Imaging biomarkers of TERT or GABPB1 silencing in TERT-positive glioblastoma.

BACKGROUND: TERT promoter mutations are observed in 80% of wild-type IDH glioblastoma (GBM). Moreover, the upstream TERT transcription factor GABPB1 was recently identified as a cancer-specific therapeutic target for tumors harboring a TERT promoter mutation. In that context, noninvasive imaging biomarkers are needed for the detection of TERT modulation. METHODS: Multiple GBM models were investigated as cells and in vivo tumors and the impact of TERT silencing, either directly or by targeting GABPB1, was determined using 1H and hyperpolarized 13C magnetic resonance spectroscopy (MRS). Changes in associated metabolic enzymes were also investigated. RESULTS: 1H-MRS revealed that lactate and glutathione (GSH) were the most significantly altered metabolites when either TERT or GABPB1 was silenced, and lactate and GSH levels were correlated with cellular TERT expression. Consistent with the drop in lactate, 13C-MRS showed that hyperpolarized [1-13C]lactate production from [1-13C]pyruvate was also reduced when TERT was silenced. Mechanistically, the reduction in GSH was associated with a reduction in pentose phosphate pathway flux, reduced activity of glucose-6-phosphate dehydrogenase, and reduced NADPH. The drop in lactate and hyperpolarized lactate were associated with reductions in glycolytic flux, NADH, and expression/activity of GLUT1, monocarboxylate transporters, and lactate dehydrogenase A. CONCLUSIONS: Our study indicates that MRS-detectable GSH, lactate, and lactate production could serve as metabolic biomarkers of response to emerging TERT-targeted therapies for GBM with activating TERT promoter mutations. Importantly these biomarkers are readily translatable to the clinic, and thus could ultimately improve GBM patient management.

Hyperpolarized 13C MRI: State of the Art and Future Directions.

Hyperpolarized (HP) carbon 13 (13C) MRI is an emerging molecular imaging method that allows rapid, noninvasive, and pathway-specific investigation of dynamic metabolic and physiologic processes that were previously inaccessible to imaging. This technique has enabled real-time in vivo investigations of metabolism that are central to a variety of diseases, including cancer, cardiovascular disease, and metabolic diseases of the liver and kidney. This review provides an overview of the methods of hyperpolarization and 13C probes investigated to date in preclinical models of disease. The article then discusses the progress that has been made in translating this technology for clinical investigation. In particular, the potential roles and emerging clinical applications of HP [1-13C]pyruvate MRI will be highlighted. The future directions to enable the adoption of this technology to advance the basic understanding of metabolism, to improve disease diagnosis, and to accelerate treatment assessment are also detailed.

Miniaturized microdosimeters as LET monitors: First comparison of calculated and experimental data performed at the 62 MeV/u 12C beam of INFN-LNS with four different detectors.

PURPOSE: The aim of this paper is to investigate the limits of LET monitoring of therapeutic carbon ion beams with miniaturized microdosimetric detectors. METHODS: Four different miniaturized microdosimeters have been used at the 62 MeV/u 12C beam of INFN Southern National Laboratory (LNS) of Catania for this purpose, i.e. a mini-TEPC and a GEM-microdosimeter, both filled with propane gas, and a silicon and a diamond microdosimeter. The y-D (dose-mean lineal energy) values, measured at different depths in a PMMA phantom, have been compared withLET¯D (dose-mean LET) values in water, calculated at the same water-equivalent depth with a Monte Carlo simulation setup based on the GEANT4 toolkit. RESULTS: In these first measurements, no detector was found to be significantly better than the others as a LET monitor. The y-D relative standard deviation has been assessed to be 13% for all the detectors. On average, the ratio between y-D and LET¯D values is 0.9 ±â€¯0.3, spanning from 0.73 ±â€¯0.08 (in the proximal edge and Bragg peak region) to 1.1 ±â€¯0.3 at the distal edge. CONCLUSIONS: All the four microdosimeters are able to monitor the dose-mean LET with the 11% precision up to the distal edge. In the distal edge region, the ratio of y-D to LET¯D changes. Such variability is possibly due to a dependence of the detector response on depth, since the particle mean-path length inside the detectors can vary, especially in the distal edge region.

