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Background Nasopharyngeal carcinoma (NPC) is a rare tumor with highly recurrent and lack of effective treatment. Long non- coding RNAs (lncRNAs) have been reported to play roles in various cancers including NPC. Methods In the current study, two cell lines of NPC (CNE-2Z and 5-8F cells) were transfected with short hairpin RNA (shRNA) targeting lncRNA-ENST00000412010 (shlncRNA) or control shRNA (shControl). Cell proliferation, survival, in vitro colony formation, and in vivo xenograft tumor formation were then investigated. Results The study found that cells transfected with shlncRNA grew significantly slower than the cells transfected with shControl as measured on day 5; increased in Annexin V expression; decreased in colony formation; and smaller in xenograft tumor size on day 45. Expression of DNA damage-inducible transcript 3, dual specificity protein phosphatase 5, insulin receptor substrate 1, interleukin-6, and tribbles homolog 3 genes was significantly up-regulated in the cells transfected with shlncRNA, while gene expression of matrix metalloproteinase-7 and cyclin-dependent kinase 4 inhibitor B was significantly down-regulated in the cells transfected with shlncRNA. Immunoblotting assay confirmed DUSP5 protein was significantly increased while proteins of MMP-7 and CDKN2B were significantly lower in the cells lacking lncRNA than that of the control cells. Conclusions These findings suggested that lncRNA-ENST00000412010 plays a role in modulating NPC survival and tumorigenesis through regulating molecules associated with cell cycle and protein phosphatase.

Betatrophin is a recently identified protein that has been shown to be associated with lipid metabolism and insulin resistance. This study aimed to measure serum betatrophin concentrations in patients with type 2 diabetes (T2DM) and evaluate the association of betatrophin with diabetic retinopthy (DR). Serum betatrophin concentrations were compared between (1) gender-, age- and body mass index-matched T2DM patients with (n=17) or without (n=33) DR; (2) gender-, age-, and body mass index-matched healthy subjects (n=31), newly-diagnosed T2DM patients before treatment (n=24), and T2DM patients under antidiabetic treatment (n=35). Serum betatrophin concentrations were determined by the enzyme-linked immunosorbent assay. Multivariate logistic regression was performed to assess the association between betatrophin concentration and DR. Serum betatrophin concentration was significantly associated with DR in T2DM patients under treatment (Odds Ratio 2.01; 95% Confidence Interval 1.12-3.60; p=0.019). Betatrophin concentrations were significantly increased in treated T2DM patients compared to the healthy subjects (4.17±0.60 vs. 0.54±0.07 ng/ml; p0.001). Serum betatrophin concentrations are increased in T2DM patients under antidiabetic treatment and positively associated with diabetic retinopathy.

Purpose Stereotactic radiosurgery (SRS) is an effective alternative to microsurgical resection or embolization for definitive treatment of arteriovenous malformations (AVMs). Digital subtraction angiography (DSA) is the gold standard for pretreatment diagnosis and characterization of vascular anatomy, but requires rigid frame (skull) immobilization when used in combination with SRS. With the advent of advanced proton and image-guided photon delivery systems, SRS treatment is increasingly migrating to frameless platforms, which are incompatible with frame-based DSA. Without DSA as the primary image, target definition may be less than optimal, in some cases precluding the ability to treat with a frameless system. This article reports a novel solution. Methods and Materials Fiducial markers are implanted into the patient’s skull before angiography. Angiography is performed according to the standard clinical protocol, but, in contrast to the previous practice, without the rigid frame. Separate images of a specially designed localizer box are subsequently obtained. A target volume projected on DSA can be transferred to the localizer system in three dimensions, and in turn be transferred to multiple CT slices using the implanted fiducials. Combined with other imaging modalities, this “virtual frame” approach yields a highly precise treatment plan that can be delivered by frameless SRS technologies. Results Phantom measurements for point and volume targets have been performed. The overall uncertainty of placing a point target to CT is 0.4 mm. For volume targets, deviation of the transformed contour from the target CT image is within 0.6 mm. The algorithm and software are robust. The method has been applied clinically, with reliable results. Conclusions A novel and reproducible method for frameless SRS of AVMs has been developed that enables the use of DSA without the requirement for rigid immobilization. Multiple pairs of DSA can be used for better conformality. Further improvement, including using nonimplanted fiducials, is potentially feasible.

