Magnetic hybrid Pd/Fe-oxide nanoparticles meet the demands for ablative thermo-brachytherapy.

OBJECTIVE: To investigate the potential of hybrid Pd/Fe-oxide magnetic nanoparticles designed for thermo-brachytherapy of breast cancer, considering their specific loss power (SLP) and clinical constraints in the applied magnetic field. METHODS: Hybrid nanoparticles consisting of palladium-core and iron oxide shell of increasing thickness, were suspended in water and their SLPs were measured at varying magnetic fields (12-26 mT peak) and frequencies (50-730 kHz) with a commercial alternating magnetic field generator (magneTherm™ Digital, nanoTherics Ltd.). RESULTS: Validation of the heating device used in this study with commercial HyperMag-C nanoparticles showed a small deviation (±4%) over a period of 1 year, confirming the reliability of the method. The integration of dual thermometers, one in the center and one at the bottom of the sample vial, allowed monitoring of homogeneity of the sample suspensions. SLPs measurements on a series of nanoparticles of increasing sizes showed the highest heating for the diameter of 21 nm (SLP = 225 W/g) at the applied frequencies of 346 and 730 kHz. No heating was observed for the nanoparticles with the size <14 nm, confirming the importance of the size-parameter. The heating ability of the best performing Pd/Fe-oxide-21 was calculated to be sufficient to ablate tumors with a radius ±4 and 12 mm using 10 and 1 mg/mL nanoparticle concentration, respectively. CONCLUSIONS: Nanoparticles consisting of non-magnetic palladium-core and magnetic iron oxide shell are suitable for magnetic hyperthermia/thermal ablation under clinically safe conditions of 346 kHz and 19.1 mT, with minimal eddy current effects in combination with maximum SLP.

MRI-guided Radiation Therapy: An Emerging Paradigm in Adaptive Radiation Oncology.

Radiation therapy (RT) continues to be one of the mainstays of cancer treatment. Considerable efforts have been recently devoted to integrating MRI into clinical RT planning and monitoring. This integration, known as MRI-guided RT, has been motivated by the superior soft-tissue contrast, organ motion visualization, and ability to monitor tumor and tissue physiologic changes provided by MRI compared with CT. Offline MRI is already used for treatment planning at many institutions. Furthermore, MRI-guided linear accelerator systems, allowing use of MRI during treatment, enable improved adaptation to anatomic changes between RT fractions compared with CT guidance. Efforts are underway to develop real-time MRI-guided intrafraction adaptive RT of tumors affected by motion and MRI-derived biomarkers to monitor treatment response and potentially adapt treatment to physiologic changes. These developments in MRI guidance provide the basis for a paradigm change in treatment planning, monitoring, and adaptation. Key challenges to advancing MRI-guided RT include real-time volumetric anatomic imaging, addressing image distortion because of magnetic field inhomogeneities, reproducible quantitative imaging across different MRI systems, and biologic validation of quantitative imaging. This review describes emerging innovations in offline and online MRI-guided RT, exciting opportunities they offer for advancing research and clinical care, hurdles to be overcome, and the need for multidisciplinary collaboration.

Radiation and/or endocrine therapy? Recurrence and survival outcomes in women over 70 with early breast cancer after breast-conserving surgery.

PURPOSE: Women over 70 with early breast cancer treated with breast-conserving surgery are typically offered adjuvant endocrine and radiation therapy. Prior studies have supported the omission of adjuvant radiation in this low-risk population. We sought to compare the effect of adjuvant treatment with endocrine therapy alone, radiation therapy alone or both versus no adjuvant treatment on local control and survival in this population. METHODS: Data were extracted on 1363 breast cancer patients over the age of 70 treated with a breast-conserving surgery from 2003 until 2018. 460 patients met inclusion criteria of pT1N0, invasive disease with negative margins and not treated with chemotherapy. The primary outcome of this population-based study was local recurrence-free survival at 5 and 10 years. RESULTS: Patients receiving no adjuvant therapy had worse local recurrence-free, loco-regional recurrence-free and disease-free survival than patients receiving at least one form of adjuvant therapy (p < 0.05). 5-year local recurrence rates were 0.8% in patients receiving both endocrine and radiation therapy, 1.5% in those receiving radiation alone, 4.2% in those receiving endocrine therapy alone and 12% in those receiving no adjuvant therapy. CONCLUSIONS: This study supports the benefit of some form of adjuvant therapy (radiation alone, endocrine therapy alone or both) in low-risk breast cancer patients over 70. Receiving no adjuvant therapy is associated with poorer outcomes. Many of these patients are candidates for Accelerated Partial Breast Irradiation which can be completed in less than a week. These patients should be offered radiation therapy, endocrine therapy or both.

Dual-Receptor-Targeted (DRT) Radiation Nanomedicine Labeled with 177Lu Is More Potent for Killing Human Breast Cancer Cells That Coexpress HER2 and EGFR Than Single-Receptor-Targeted (SRT) Radiation Nanomedicines.