A 13C(d,n)-based epithermal neutron source for Boron Neutron Capture Therapy.

PURPOSE: Boron Neutron Capture Therapy (BNCT) requires neutron sources suitable for in-hospital siting. Low-energy particle accelerators working in conjunction with a neutron producing reaction are the most appropriate choice for this purpose. One of the possible nuclear reactions is 13C(d,n)14N. The aim of this work is to evaluate the therapeutic capabilities of the neutron beam produced by this reaction, through a 30mA beam of deuterons of 1.45MeV. METHODS: A Beam Shaping Assembly design was computationally optimized. Depth dose profiles in a Snyder head phantom were simulated with the MCNP code for a number of BSA configurations. In order to optimize the treatment capabilities, the BSA configuration was determined as the one that allows maximizing both the tumor dose and the penetration depth while keeping doses to healthy tissues under the tolerance limits. RESULTS: Significant doses to tumor tissues were achieved up to ∼6cm in depth. Peak doses up to 57Gy-Eq can be delivered in a fractionated scheme of 2 irradiations of approximately 1h each. In a single 1h irradiation, lower but still acceptable doses to tumor are also feasible. CONCLUSIONS: Treatment capabilities obtained here are comparable to those achieved with other accelerator-based neutron sources, making of the 13C(d,n)14N reaction a realistic option for producing therapeutic neutron beams through a low-energy particle accelerator.

Cardiac perfusion imaging using hyperpolarized (13)C urea using flow sensitizing gradients.

PURPOSE: To demonstrate the feasibility of imaging the first passage of a bolus of hyperpolarized (13)C urea through the rodent heart using flow-sensitizing gradients to reduce signal from the blood pool. METHODS: A flow-sensitizing bipolar gradient was optimized to reduce the bright signal within the cardiac chambers, enabling improved contrast of the agent within the tissue capillary bed. The gradient was incorporated into a dynamic golden angle spiral (13)C imaging sequence. Healthy rats were scanned during rest (n = 3) and under adenosine stress-induced hyperemia (n = 3). RESULTS: A two-fold increase in myocardial perfusion relative to rest was detected during adenosine stress-induced hyperemia, consistent with a myocardial perfusion reserve of two in rodents. CONCLUSION: The new pulse sequence was used to obtain dynamic images of the first passage of hyperpolarized (13)C urea in the rodent heart, without contamination from bright signal within the neighboring cardiac lumen. This probe of myocardial perfusion is expected to enable new hyperpolarized (13)C studies in which the cardiac metabolism/perfusion mismatch can be identified. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance.

Clinical evidence of particle beam therapy (carbon).

Carbon ion radiotherapy (CIRT) is unique as it possesses well-localized and superior-depth dose distribution in addition to less repairable radiobiological effects. The use of CIRT for various diseases has been explored as clinical trials at the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. Since 1994, when the first clinical study of cancer therapy with carbon ion beams was started, about 50 clinical studies have been completed safely and effectively. These studies revealed that intractable cancers such as inoperable bone and soft-tissue sarcomas can be cured safely in a shorter overall treatment time, as can cancers in the head, neck, lung, liver, prostate, and postoperative pelvic recurrence of rectal cancer. The number of patients receiving CIRT has reached 6,000, and the therapy was approved as a highly advanced medical technology in 2003. Based on these experiences, we embarked on the research and development of new-generation beam delivery facilities such as a 3D scanning method with a pencil beam and a compact rotating gantry. Clinical research using pencil-beam scanning has been in operation since May 2011.

[A case of mediastinal lymph node metastasis from rectal cancer successfully treated by carbon ion radiotherapy].