Purpose: To compare the effect of respiration-induced motion on delivered dose (the interplay effect) for different treatment techniques under realistic clinical conditions. Methods: A flexible resin tumor model was created using rapid prototyping techniques based on a computed tomography (CT) image of an actual tumor. Twenty micro-MOSFETs were inserted into the tumor model and the tumor model was inserted into an anthropomorphic breathing phantom. Phantom motion was programed using the motion trajectory of an actual patient. A four-dimensional CT image was obtained and several treatment plans were created using different treatment techniques and planning systems: Conformal (Eclipse), step-and-shoot intensity-modulated radiation therapy (IMRT) (Pinnacle), step-and-shoot IMRT (XiO), dynamic IMRT (Eclipse), complex dynamic IMRT (Eclipse), hybrid IMRT [60% conformal, 40% dynamic IMRT (Eclipse)], volume-modulated arc therapy (VMAT) [single-arc (Eclipse)], VMAT [double-arc (Eclipse)], and complex VMAT (Eclipse). The complex plans were created by artificially pushing the optimizer to give complex multileaf collimator sequences. Each IMRT field was irradiated five times and each VMAT field was irradiated ten times, with each irradiation starting at a random point in the respiratory cycle. The effect of fractionation was calculated by randomly summing the measured doses. The maximum deviation for each measurement point per fraction and the more » probability that 95% of the model tumor had dose deviations less than 2% and 5% were calculated as a function of the number of fractions. Tumor control probabilities for each treatment plan were calculated and compared. Results: After five fractions, measured dose deviations were less than 2% for more than 95% of measurement points within the tumor model for all plans, except the complex dynamic IMRT, step-and-shoot IMRT (XiO), complex VMAT, and single-arc VMAT plans. Reducing the dose rate of the complex IMRT plans from 600 to 200 MU/min reduced the dose deviations to less than 2%. Dose deviations were less than 5% after five fractions for all plans, except the complex single-arc VMAT plan. Conclusions: Rapid prototyping techniques can be used to create realistic tumor models. For most treatment techniques, the dose deviations averaged out after several fractions. Treatments with unusually complicated multileaf collimator sequences had larger dose deviations. For IMRT treat-ments, dose deviations can be reduced by reducing the dose rate. For VMAT treatments, using two arcs instead of one is effective for reducing dose deviations. « less

Purpose There are no data on how complication rates after accelerated partial-breast irradiation delivered by three-dimensional conformal radiotherapy are affected by treatment technique. We therefore examined the risk of pneumonitis in relation to lung dose-volume parameters. Patients and Methods Our prospective dose-escalation trial enrolled 198 treated patients from 2003 to 2007. Patients received 32 or 36 Gy in 4-Gy fractions, given twice daily: 29 (14%) were treated with pure photons; 149 (77%) with mixed photons and electrons; and 20 (10%) with protons. Results There were four cases of pneumonitis at 4, 4, 7, and 9 months after treatment. All were in the 36-Gy cohort and were treated with pure photons. The risk of pneumonitis for the two cohorts combined was: 17% (four of 24) for an ipsilateral lung volume (ILV) receiving 20 Gy or higher (ILV, 20 Gy) of 3% or higher (P = .0002 for comparison to ILV 20 Gy < 3%, Fisher's exact test); 20% (four of 20) for an ILV 10 Gy of 10% or higher (P = .0001); and 15% (four of 26) for an ILV 5 Gy of 20% or higher (P = .0002). Conclusion The risk of pneumonitis appeared related to the ILV treated. This volume can be reduced by using mixed photons and electron when possible. We recommend that the ILV 20 Gy should be lower than 3%, the ILV 10 Gy lower than 10%, and the ILV 5 Gy lower than 20% when purely coplanar techniques are used.

