Muon disrupts AKT hydrogen bond network in cancer.

A cancer microenvironment generates strong hydrogen bond network system by the positive feedback loops supporting cancer complexity and robustness. Such network functions through the AKT locus generating high entropic energy supporting cancer metastatic robustness. Charged lepton particle muon follows the rule of Bragg effect during a collision with hydrogen network in cancer cells. Muon beam dismantles hydrogen bond network in cancer by the muon-catalyzed fusion, leading to apoptosis of cancer cells. Muon induces cumulative energy appearance on the hydrogen bond network in a cancer cell with its fast decay to an electron and two neutrinos. Thus, muon beam, muonic atom, muon neutrino shower, and electrons simultaneously cause fast neutralization of the AKT hydrogen bond network by the conversion of hydrogen into deuterium or helium, inactivating the hydrogen bond networks and inducing failure of cancer complexity and robustness with the disappearance of a malignant phenotype.

Upper bound dose values for meson radiation in heavy-ion therapy.

Radiation treatment of cancer has evolved to include massive particle beams, instead of traditional irradiation procedures. Thus, patient doses and worker radiological protection have become issues of constant concern in the use of these new technologies, especially for proton- and heavy-ion-therapy. In the beam energies of interest of heavy-ion-therapy, secondary particle radiation comes from proton, neutron, and neutral and charged pions produced in the nuclear collisions of the beam with human tissue atoms. This work, for the first time, offers the upper bound of meson radiation dose in organic tissues due to secondary meson radiation in heavy-ion therapy. A model based on intranuclear collision has been used to follow in time the nuclear reaction and to determine the secondary radiation due to the meson yield produced in the beam interaction with nuclei in the tissue-equivalent media and water. The multiplicity, energy spectrum, and angular distribution of these pions, as well as their decay products, have been calculated in different scenarios for the nuclear reaction mechanism. The results of the produced secondary meson particles has been used to estimate the energy deposited in tissue using a cylindrical phantom by a transport Monte Carlo simulation and we have concluded that these mesons contribute at most 0.1% of the total prescribed dose.

Pion treatment of prostate carcinoma at Paul Scherrer Institute (formerly Swiss Institute for Nuclear Research (SIN)) from 1983 to 1992.

BACKGROUND: - Between 1983 and 1992 a total of 55 patients suffering from prostate cancer were treated with pions (pi-mesons) at the Paul Scherrer Institute in Villigen, Switzerland. This form of therapy was used at only three centers world wide on 245 patients with this diagnosis. Since the last project in Vancouver, Canada, was closed in 1994, this form of therapy has been relegated to the realm of history. METHODS: - In a retrospective analysis, the data of 49 of the 55 patients, that was qualified for evaluation was brought up-to-date and evaluated. Median and mean age at the time of therapy was 65 years. Advanced stage tumors were overly represented, in respect to T-stages (35/49 stage T3 and T4) and differentiation (11/49 G1). The treatment volumes were between 67 and 1330 cm(3), and the mean delivered dose was 32.2 pion-Gray. Survival probability, the probability of metastases and the local control rate were calculated according to Kaplan-Meier. RESULTS: - Seven of the 49 patients had already been diagnosed with metastatic disease before treatment began, 16 developed metastases during the follow-up observation period. Local control after 2 years was 89%, and after 5 years 83%. The survival rate after 2 years was 87%, and 66% after 5 years, excluding non-tumor related deaths. The rate of late toxicity was acceptable. CONCLUSIONS: - Seen in retrospect, pion treatment of prostate carcinoma proved to be an effective form of therapy with a low rate of late toxicity. But, in comparison to the possibilities offered by modern conventional radiation therapy, this method would certainly not be today's first choice.

Report on the quality of life analysis from the phase III trial of pion versus photon radiotherapy in locally advanced prostate cancer.

This report examines the quality of life (QOL) of 215 patients entered into a randomised trial between pion and photon radiotherapy for prostate cancer at a single institution. The survival and local control results of the trial were equivalent in both arms. A modification of the Rotterdam Symptom Checklist (RSCL) was used to assess QOL. Global QOL, toxicity and physical scores were found to be worse in pion-treated patients at the end of treatment (P<0.001, P<0.001, and P=0.02 respectively). There are no long-term differences in the QOL of pion- versus photon-treated patients. Sexual function was a concern for patients even at baseline. There was a progressive loss of sexual interest and erectile function. There was a significant impact from hormonal therapy at relapse. Hormonal treatment produced a stepwise significant worsening in global QOL, particularly for physical and psychological domains.

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.

Pion conformal radiation of prostate cancer: results of a randomized study.