We report a case of mediastinal lymph node metastasis from rectal cancer successfully treated by carbon ion radiotherapy. A 65-year-old woman underwent sigmoid colostomy against unresectable rectal cancer. After chemoradiotherapy, primary rectal cancer became resectable and low anterior resection was performed. Curative local resection was done and chemoradiotherapeutic effect was grade 2. Chemotherapy after the operation wasn't effective enough and the size of the mediastinal lymph node increased. So she underwent carbon ion radiotherapy (52.8 Gy) which markedly decreased the lymph node size (-48%). Multi-modality therapy, such as radiation, chemotherapy, operation and carbon ion radiotherapy was applied. Successfully, locally advanced rectal cancer was resected and distant lymph node metastasis was controllable.

Treatment of malignant sinonasal tumours with intensity-modulated radiotherapy (IMRT) and carbon ion boost (C12).

BACKGROUND: Most patients with cancers of the nasal cavity or paranasal sinuses are candidates of radiation therapy either due incomplete resection or technical inoperability. Local control in this disease is dose dependent but technically challenging due to close proximity of critical organs and accompanying toxicity. Modern techniques such as IMRT improve toxicity rates while local control remains unchanged. Raster-scanned carbon ion therapy with highly conformal dose distributions may allow higher doses at comparable or reduced side-effects. METHODS/DESIGN: The IMRT-HIT-SNT trial is a prospective, mono-centric, phase II trial evaluating toxicity (primary endpoint: mucositis ≥ CTCAE°III) and efficacy (secondary endpoint: local control, disease-free and overall survival) in the combined treatment with IMRT and carbon ion boost in 30 patients with histologically proven (≥R1-resected or inoperable) adeno-/or squamous cell carcinoma of the nasal cavity or paransal sinuses. Patients receive 24 GyE carbon ions (8 fractions) and IMRT (50 Gy at 2.0 Gy/fraction). DISCUSSION: The primary objective of IMRT-HIT-SNT is to evaluate toxicity and feasibility of the proposed treatment in sinonasal malignancies. TRIAL REGISTRATION: Clinical trial identifier NCT 01220752.

Analysis of the reliability of the local effect model for the use in carbon ion treatment planning systems.

In radiotherapy with carbon ions, biological effects of treatments have to be predicted. For this purpose, one of the most used models is the local effect model (LEM) developed at the Gesellschaft für Schwerionenforschung (GSI), Germany. At the Istituto Nazionale di Fisica Nucleare, Italy, the reliability of the last published version of LEM (LEM III) in reproducing radiobiological data has been checked under both monoenergetic and spread-out Bragg peak (SOBP) carbon-ion irradiation. The reproduction of the monoenergetic measurements with the LEM was rather successful for some cell lines, while it failed for the less-radioresistant ones. The SOBP experimental trend was predicted by the LEM, but a large shift between model curves and measured points was observed.

Compensatory enlargement of the liver after treatment of hepatocellular carcinoma with carbon ion radiotherapy - relation to prognosis and liver function.

BACKGROUND AND PURPOSE: To examine whether liver volume changes affect prognosis and hepatic function in patients treated with carbon ion radiotherapy (CIRT) for hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Between April 1995 and March 2003, among the cases treated with CIRT, 43 patients with HCC limited to the right hepatic lobe were considered eligible for the study. The left lateral segment was defined as the non-irradiated region. Liver volume was measured using contrast CT at 0, 3, 6, and 12 months after CIRT. We examined serum albumin, prothrombin activity, and total bilirubin level as hepatic functional reserve. RESULTS: After CIRT, the non-irradiated region showed significant enlargement, and enlarged volume of this region 3 months after CIRT 50 cm(3) was a prognostic factor. The 5-year overall survival rates were 48.9% in the larger enlargement group (enlarged volume of non-irradiated region 3 months after CIRT > or =50 cm(3)) and 29.4% in the smaller enlargement group (as above, <50 cm(3)). The larger enlargement group showed better hepatic functional reserve than the smaller enlargement group 12 months after CIRT. CONCLUSIONS: This study suggests that compensatory enlargement in the non-irradiated liver after CIRT contributes to the improvement of prognosis.

