulsed mode.

No evidence for a different RBE between pulsed and continuous 20 MeV protons.

To obtain greater insight into the future potential of tumor radiotherapy using proton beams generated from high-intensity lasers, it is important to characterize the ionization quality of the new beams by measuring the relative biological effectiveness (RBE) under conditions where the full dose at one irradiation site will be deposited by a few proton pulses less than 1 ns in duration. HeLa cells attached to a Mylar foil were irradiated with 70 kV X rays to obtain a reference dose-response curve or with 3 Gy of 20 MeV protons at the Munich tandem accelerator (Garching), either using a continuous mode where a cell sample was irradiated within a 100-ms time span or using a pulsed mode where radiation was given in a single proton pulse of about 1 ns. After irradiation cytochalasin B was added; 24 h later cells were fixed and stained with acridine orange and micronuclei were counted. The X-ray dose-response curve for the production of micronuclei in HeLa cells followed a linear-quadratic model. The corresponding RBE values for 20 MeV protons in pulsed and continuous irradiation modes were 1.07 +/- 0.08 and 1.06 +/- 0.10 in the first proton experiment and 1.09 +/- 0.08 and 1.05 +/- 0.11 in the second, respectively. There was no evidence for a difference in the RBE for pulsed and continuous irradiation of HeLa cells with 20 MeV protons.

A radiation-induced gene signature distinguishes post-Chernobyl from sporadic papillary thyroid cancers.

We investigated selected gene targets to differentiate radiation-induced papillary thyroid cancers (PTCs) from other etiologies. Total RNA was isolated from 11 post-Chernobyl PTCs and 41 sporadic PTCs characterized by a more aggressive tumor type and lacking a radiation exposure history. RNA from 10 tumor samples from both groups was pooled and hybridized separately on a whole genome microarray for screening. Then 92 selected gene targets were examined quantitatively on each tumor sample using an RTQ-PCR-based low-density array (LDA). Screening for more than fivefold differences in gene expression between the groups by microarray detected 646 up-regulated and 677 down-regulated genes. Categorization of these genes revealed a significant (P < 0.0006) over-representation of the number of up-regulated genes coding for oxidoreductases, G-proteins and growth factors, while the number of genes coding for immunoglobulin appeared to be significantly down-regulated. With the LDA, seven genes (SFRP1, MMP1, ESM1, KRTAP2-1, COL13A1, BAALC and PAGE1) made a complete differentiation between the groups possible. Gene expression patterns known to be associated with a more aggressive tumor type in older patients appeared to be more pronounced in post-Chernobyl PTC, thus underlining the known aggressiveness of radiation-induced PTC. Seven genes were found that completely distinguished post-Chernobyl (PTC) from sporadic PTC.

Ten-year data on 138 patients with endometrial carcinoma and postoperative vaginal brachytherapy alone: no need for external-beam radiotherapy in low and intermediate risk patients.

OBJECTIVE: To evaluate long-term outcome, risk factors, and causes of death in stage I-IIIA endometrial carcinoma (EC) patients treated only with adjuvant vaginal brachytherapy (VB) and to clarify for which subgroups of patients it is safe to omit external-beam radiotherapy (EBRT). METHODS: Out of 224 EC patients receiving postoperative radiotherapy between 1990 and 2002, 138 had VB alone in curative intent (FIGO [2002]: 85%I, 12%II, 3%IIIA; 18 low risk [IA G1-2, IB G1], 103 intermediate risk [IB G2-3, IC G1-2, IIA-B G1-2], 17 high risk [IC G3, IIIA]). After surgery+/-lymphadenectomy, HDR-brachytherapy prescription (in 95.7% of patients) was 3x10 Gy to the surface or 3x5 Gy at 5 mm tissue depths. RESULTS: Median follow-up was 107 months (range 3-185). Three intermediate and 7 high risk-patients relapsed. The 10-year vaginal control was 99.2%, locoregional control was 95.2% (low/intermediate/high risk: 100%/98.9%/68.8%), and disease-free survival (DFS) was 91.7% (100%/96.8%/55.2%). Risk factors for poor DFS were lymphovascular space invasion, > or = 50% myometrial invasion (univariate, p<0.05), pathological FIGO-stage, and grade 3 (uni-/multivariate, p<0.05). Leading causes of deaths (n=41) were cardiovascular disease (29%) and other malignancies (24%) ahead of EC (19.5%). The 10-year overall survival was 68.5% and the disease-specific survival was 92.4%. Thirty-five secondary tumors in 31 patients led to a higher actuarial death rate (10-year 9.9%, 15-year 17.7%) than EC (7.6%). CONCLUSIONS: Restricting adjuvant therapy to VB alone seems to be safe in low and intermediate risk EC and can be recommended. As death rarely relates to early-stage EC, value of adjuvant therapy is probably better reflected by DFS rather than by overall survival.

Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study.