Resistance to HER2-targeted therapies in breast cancer (BC) is associated in some cases with an increased expression of epidermal growth factor receptors (EGFR). We describe a dual-receptor-targeted (DRT) radiation nanomedicine for local intratumoral (i.t.) treatment of BC composed of 15 nm sized gold nanoparticles (AuNPs) modified with trastuzumab (TmAb) to target HER2 and panitumumab (PmAb) to target EGFR. The AuNPs were modified with poly(ethylene glycol) (PEG3k) linked to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex the ß-particle emitter, 177Lu. Our aim was to compare the properties of these DRT-AuNP-177Lu with single-receptor-targeted (SRT)-TmAb-AuNP-177Lu or PmAb-AuNP-177Lu or nontargeted (NT)-AuNP-177Lu using human BC cells that expressed HER2, EGFR, or both receptors. To construct these radiation nanomedicines, PEG5K was linked to TmAb or PmAb, while PEG3k was linked to DOTA. These polymers were conjugated to AuNP via two Au-thiol bonds using a terminal lipoic acid (LA) group on the polymers. NT-AuNP-177Lu were constructed without modification with TmAb or PmAb. MDA-MB-231-H2N, MDA-MB-468, and BT-474 human BC cells were designated as HER2mod/EGFRmod, EGFRhigh/HER2neg, and HER2high/EGFRlow, respectively, based on the expression of these receptors. Specific binding to HER2 and/or EGFR was assessed by incubating BC cells with DRT-AuNP-177Lu or TmAb-AuNP-177Lu or PmAb-AuNP-177Lu, or NT-AuNP-177Lu in the absence or presence of an excess of TmAb or PmAb or both competitors. Binding and internalization of AuNP by BC cells were assessed by dark-field microscopy. Cell fractionation studies were conducted to quantify AuNP-177Lu bound and internalized. The cytotoxicity of DRT-AuNP-177Lu was determined in clonogenic survival (CS) assays after an exposure of 5 × 105 BC cells to 3 MBq (1.4 × 1012 AuNP) for 16 h and then seeding and culturing the cells for 7-15 days. CS was compared to exposure to TmAb-AuNP-177Lu and PmAb-AuNP-177Lu or NT-AuNP-177Lu. The absorbed doses to the nucleus in these CS assays were estimated. DRT-AuNP-177Lu were specifically bound by BC cells that expressed HER2 or EGFR or both receptors. In contrast, SRT-TmAb-AuNP-177Lu and PmAb-AuNP-177Lu were bound and internalized only by BC cells that expressed HER2 or EGFR, respectively. NT-AuNP-177Lu exhibited very low binding to BC cells. DRT-AuNP-177Lu and SRT-TmAb-AuNP-177Lu or PmAb-AuNP-177Lu were internalized by BC cells in accordance with the receptor expression. Importantly, DRT-AuNP-177Lu were more potent in vitro than PmAb-AuNP-177Lu for killing MDA-MB-231-H2N cells that coexpress HER2 and EGFR (CS = 18.8 ± 1.0 vs 51.5 ± 10.4%; P = 0.006). Furthermore, DRT-AuNP-177Lu were more potent for killing BT-474 cells with high HER2 but low EGFR expression than TmAb-AuNP-177Lu (CS = 8.9 ± 3.3 vs 20.7 ± 2.4%; P = 0.007) or PmAb-AuNP-177Lu (CS = 63.9 ± 1.7%; P < 0.0001). Even for MDA-MB-468 cells that overexpress EGFR but have negligible HER2, DRT-AuNP-177Lu were more potent for cell killing than PmAb-AuNP-177Lu (CS = 3.2 ± 3.0 vs 7.5 ± 1.8%; P = 0.001) or TmAb-AuNP-177Lu (63.2 ± 3.2%; P = 0.0002). All targeted forms of AuNP-177Lu were more cytotoxic to BC cells than those of NT-AuNP-177Lu. High absorbed doses (36-119 Gy) were deposited in the nucleus of BC cells by DRT-AuNP-177Lu. We conclude that a DRT radiation nanomedicine is more potent for killing BC cells that coexpress HER2 and EGFR than SRT radiation nanomedicines. These results are promising for further evaluation of these DRT-AuNP-177Lu in vivo for the local radiation treatment of human BC tumors that coexpress HER2 and EGFR in mice following i.t. injection, especially tumors that are resistant to HER2-targeted therapies.

Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab-Modified Gold Nanoparticles Labeled with 177Lu.