Monte Carlo study on secondary neutrons in passive carbon-ion radiotherapy: identification of the main source and reduction in the secondary neutron dose.

PURPOSE: Recent successful results in passive carbon-ion radiotherapy allow the patient to live for a longer time and allow younger patients to receive the radiotherapy. Undesired radiation exposure in normal tissues far from the target volume is considerably lower than that close to the treatment target, but it is considered to be non-negligible in the estimation of the secondary cancer risk. Therefore, it is very important to reduce the undesired secondary neutron exposure in passive carbon-ion radiotherapy without influencing the clinical beam. In this study, the source components in which the secondary neutrons are produced during passive carbon-ion radiotherapy were identified and the method to reduce the secondary neutron dose effectively based on the identification of the main sources without influencing the clinical beam was investigated. METHODS: A Monte Carlo study with the PHITS code was performed by assuming the beamline at the Heavy-Ion Medical Accelerator in Chiba (HIMAC). At first, the authors investigated the main sources of secondary neutrons in passive carbon-ion radiotherapy. Next, they investigated the reduction in the neutron dose with various modifications of the beamline device that is the most dominant in the neutron production. Finally, they investigated the use of an additional shield for the patient. RESULTS: It was shown that the main source is the secondary neutrons produced in the four-leaf collimator (FLC) used as a precollimator at HIAMC, of which contribution in the total neutron ambient dose equivalent is more than 70%. The investigations showed that the modification of the FLC can reduce the neutron dose at positions close to the beam axis by 70% and the FLC is very useful not only for the collimation of the primary beam but also the reduction in the secondary neutrons. Also, an additional shield for the patient is very effective to reduce the neutron dose at positions farther than 50 cm from the beam axis. Finally, they showed that the neutron dose can be reduced by approximately 70% at any position without influencing the primary beam used in treatment. CONCLUSIONS: This study was performed by assuming the HIMAC beamline; however, this study provides important information for reoptimizing the arrangement and the materials of beamline devices and designing a new facility for passive carbon-ion radiotherapy and probably passive proton radiotherapy.

Comparison of carbon ions versus protons.

At present, beam ion beam therapy has started to spread worldwide. In Europe and Asia, combined carbon/proton facilities are favored, but in the US, only proton centers are under construction. This development is partially due to the different funding procedures and partially due to the more complex physical and especially biologic features of the heavy ions. In this article, the basic properties of both ions are presented, and their features for therapy are outlined. This refers to the dose conformity, the general precision of the treatment, and the ability to monitor via in-beam positron emission tomography the ions range inside the patient. Then the very complex biologic features are treated, and, finally, the treatment plans are compared.

Comparison of the radiobiological effect of carbon ion beam therapy and conventional radiation therapy on cervical cancer.

Little clinical evidence has been provided to show the minimization of radiation resistance of tumors using high linear energy transfer radiation. We therefore investigated the radiobiological and molecular pathological aspects of carbon beam therapy. A total of 27 patients with squamous cell carcinoma (SCC) of the cervix were treated using a carbon beam and 50 control patients with SCC of the cervix using a photon beam. The expression of Ki-67, p53, and p27 proteins before radiotherapy and 5 and 15 days after therapy initiation were investigated using immunohistochemistry. Similar changes were observed in Ki-67 labeling index (LI) and p53 LI during carbon and photon beam therapies. However, for carbon beam therapy, the mean p27 LI significantly decreased from 25.2% before treatment to 18.6% on the 5th day after treatment initiation, followed by a significant increase to 36.1% on the 15th day. In contrast, for photon beam therapy, the p27 LI consistently decreased from the initial 19.9% to 13.7% on the 15th day. Histological effects were observably stronger under carbon than photon beam therapy, though no statistically significant difference was observed (p = 0.07 on the 5th day and p = 0.10 on the 15th day). The changes in p27 LI under carbon beam therapy were significantly different from those under photon beam therapy, which suggests important molecular differences in the radio-biological response between therapies. Further investigation is required to elucidate the clinical relevance of these putative changes and optimize the relative biological effectiveness of carbon beam to X-ray.