For short-range high-LET radiation therapy, the biological effects are strongly affected by the heterogeneity of the specific energy distribution delivered to tumor cells. Three-dimensional information at the cellular level is ideal for this type of study, but it is extremely difficult to obtain. In this paper, a novel microdosimetry analysis, which obtains the specific energy distribution directly from the morphological information in individual autoradiographic sections, is applied to in vivo human glioblastoma multiforme and normal brain tissue in boron neutron capture therapy. Specific energy distributions were obtained for both specimens, and they are consistent with a uniform boron microdistribution. We also used a biophysical model for cell survival analysis based on the specific energy and were able to bridge it with the model based on the corresponding macroscopic parameter (dose) using existing experimental data. The survival constant for the microscopic model was determined; cell survival curves were predicted for uniform and non-uniform source distributions, i.e., sources and cell nuclei bound together totally or only partially. The results indicate that the behavior of the survival curve can vary widely, which may have important clinical implications.

Purpose Respiratory motion presents a significant challenge in stereotactic body radiosurgery. Respiratory tracking that follows the translational movement of the internal fiducials minimizes the uncertainties in dose delivery. However, the effect of deformation, defined as any changes in the body and organs relative to the center of fiducials, remains unanswered. This study investigated this problem and a possible solution. Methods and Materials Dose delivery using a robotic respiratory-tracking system was studied with clinical data. Each treatment plan was designed with the computed tomography scan in the end-expiration phase. The planned beams were applied to the computed tomography scan in end-inspiration following the shift of the fiducials. The dose coverage was compared with the initial plan, and the uncertainty due to the deformation was estimated. A necessary margin from the clinical target volume to the planning target volume was determined to account for this and other sources of uncertainty. Results We studied 12 lung and 5 upper abdomen lesions. Our results demonstrated that for lung patients with properly implanted fiducials a 3-mm margin is required to compensate for the deformation and a 5-mm margin is required to compensate for all uncertainties. Our results for the upper abdomen tumors were still preliminary but indicated a similar result, although a larger margin might be required. Conclusion The effect of body deformation was studied. We found that adequate dose coverage for lung tumors can be ensured with proper fiducial placement and a 5-mm planning target volume margin. This approach is more practical and effective than a recent proposal to combine four-dimensional planning with respiratory tracking.

For short range high linear energy transfer (LET) radiation therapy the biological effects are strongly affected by the heterogeneity of the specific energy (z) distribution delivered to tumour cells. Three-dimensional (3-D) dosimetry information at the cellular level is required for this study. An ideal approach would be the reconstruction of the cell and the radiation source microdistribution from sequential autoradiographic sections, which is, however, not a practical solution. In this paper, a novel microdosimetry analysis method, which obtains the specific energy (z) distribution directly from the morphological information in individual autoradiographic sections, is applied to human glioblastoma multifore (GBM) and normal brain tissue specimens in boron neutron capture therapy. The results are consistent with Monte Carlo simulation and demonstrate a uniform radiation source distribution in both GBM and normal brain tissues. We also hypothesise a biophysical model based on specific energy for survival analysis. The specific energy distributions to cell nuclei were calculated with a uniform radiation source distribution. By combining this microdosimetric analysis with measured cell survival data at the low dose region, a cell survival curve at high doses is predicted, which is consistent with the commonly used simple exponential curve model for high LET radiation.