PURPOSE: Hypoxia is an important negative prognostic factor for radiation treatment of head and neck cancer. This study was performed to evaluate the feasibility of use of (18)F-labelled fluoroazomycin arabinoside ([(18)F]FAZA) for clinical PET imaging of tumour hypoxia. METHODS: Eleven patients (age 59.6 +/- 9 years) with untreated advanced head and neck cancer were included. After injection of approximately 300 MBq of [(18)F]FAZA, a dynamic sequence up to 60 min was acquired on an ECAT HR+ PET scanner. In addition, approximately 2 and 4 h p.i., static whole-body PET (n = 5) or PET/CT (n = 6) imaging was performed. PET data were reconstructed iteratively (OSEM) and fused with CT images (either an external CT or the CT of integrated PET/CT). Standardised uptake values (SUVs) and tumour-to-muscle (T/M) ratios were calculated in tumour and normal tissues. Also, the tumour volume displaying a T/M ratio >1.5 was determined. RESULTS: Within the first 60 min of the dynamic sequence, the T/M ratio generally decreased, while generally increasing at later time points. At 2 h p.i., the tumour SUV(max) and SUV(mean) were found to be 2.3 +/- 0.5 (range 1.5-3.4) and 1.4 +/- 0.3 (range 1.0-2.1), respectively. The mean T/M ratio at 2 h p.i. was 2.0 +/- 0.3 (range 1.6-2.4). The tumour volume displaying a T/M ratio above 1.5 was highly variable. At 2 h p.i., [(18)F]FAZA organ distribution was determined as follows: kidney > gallbladder > liver > tumour > muscle > bone > brain > lung. CONCLUSION: [(18)F]FAZA PET imaging appears feasible in head and neck cancer patients, and the achieved image quality is adequate for clinical purposes. Based on our initial results, [(18)F]FAZA warrants further evaluation as a hypoxia PET tracer for imaging of cancer.

[Soft tissue sarcoma of the extremities: current state of the art of adjuvant therapy]. / Mit der Strahlentherapie wird die Amputation zur Ausnahme.

Today, most sarcoma patients can be spared an amputation through the use of adjuvant radiotherapy. Treatment by an experienced multidisciplinary team offers the best chance of achieving permanent tumor control. Histopathologically-free resection margins are of the greatest importance. The indication for radiotherapy is determined by the recurrence risk profile of the individual patient. In addition to the well-proven postoperative irradiation, neoadjuvant radiotherapy is also successful. In the event of an unfavorably sited tumor, intra-operative irradiation can be applied in combination with either form. Patients with large G3 tumors can be given adjuvant chemotherapy to reduce the risk of distant metastases. On account of its appreciable toxicity, however, it should be reserved for patients younger than 65 in a good state of health.

[Remembering DEGRO 2000-evaluation of the refresher course survey]. / Nachlese zum DEGRO 2000-die Auswertung der Refresherkurs-Umfrage.

BACKGROUND: Refresher courses as presented at the annual DEGRO meeting are important parts in the continuous training of radiotherapists. For further quality improvement, knowledge about the participants' needs is essential. METHODS: During the DEGRO meeting 10/2000 in Munich, participants of refresher courses were encouraged to grade the presentations with regard to six questions with marks from 1 ("very good") to 6 ("not acceptable"). Free comments were welcomed. The individual results were handed over to future organizing committees and the speakers themselves, cumulative results can be read up in the present note. RESULTS: Approximately 1,000 participants of refresher courses filled in 381 questionnaires concerning 24 different training sessions. Altogether 48.5% of all answers said "very good", 31.7% "good" and 11.1% "satisfactory" (all worse marks together 3%, no statement in 5.7%). Free comments dealt mainly with handouts and a later starting time for the refresher courses than 7:30 a.m. CONCLUSION: Participants of the annual DEGRO meeting show a great amount of interest in refresher courses and seem to be quite content with the present findings. First steps are taken to get the proposals under way.

Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population.

Neural tube defects (NTD) are likely to result from an interaction of several genes and environmental factors. Because periconceptional folate intake reduces the NTD risk in the fetus, and because mothers of children with NTD showed elevated plasma homocysteine levels, gene polymorphisms of the folate and homocysteine pathway, such as 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T, MTHFR 1298A-->C and cystathionine beta-synthase (CBS) 844ins68, have been implicated in the etiology of NTD. Several studies have demonstrated that these polymorphisms may indeed be associated with NTD in some populations. In order to evaluate the role of these polymorphisms and their interaction in NTD, we genotyped 417 individuals for case-control studies and 129 families for transmission disequilibrium tests. We are the first to present detailed data on MTHFR haploid genotypes in combination with CBS 844ins68. The MTHFR risk genotype 677CT/1298AC, known to be associated with decreased enzyme activity and increased homocysteine, was found significantly more often in patients than in controls (P = 0.02). A CBS insertion allele in addition to MTHFR 677CT/ 1298AC heterozygosity or MTHFR 677TT/1298AA homozygosity did not result in an increased risk for NTD. This is in agreement with the recently reported homocysteine-lowering effect of the CBS 844ins68 allele in carriers of MTHFR variants.

Older adult norms for the Southern California Figure-Ground Visual Perception Test.