Comparison between in-beam and offline positron emission tomography imaging of proton and carbon ion therapeutic irradiation at synchrotron- and cyclotron-based facilities.

PURPOSE: The benefit of using dedicated in-beam positron emission tomography (PET) detectors in the treatment room instead of commercial tomographs nearby is an open question. This work quantitatively compares the measurable signal for in-beam and offline PET imaging, taking into account realistic acquisition strategies at different ion beam facilities. Both scenarios of pulsed and continuous irradiation from synchrotron and cyclotron accelerators are considered, because of their widespread use in most carbon ion and proton therapy centers. METHODS AND MATERIALS: A mathematical framework is introduced to compare the time-dependent amount and spatial distribution of decays from irradiation-induced isotope production. The latter is calculated with Monte Carlo techniques for real proton treatments of head-and-neck and paraspinal tumors. Extrapolation to carbon ion irradiation is based on results of previous phantom experiments. Biologic clearance is modeled taking into account available data from previous animal and clinical studies. RESULTS: Ratios between the amount of physical decays available for in-beam and offline detection range from 40% to 60% for cyclotron-based facilities, to 65% to 110% (carbon ions) and 94% to 166% (protons) at synchrotron-based facilities, and increase when including biologic clearance. Spatial distributions of decays during irradiation exhibit better correlation with the dose delivery and reduced influence of biologic processes. CONCLUSIONS: In-beam imaging can be advantageous for synchrotron-based facilities, provided that efficient PET systems enabling detection of isotope decays during beam extraction are implemented. For very short (<2 min) irradiation times at cyclotron-based facilities, a few minutes of acquisition time after the end of irradiation are needed for counting statistics, thus affecting patient throughput.

Quality of life in men treated with carbon ion therapy for prostate cancer.

PURPOSE: To prospectively assess patient quality of life (QOL) after carbon ion radiotherapy (C-ion RT) for prostate cancer, using established questionnaires. METHODS AND MATERIAL: The subjects were 150 patients who underwent C-ion RT. Of these, 25 patients with low-risk prostate cancer received C-ion RT alone, whereas the remaining 125 patients with a high-risk tumor also received androgen deprivation therapy. Quality of life was assessed using the self-administered Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire in all patients three times. In addition, the University of California-Los Angeles Prostate Cancer Index (UCLA-PCI) was conducted in the low-risk patients. RESULTS: The FACT-General (FACT-G) and FACT-P scores at 12 months after treatment averaged over all 150 patients showed no significant change compared with those before C-ion RT. In FACT-P subscales, emotional well-being increased significantly just after and 12 months after treatment. In contrast, physical well-being (PWB) and social/family well-being (S/FWB) decreased significantly at 12 months, whereas the prostate cancer subscale (PCS) decreased significantly just after treatment. Average scores for FACT-G, FACT-P, PWB, S/FWB, and PCS for the 125 patients receiving hormone therapy showed substantial detrimental changes at 12 months. In contrast, those of the 25 low-risk patients who had no hormone therapy showed no significant change. Similarly no significant change in the average of the UCLA-PCI scores in the low-risk patients was seen at 12 months. CONCLUSIONS: Average QOL parameters reported by patients with localized prostate cancer treated with C-ion RT, in the absence of hormone therapy, showed no significant decrease 12 months after C-ion RT.

Dose contributions from large-angle scattered particles in therapeutic carbon beams.