A Phase I/II clinical trial of neutron capture therapy (NCT) was conducted at Harvard–MIT using a fission converter epithermal neutron beam. This epithermal neutron beam has nearly ideal performance characteristics (high intensity and purity) and is well-suited for clinical use. Six glioblastoma multiforme (GBM) patients were treated with NCT by infusion of the tumor-selective amino acid boronophenylalanine-fructose (BPA-F) at a dose of 14.0 g/m 2 body surface area over 90 min followed by irradiation with epithermal neutrons. Treatments were planned using NCTPlan and an accelerated version of the Monte Carlo radiation transport code MCNP 4B. Treatments were delivered in two fractions with two or three fields. Field order was reversed between fractions to equalize the average blood boron concentration between fields. The initial dose in the dose escalation study was 7.0 RBE Gy, prescribed as the mean dose to the whole brain volume. This prescription dose was increased by 10% to 7.7 RBE Gy in the second cohort of patients. A pharmacokinetic model was used to predict the blood boron concentration for determination of the required beam monitor units with good accuracy; differences between prescribed and delivered doses were 1.5% or less. Estimates of average tumor doses ranged from 33.7 to 83.4 RBE Gy (median 57.8 RBE Gy), a substantial improvement over our previous trial where the median value of the average tumor dose was 25.8 RBE Gy.

The Cyberknife delivers frameless image-guided stereotactic radiosurgery to intracranial and extracranial tumors. We report our use of Cyberknife radiosurgery on a medullary plasmacytoma in the clivus extending into the foramen magnum. No acute toxicity was seen during or within 24 hours of treatment, and the subject had a complete and durable radiographic response on MRI 12+ months after treatment. To our knowledge, this is a first case of successful Cyberknife radiosurgery of a medullary plasmacytoma.

A phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase I trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24-78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15 cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The 10B carrier, L-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250 mg kg(-1) over 1 h (10 subjects), 300 mg kg(-1) over 1.5 h (two subjects), or 350 mg kg(-1) over 1.5-2 h (10 subjects). The pharmacokinetic profile of 10B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.

High-energy photon beams (>10 MV X-rays) are traditionally used for the treatment of prostate cancer to doses in excess of 70 Gy. This requires the availability of a high-energy accelerator. With the recent development of intensity modulated radiation therapy (IMRT), it has become possible to design conformal plans that significantly reduce the dose to the surrounding normal tissues. In this study the authors have investigated the feasibility of using 6 MV IMRT beams for the treatment of localized prostate cancer. The study confirms that the use of the conventional low-energy X-rays should be avoided in the high dose prostate treatment. However, the dose distributions and DVHs with 6 MV X-rays using IMRT techniques were quite acceptable and comparable to those with 15 MV X-rays in the 81 Gy treatment, despite a/spl sim/18% increase in the number of monitor units.

In radiation therapies using radionuclides emitting short-range particles, such as radioimmunotherapy or boron neutron capture therapy, the biological effects are strongly affected by the heterogeneity of the absorbed dose distribution delivered to tumor cells. The three-dimensional (3D) information of the source distribution at the cellular level is required to accurately determine the absorbed dose distribution to the individual tumor cells. Two-dimensional distribution of cell and nuclide with a resolution of 1 microm can be obtained from individual tissue sections by microautoradiography. To obtain such information in 3D, an ideal approach would be to align the serial tissue sections from a block and analyze all of them. This is straightforward in theory, but extremely difficult in practice. Furthermore, every section in the block has to be processed and analyzed, and the usage of the data from this laborious work is very inefficient. An approach presented here is to estimate the absorbed dose based on individual sections without 3D reconstruction. It is realistically workable since it avoids the most difficult task of alignment for the serial tissue sections. In addition, the absorbed dose can be estimated based on a limited number of noncontiguous sections. The validity of this approach has been tested by a Monte Carlo simulation for two representative radionuclide configurations: (a) a uniform distribution of sources and (b) a cell membrane bound source distribution. With only a limited number of sampling sections, the uncertainties in the dose estimation were estimated to approximately 15% for short-range particles.

