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.

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.

[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.

Soft tissue surgery in Charcot-Marie-Tooth disease.

Ten patients with Charcot-Marie-Tooth disease have been reviewed at an average of 14 years after soft tissue procedures to correct foot deformities. No patient has so far required triple arthrodesis and the overall results as regards function, appearance and symptoms are satisfactory in all patients. It is concluded that soft tissue procedures can certainly postpone the need for triple arthrodesis and in many cases may obviate it altogether.

The surgical treatment of equinovarus deformity in adults with spasticity.

Adults with deformities of the lower limb due to spasticity may be considerably improved by operation, but thorough pre-operative assessment as an inpatient is essential in order to pinpoint the disability. The commonest deformity is equinovarus which often responds to simple operative procedures. The results of seventy-seven operative procedures in fifty patients are recorded. Correction once achieved is stable and the deformity does not recur.

The Roper-Day total shoulder replacement.

A simple unconstrained shoulder prosthesis has been used in 22 patients (25 shoulders) with incapacitating pain and severely damaged joints who, because of age or generalised rheumatoid disease, have limited functional requirements. All reported good and lasting pain relief. Improvement in range of movement was modest, but there was marked improvement in function. In this group of patients, rotator cuff damage is common, but does not preclude a satisfactory result.

A new unconstrained elbow. A prospective review of 60 replacements.

Sixty unconstrained elbow replacements of a new design have been followed prospectively for three to nine years. Review showed that 50% had excellent relief of pain and return of function, 27% had had major complications requiring removal or revision of the prosthesis and 23% had minor complications which marred the result. Further research in this field seems worthwhile.

Functional assessment after pollicisation.

Nine children with congenital aplasia or hypoplasia of the thumb were treated by pollicisation of the index finger. Functional assessment was performed on average five years after surgery. It demonstrated normal sensation and a power grip, pinch grip and adductor grip of the thumb of 63%, 56% and 63% respectively of the unoperated hand. Efficient use of the hand increased after surgery and continued to improve for some years. The results indicate that pollicisation benefits hand function and should be performed early.

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.

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.

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.