PURPOSE: To compare the efficacy of pion radiation therapy with conventional external beam photon therapy, for the treatment of locally advanced stage T3/4, N0, M0 adenocarcinoma of the prostate. METHODS AND MATERIALS: Two hundred seventeen eligible patients were randomly allocated to either photon or pion therapy. No adjuvant hormone therapy was used. RESULTS: Median follow-up was 42 months (range 2-90). Acute bladder toxicity was worse in the pion arm, p = 0.2, but other acute toxicity did not differ. Late grade 2 toxicity was significantly less in the pion arm (29% at 5 years versus 48%, p = 0.002), but late grade 3 or 4 toxicity did not differ. Clinical local control was not significantly different between treatment arms (64% after 5 years with photons, 56% with pions, p = 0.6). Cause-specific and overall survival also did not differ (p = 0.7). There was a significant delay in time to first failure in the photon arm, largely as a result of decreased biochemical relapse, p = 0.01. A multivariate analysis is presented. CONCLUSION: Pion therapy was well tolerated, with increased acute toxicity and significantly decreased late tissue injury. This contrasts with the late toxicity observed with higher LET particle therapy such as neutron therapy. No improvement in local control with pion therapy was observed.

Pion radiation for high grade astrocytoma: results of a randomized study.

PURPOSE: This study attempted to compare within a randomized study the outcome of pion radiation therapy vs. conventional photon irradiation for the treatment of high-grade astrocytomas. METHODS AND MATERIALS: Eighty-four patients were randomized to pion therapy (33-34.5 Gy pi), or conventional photon irradiation (60 Gy). Entry criteria included astrocytoma (modified Kernohan high Grade 3 or Grade 4), age 18-70, Karnofsky performance status (KPS) > or = 50, ability to start irradiation within 30 days of surgery, unifocal tumor, and treatment volume < 850 cc. The high-dose volume in both arms was computed tomography enhancement plus a 2-cm margin. The study was designed with the power to detect a twofold difference between arms. RESULTS: Eighty-one eligible patients were equally balanced for all known prognostic variables. Pion patients started radiation 7 days earlier on average than photon patients, but other treatment-related variables did not differ. There were no significant differences for either early or late radiation toxicity between treatment arms. Actuarial survival analysis shows no differences in terms of time to local recurrence or overall survival where median survival was 10 months in both arms (p = 0.22). The physician-assessed KPS and patient-assessed quality of life (QOL) measurements were generally maintained within 10 percentage points until shortly before tumor recurrence. There was no apparent difference in the serial KPS or QOL scores between treatment arms. CONCLUSION: In contrast to high linear energy transfer (LET) therapy for central nervous system tumors, such as neutron or neon therapy, the safety of pion therapy, which is of intermediate LET, has been reaffirmed. However, this study has demonstrated no therapeutic gain for pion therapy of glioblastoma.

Early skin response to fractionated doses of pions for determining therapeutic gain factors.

This study concerns the biological effectiveness of fractionated doses of pions on early skin reactions near the implanted tumor, to evaluate the therapeutic gain factors of pions. The C3H mouse limbs bearing microscopical SCCVII tumors were irradiated with pions (9.6-38.4 Gy) or x-rays (14.4-50.4 Gy) in 2-7 fractions. Nicotinamide (500 mg/kg) and carbogen (a mixture of 95% O2 + 5% CO2), as hypoxic radiosensitizers, were administered prior to the x-rays, to confirm the presence of hypoxic cells in the skin. The mean skin scores and number of damaged nails assessed. The ratios of x-ray/pion doses needed for giving comparable skin reactions were 1.3-1.5. Nicotinamide and carbogen enhanced the skin reactions. When the ratios were compared with those of tumor cure, the pions showed no therapeutic gains. One of the possible causes was that the presence of hypoxic cells in the skin may have reduced the therapeutic gain.

Particle radiotherapy: historical developments and current status.

The current status of particle radiotherapy from a historical perspective is presented. This is done with a personal view and contains personal references and memories during the development of particle radiotherapy. The particles covered are fast neutrons, neutron capture therapy, protons, helium ions, pions and heavy ions. International cooperation in the development of the field of particle therapy, its impact on radiobiology and conventional radiotherapy, and some personal reflections and conclusions are also presented briefly.

Radiosensitizing effect of nicotinamide and carbogen combined in fractionated pions or x-rays in SCCVII tumors.