Objectives: Stereotactic radiosurgery is an effective alternative to microsurgical resection or embolization for arteriovenous malformations (AVMs). Digital subtraction angiography (DSA), with its superior vascular resolution and dynamic demonstration of contrast flow, is the gold standard for diagnosis and anatomic characterization. In some cases, it is the only means available for making a distinction between the nidus and surrounding vasculatures. Other modalities, including CT angiography (CTA) and MR angiography (MRA), are used for radiosurgical targeting or supplying complementary information. Traditionally stereotactic radiosurgery implies the fixation of a frame as a Cartesian reference to the skull. During angiography a localizer box is attached to the frame, the 2D projected nidus in DSA is transferred to the frame’s 3D coordinate system. During CT a CT localization device is attached to the frame, so the CT image is correlated to the frame. The AVM can then be contoured in the CT and a treatment is planned. During treatment the frame is attached to a stand such that the center of the AVM is accurately placed in the isocenter. The technique allows for precise treatment. However, using a frame is uncomfortable for the patient and it somewhat limits radiosurgical options. A frameless targeting system is a major advancement in the field. The frame and other localizer boxes are no longer needed and multi-fraction treatment can be routinely performed. However, for AVM patients the standard method based on DSA is no longer possible. With CyberKnife, AVM patients can now be treated relying only on CTA, 3D rotational angiography (3DRA) or others but not DSA. This study is to develop a method with high precision that is integrated into the frameless intracranial treatment system and uses DSA as the primary imaging.

This paper describes the design of a novel ultrasonic therapy system dedicated to the breast cancer treatment and the theoretical investigation of the heating characteristics of the system. The applicator is a cylinder comprised of a stack of rings. Each ring has up to 48 transducers mounted on the inside of the ring and directed towards the centre. The transducers operate in one of two frequency bands (1.8-2.8 MHz and 4.3-40.8 MHz), arranged alternately in each ring. During treatment the patient is positioned in prone position, with the breast immersed in water and surrounded by this array. This design was modelled and optimized by 3-D simulations for a variety of treatment conditions. The simulated results demonstrate that the system has an excellent capability to achieve and maintain a temperature distribution (41.5-44 degrees C) in a quadrant to a whole breast. Initial experiments using a single ring of transducers has been performed to verify the power deposition calculation.

A site-specific ultrasound hyperthermia system has been designed for the treatment of intact breast. The system incorporates both therapeutic and imaging capabilities utilizing a cylindrical array applicator which surrounds the breast with the patient in a prone position. It is dedicated to optimizing the synergistic effect between thermal therapy and radiation in the treatment of early stage breast disease in patients with an extensive intraductal component of tumor

Purpose: Stereotactic radiosurgery(SRS) is an effective alternative to microsurgical resection or embolization for arteriorvenous malformations (AVMs). Digital Subtraction Angiography(DSA) is the gold standard for diagnosis and characterization of vascular anatomy, but it requires a frame attached to the skull. Proton and the new image‐guidedLINACSRS systems are frameless. These frameless systems represent a major progress in radiotherapy — however, they prevent the usage of DSA. Without DSA as the primary image, the outcome may be less‐than‐optimal and sometimes even impossible to treat. This study intends to solve the problem. Methods: The solution is based on a conceptual breakthrough whereby, in contrast to the previous practice where a localizer was fixed to the skull during angiography, the patient can now be angiographed under standard clinical conditions without frame and localizer, while a newly‐designed localizer box is radiographed separately. Based on several fiducials implanted into the skull, a target volume on DSA can be transferred to the localizer system in 3D, then further transferred to contours in multi‐CT slices. Combined with other imaging modalities, a treatment can be planned and executed by a routine frameless SRS. Results: Phantom tests demonstrated that the uncertainty in transferring a point target to the localizer is less than 0.3 mm. The maximum transformation errors from the localizer to CT system are ∼0.3 mm. The overall uncertainty of placing a point target to CT is 0.4 mm. For volume targets the volume determined is accurate within < 6%. The algorithm and software are robust and accurate. The method has been successfully applied clinically. Conclusions: A new reliable method for frameless Stereotactic Radiosurgery has been developed, which allows using DSA as the primary imaging in AVM treatment. Implanted fiducials are required for the time being, but using non‐implanted fiducials is feasible. This work is partially supported by the JCRT Foundation.