In carbon therapy, doses at center of spread-out Bragg peaks depend on field size. For a small field of 5 x 5 cm2, the central dose reduces to 96% of the central dose for the open field in case of 400 MeV/n carbon beam. Assuming the broad beam injected to the water phantom is made up of many pencil beams, the transverse dose distribution can be reconstructed by summing the dose distribution of the pencil beams. We estimated dose profiles of this pencil beam through measurements of dose distributions of broad uniform beams blocked half of the irradiation fields. The dose at a distance of a few cm from the edge of the irradiation field reaches up to a few percent of the central dose. From radiation quality measurements of this penumbra, the large-angle scattered particles were found to be secondary fragments which have lower LET than primary carbon beams. Carbon ions break up in beam modifying devices or in water phantom through nuclear interaction with target nuclei. The angular distributions of these fragmented nuclei are much broader than those of primary carbon particles. The transverse dose distribution of the pencil beam can be approximated by a function of the three-Gaussian form. For a simplest case of mono-energetic beam, contributions of the Gaussian components which have large mean deviations become larger as the depth in the water phantom increases.

Carbon ion radiotherapy of skull base chondrosarcomas.

PURPOSE: To evaluate the effectiveness and toxicity of carbon ion radiotherapy in chondrosarcomas of the skull base. PATIENTS AND METHODS: Between November 1998 and September 2005, 54 patients with low-grade and intermediate-grade chondrosarcomas of the skull base have been treated with carbon ion radiation therapy (RT) using the raster scan technique at the Gesellschaft für Schwerionenforschung in Darmstadt, Germany. All patients had gross residual tumors after surgery. Median total dose was 60 CGE (weekly fractionation 7 x 3.0 CGE). All patients were followed prospectively in regular intervals after treatment. Local control and overall survival rates were calculated using the Kaplan-Meier method. Toxicity was assessed according to the Common Terminology Criteria (CTCAE v.3.0) and the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) score. RESULTS: Median follow-up was 33 months (range, 3-84 months). Only 2 patients developed local recurrences. The actuarial local control rates were 96.2% and 89.8% at 3 and 4 years; overall survival was 98.2%at 5 years. Only 1 patient developed a mucositis CTCAE Grade 3; the remaining patients did not develop any acute toxicities >CTCAE Grade 2. Five patients developed minor late toxicities (RTOG/EORTC Grades 1-2), including bilateral cataract (n = 1), sensory hearing loss (n = 1), a reduction of growth hormone (n = 1), and asymptomatic radiation-induced white matter changes of the adjacent temporal lobe (n = 2). Grade 3 late toxicity occurred in 1 patient (1.9%) only. CONCLUSIONS: Carbon ion RT is an effective treatment for low- and intermediate-grade chondrosarcomas of the skull base offering high local control rates with low toxicity.

Biological gain of carbon-ion radiotherapy for the early response of tumor growth delay and against early response of skin reaction in mice.

The biological effectiveness of carbon ions relative to gamma rays (RBE) was compared between the tumor growth delay and an early skin reaction of syngeneic mice. The RBE was larger for a tumor than skin when irradiated with large doses of high-LET (linear energy transfer) carbon ions. The intra-track damage (a term of a linear quadratic model) of a tumor and skin increased equally with an increase of the LET, while the inter-track damage (beta term) of skin alone increased with the LET. These data provide evidence that high-LET radiotherapy could achieve therapeutic gain by minimizing the difference in response to fractionated irradiation between the tumor and normal tissue.

Two cases of orbital adenocarcinoma treated with heavy charged carbon particle irradiation.

BACKGROUND: Orbital adenocarcinoma is a relatively rare, primary orbital malignant epithelial tumor, and shares the poor prognosis of orbital adenoid cystic carcinoma. We report the cases of two patients with orbital adenocarcinoma who were treated with heavy charged carbon particle irradiation and followed up for more 6 years. METHOD: Two patients with orbital adenocarcinoma, 62 and 74 years old, received 57.6 GyE of heavy charged particle irradiation therapy. RESULTS: In both cases, the size of the tumor gradually decreased after carbon ion irradiation therapy. No recurrences or metastasis of the tumor were found for more than 6 years. CONCLUSION: Orbital adenocarcinoma has a poor prognosis in general. Two patients with orbital adenocarcinoma were treated with heavy charged carbon particle irradiation therapy and had a relatively good outcome and good prognosis. We believe that heavy charged carbon particle irradiation therapy is a promising therapy for orbital adenoid cystic carcinoma and adenocarcinoma.