Well-known radiotherapeutic strategies for hypoxic cells include hypoxic radiosensitizers, heavy particles, and fractionated irradiation. This study attempted to obtain the ultimate effectiveness of these strategies by combining nicotinamide plus carbogen (N + C) as a hypoxic radiosensitizer with fractionated pions. In addition, the influence on the N + C effect of X-ray dose rate used as a reference radiation was evaluated. When SCCVII tumors in the dorsum of feet reached 50 mm3 in volume, they were irradiated with pions (0.2 Gy/min), the same dose rate (LDR; 0.2 Gy/min) X-rays, or high dose rate (HDR; 1.5 Gy/min) X-rays in 10 fractions over 11 days. Nicotinamide (0.5 mg/g) was administered i.p. one hour before irradiation, and normobaric carbogen (95% oxygen and 5% carbon dioxide) was breathed from 10 min before irradiation. The effect was evaluated by tumor growth time (TGT50) assay. The combination of N + C significantly enhanced the effect of 30 Gy LDR and 28 Gy HDR X-rays, with the effect corresponding to that of 39 Gy HDR X-rays: the enhancement ratios were 1.2 and 1.4, respectively. The effect of 20 Gy pions was equivalent to the effect of 33 Gy HDR X-rays (ratio of 1.65), or the effect of N + C combined with 28 Gy HDR X-rays. However, N + C did not enhance the effect of 20 Gy pions. This suggested that the fractionated pions had great biological effectiveness against hypoxic cells. In conclusion, N + C afforded no additional benefit with fractionated pions, but it was thought to be of value for fractionated X-rays, even in a dose rate of 0.2 Gy/min.

Biological effectiveness of fractionated dose of pions in microscopic SCCVII tumors: comparison between tumor control dose and tumor growth time assays.

The relative biological effectiveness (RBE) of fractionated pions for tumor growth time (TGT) assay changes with the endpoints, so it is essential to determine the RBE for tumor control dose (TCD) assay. For this purpose, the TCD50 of fractionated pions was compared with that of photons, and the RBEs for TGT and TCD assays were concurrently compared as a function of the effect level. A "convenient" RBE (cRBE) was substituted for the RBE when the comparison was made between similar fractionation schedules with different dose per fraction. SCCVII tumors (2 x 10(4) or 2 x 10(5) cells) were implanted into the feet of C3H mice and irradiated starting from 2 days after implantation at a total dose range of either 9.6-38.4 Gy pions (2.4-6.4 Gy per fraction) or 14.4-50.4 Gy photons (3.6-7.2 Gy per fraction) in 2-10 fractions over 5-6 days. The cRBE and the RBE at the iso-effective level of 30 days TGT were 1.53-1.60 for 2.4-4.8 Gy pions and 1.50 for 4-fractionated pions, respectively: there were only small differences within these schedules used. However, the cRBE values decreased from 1.60 to 1.15 with increasing TGT from 30 to 75 days. In contrast, the cRBE values for TCD50 increased from 1.08 to 1.40 (95% confidence limits [CL]; 1.18-1.63) with increasing evaluation time from 60 to 100 days: pions significantly inhibited late tumor appearance. The TCD50 at 100 days was 28.7 Gy (CL; 25.0-32.5 Gy) for pions and 40.3 Gy (CL; 36.3-44.2 Gy) for photons. In conclusion, the RBE for TCD50 was not predictable from the RBE for TGT assay. The cRBE value of 1.4 for microscopic tumor control was in close agreement with the reported values for skin reaction.

Repair inhibition in tumours irradiated with fast protons and negative pions.

Solid Ehrlich mouse tumours were irradiated in the 80 MeV proton beam of the Paul-Scherrer-Institute. The tumour volume was measured as a function of time after irradiation and two experimental endpoints were determined: local tumour control and minimal tumour volume after irradiation. The application of 2-deoxy-D-glucose (2-DG; 2 mg/kg) increased the radiation effect of protons by a factor of 1.4. The same tumour system was used with negative pions. Human tumours are usually irradiated with a mixed radiation produced by the "spot-scan-technique". This radiation quality was simulated in the mouse experiment by two successive irradiations with a spot of densely ionizing peak pions and a spot of sparsely ionizing plateau pions. Application of 2-DG raised the radiation effect due to the sparsely ionizing component again by a factor of 1.4. This indicates that clinical results in radiotherapy might be improved by application of 2-DG during the treatment.

An intercomparison of two dynamic treatment techniques, ring scan and spot scan, for head and neck tumors with the Piotron.

An evaluation of the ring scan and the spot scan was made for the pion irradiation of head and neck tumors with the Piotron. For the geometry of the Piotron, with its 60 radially converging beams, two scanning techniques have been developed, ring scan and spot scan. They have different characteristics concerning achievable dose distributions and sensitivity to tissue inhomogenities. The optimized 3-dimensional dose distributions for the treatment with ring scan and spot scan techniques were calculated for two examples of the target volume. The comparison of the dose distributions has shown that the ring scan is better in sparing normal tissues than the spot scan for a simple shape target volume but not for an irregular shape target volume with the present status of the technique. The irradiation time needed for the ring scan is longer, for the present examples three times, than for the spot scan. From the practical view point the spot scan is preferable to the ring scan for the treatment of head and neck tumors with the Piotron.