Older adult norms for men are provided for the Southern California Figure-Ground Visual Perception Test (FG; Ayres, 1966), based on the performance of 117 patients from a geriatric medicine and rehabilitation facility ranging in age from 40 to 77 years. Reasons are presented for administering the entire test rather than using the traditional cutoff. When comparing FG performance to norms of younger adults (Bieliauskas, Newberry, & Gerstenberger, 1988), results indicate that figure-ground discrimination is poorer in older individuals. The norms provided here serve to complement the previous study employing FG, and it is hoped that they will encourage its wider use.

PPVT-R as an estimate of premorbid intelligence in older adults.

The Peabody Picture Vocabulary Test-Revised (PPVT-R) was examined as an estimate of premorbid intelligence in a clinical sample of elderly patients (N = 150) undergoing clinical neuropsychological evaluation. PPVT-R standard scores were compared across grossly cognitively intact, mildly/moderately and severely impaired groups of patients, and compared to a short form of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Barona regression equation. Results indicate that, while the PPVT-R is vulnerable to increasing levels of cognitive impairment among patients with fewer years of education, the PPVT-R is stable across mild to moderate levels of impairment for patients with greater than 12 years of education. In a sub-sample of grossly cognitively intact patients (n = 91), the PPVT-R standard score correlated significantly with estimated WAIS-R FSIQ (r =.61). Compared to the Barona equation, the PPVT-R was less likely to over-estimate WAIS-R FSIQ in the grossly cognitively intact patients. These data suggest the PPVT-R to be a useful estimate of premorbid ability for patients with a greater than high-school education.

Limited accuracy of premorbid intelligence estimators: a demonstration of regression to the mean.

Regression-based premorbid intelligence estimators have been devised by Barona, Reynolds, and Chastain (1984), Barona and Chastain (1986), Hamsher (1984), Krull, Scott, and Sherer (1995; the Oklahoma Premorbid Intelligence Estimate: OPIE), and Vanderploeg, Schinka, and Axelrod (1996; BEST-3 approach), but little is known of their relative accuracy, particularly in outer ranges of intellectual ability (e.g., below-average, superior, etc.). Towards this end, the Wechsler Adult Intelligence Scale-Revised (WAIS-R) was administered to 150 neurologically normal adults, and estimated VIQ, PIQ, and FSIQ scores were computed according to each regression method. Results showed that methods based solely on demographic factors were most susceptible to meanward regression, rendering them poor estimators of IQ scores in outer ranges. Although the OPIE and BEST-3 performed somewhat better, their accuracy remained relatively weak. The findings suggest that regression-based estimates of premorbid IQ are very susceptible to error, particularly in outer ranges of intellectual function.

Use of the odds ratio to translate neuropsychological test scores into real-world outcomes: from statistical significance to clinical significance.

Standard parametric tests generate p values and effect sizes, but often these are difficult to translate into real-world outcomes. In this study, the odds ratio was applied to neuropsychological testing and was compared to parametric approaches. Participants were 26 community-dwelling adults with possible or probable Alzheimer's disease and 25 matched healthy community-dwelling volunteers. Odds ratios were computed to estimate the probability of concurrent diagnosis given neuropsychological performance level. Odds ratios discriminated the groups at magnitudes that could not be discerned from t-test significance tables. These values were compared to sensitivity, specificity, and overall accuracy. Clinical and research applications and implications were addressed.

Comparability and validity of computerized adaptive testing with the MMPI-2.

The comparability and validity of a computerized adaptive (CA) Minnesota Multiphasic Personality Inventory-2 (MMPI-2) were assessed in a sample of 571 undergraduate college students. The CA MMPI-2 administered adaptively Scales L, E the 10 clinical scales, and the 15 content scales, utilizing the countdown method (Butcher, Keller, & Bacon, 1985). All subjects completed the MMPI-2 twice, with three experimental conditions: booklet test-retest, booklet-CA, and conventional computerized (CC)-CA. Profiles across administration modalities show a high degree of similarity, providing evidence for the comparability of the three forms. Correlations between MMPI-2 scales and other psychometric measures (Beck Depression Inventory; Symptom Checklist-Revised; State-Trait Anxiety and Anger Scales; and the Anger Expression Scale) support the validity of the CA MMPI-2. Substantial item savings may be realized with the implementation of the countdown procedure.

Failed back surgeries and minnesota multiphasic personality inventory (MMPI) profiles.

MMPI profiles were evaluated for 105 prospective surgical patients who had previously undergone surgery or other procedures for treatment of back pain. Patients were classified into groups having undergone zero, one, two, three, or four or more previous surgeries. While all groups demonstrated a characteristicsomatogenic profile, none of the MMPI validity or clinical scales significantly differentiated the groups and there was no relationship between increased number of surgeries and MMPI scale characteristics. These results support the nonoptimistic prognostication of thesomatogenic MMPI profile for surgical intervention for back pain but show no clear relationship of MMPI profile characteristics to degree of experience of previously failed surgery.

Olecranon spur.

Full extension of the elbow is normally made possible by accommodation of the olecranon within an appropriately shaped fossa in the distal humerus. We report three cases where disability has resulted from an abnormally shaped olecranon.