Purpose: To evaluate an anatomical breathing phantom and modellungtumor for IGRT and 4D applications. Method and Materials: The shape of a tumor was extracted from a patient's CTimage, and a replica tumor created in a flexible resin using rapid‐prototyping techniques. A 5mm grid of fine holes was included in the modeltumor to allow insertion of up to 30 micro‐mosfets. The physical characteristics of this tumor were compared with those of real patient tumors. This tumor was inserted into a commercial anatomic breathing phantom (RSD Inc.). This phantom includes spine, and a flexible ribcage. The tumor and phantom's chest motion were programmed using real patient traces. CTimages (4D and free breathing), kilo‐voltage setup images (including fluoroscopy), and mega‐voltage portal images were compared with those from real patients. Twenty mosfets were inserted into the modeltumor, and the phantom was irradiated using a step‐and‐shoot IMRT plan. The expected dose distribution was calculated using a previously validated 4D Monte Carlo technique. Results: The appearance of the phantom/tumor in kV and MV images was very similar to real patient images. The average CT number of the modeltumor was 76 (at 120kVp), compared with 30 for the real patient (an effective difference in electron density of 2%). Its physical density and hardness was 1.3g cm−3 and 27durometers (range for real tumors: 0–60), respectively. The CT numbers of the bone and soft tissue regions of the breathing phantom were in the range found for real patients. The CT number of the lung material was the same as air. Agreement between the 4D Monte Carlo and experimental DVH was better than 3%. Conclusion: Rapidprototyping techniques can be used to produce realistic low cost modeltumors that, in combination with an anatomical breathing phantom, can be used for IGRT and 4D applications.

Purpose: Accuracy in proton beam treatment planning is intimately related to the quality of the treatment planningCTimage set characterized by Hounsfield unit (HU). Relative electron density (ED) or relative stopping power (RSP) is associated with HU for inhomogeneity corrections. Variability of these parameters from several scanners is evaluated. Methods: HU‐ED curves were obtained from 15 CTscanners and a TomoTherapy unit operated in a scanner mode from nine different institutions. In all, five different RMI467 CT phantoms were used to obtain the different curves. The ED was converted to RSP using the Bethe‐Bloch formula and ionization energies in ICRU49. The various HU‐RSP curves were then compared. Results: The differences in material composition between the five RMI phantoms were well within the acceptable variation specified by the manufacturer (ranging from 8% for Lung300 to 0.5% for inner bone). The HU‐RSP curve for the TomoTherapy scanner was almost linear. The calibration curves for the 15 CTscanners exhibit similar shapes and can be described by three linear segments. In the HU range −700 to zero, the HU‐RSP curves are almost linear for all scanners, and are within 6% of each other. For the region immediately above water to RSP∼1.1, the RSP changed slowly with HU. Above RSP=1.1, the curves increases approximately linearly with HU. Except for one CTscanner, all other curves have 1.8, present HU‐RSP variation only allows linear extrapolation. Conclusion: While most CTscanners provide very similar tissue characterization, some exhibit larger variations than others probably because of the x‐ray spectrum. The RMI CT phantom could be modified to accommodate higher density materials covering the range RSP=2.0–7.0 (eg. Al‐Ta) for more accurate inhomogeneity correction for high Z materials. A point at RSP∼0.1–0.2 should also be added for the low density region.

A thermotherapy device for use in treating cancer. The thermotherapy device includes a radio frequency power source for energizing transducers to output ultrasound waves to heat a patient treatment site. The transducers are arranged in a cylindrical shape to treat the patient and a variable number of ultrasound transducers can provide a customized therapy treatment.