PURPOSE: To compare the effectiveness of trastuzumab-modified gold nanoparticles (AuNP) labeled with 177Lu (trastuzumab-AuNP-177Lu) targeted to HER2 with non-targeted AuNP-177Lu for killing HER2-overexpressing breast cancer (BC) cells in vitro and inhibiting tumor growth in vivo following intratumoral (i.t.) injection. METHODS: AuNP (30 nm) were modified with polyethylene glycol (PEG) polymers linked to trastuzumab or to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex 177Lu. The binding and internalization of trastuzumab-AuNP-177Lu in HER2-positive SK-BR-3, BT-474 and MDA-MB-361 human BC cells were studied. Clonogenic survival and DNA double-strand breaks (DSBs) were measured after exposure of SK-BR-3 or MDA-MB-361 cells to trastuzumab-AuNP-177Lu or AuNP-177Lu. NOD/SCID mice with s.c. MDA-MB-361 tumor xenografts were treated by i.t. injection of 3 MBq (0.15 mg) of trastuzumab-AuNP-177Lu, AuNP-177Lu or normal saline. Tumor growth was measured over 16 days and normal tissue toxicity evaluated. RESULTS: Trastuzumab-AuNP-177Lu was bound and internalized by HER2 positive BC cells (KD = 7.6 ± 2.0 nM). Trastuzumab-AuNP-177Lu was 42.9 and 2.6-fold more effective than AuNP-177Lu at decreasing the clonogenic survival of SK-BR-3 (1.3 × 106 HER2/cell) and MDA-MB-361 (5.1 × 105 HER2/cell) cells, respectively, exposed overnight to these agents (1.5 nM; 20 MBq/mg Au). Under the same treatment conditions, 10-fold and 2.8-fold more DNA DSBs were observed in SK-BR-3 and MDA-MB-361 cells, respectively, exposed to trastuzumab-AuNP-177Lu than AuNP-177Lu. Trastuzumab-AuNP-177Lu was 1.8-fold more effective at inhibiting tumor growth than AuNP-177Lu. No or minimal normal tissue toxicity was observed for trastuzumab-AuNP-177Lu or AuNP-177Lu treatments. CONCLUSION: Trastuzumab-AuNP-177Lu enables an efficient local radiation treatment of HER2-positive BC.

Stability and Biodistribution of Thiol-Functionalized and (177)Lu-Labeled Metal Chelating Polymers Bound to Gold Nanoparticles.

We are studying a novel radiation nanomedicine approach to treatment of breast cancer using 30 nm gold nanoparticles (AuNP) modified with polyethylene glycol (PEG) metal-chelating polymers (MCP) that incorporate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the ß-particle emitter, (177)Lu. Our objective was to compare the stability of AuNP conjugated to MCP via a single thiol [DOTA-PEG-ortho-pyridyl disulfide (OPSS)], a dithiol [DOTA-PEG-lipoic acid (LA)] or multithiol end-group [PEG-pGlu(DOTA)8-LA4] and determine the elimination and biodistribution of these (177)Lu-labeled MCP-AuNP in mice. Stability to aggregation in the presence of thiol-containing dithiothreitol (DTT), L-cysteine or glutathione was assessed and dissociation of (177)Lu-MCP from AuNP in human plasma measured. Elimination of radioactivity from the body of athymic mice and excretion into the urine and feces was measured up to 168 h post-intravenous (i.v.) injection of (177)Lu-MCP-AuNP and normal tissue uptake was determined. ICP-AES was used to quantify Au in the liver and spleen and these were compared to (177)Lu. Our results showed that PEG-pGlu(DOTA)8-LA4-AuNP were more stable to aggregation in vitro than DOTA-PEG-LA-AuNP and both forms of AuNP were more stable to thiol challenge than DOTA-PEG-OPSS-AuNP. PEG-pGlu((177)Lu-DOTA)8-LA4 was the most stable in plasma. Whole body elimination of (177)Lu was most rapid for mice injected with (177)Lu-DOTA-PEG-OPSS-AuNP. Urinary excretion accounted for >90% of eliminated (177)Lu. All (177)Lu-MCP-AuNP accumulated in the liver and spleen. Liver uptake was lowest for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP but these AuNP exhibited the greatest spleen uptake. There were differences in Au and (177)Lu in the liver for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP. These differences were not correlated with in vitro stability of the (177)Lu-MCP-AuNP. We conclude that conjugation of AuNP with PEG-pGlu((177)Lu-DOTA)8-LA4 via a multithiol functional group provided the greatest stability in vitro and lowest liver uptake in vivo and is, therefore, the most promising for constructing (177)Lu-MCP-AuNP for radiation treatment of breast cancer.

Prognostic role of adjuvant radiotherapy in triple-negative breast cancer: A historical cohort study.

The value of adjuvant radiotherapy in triple-negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N = 1,138) were included. Survival between patients receiving mastectomy only, breast-conserving therapy (BCT, lumpectomy and adjuvant radiotherapy) and mastectomy with radiotherapy were compared, and adjusted for demography, tumor characteristics and chemotherapy types. Median age at diagnosis was 53 years (range: 23-96 years). Median tumor size at diagnosis was 2.5 cm and most patients had lymph node-negative disease. The majority of patients received adjuvant chemotherapy (n = 861, 76%) comprising predominantly anthracycline-based regimes. In 775 women with T1-2, N0-1, M0 TNBCs, 5-year relative survival ratio (RSR) was highest in patients undergoing mastectomy only (94.7%, 95% CI: 88.8-98.8%), followed by BCT (90.8%, 95% CI: 85.0-94.7%), and mastectomy with radiotherapy (82.3%, 95% CI: 73.4-88.1%). The adjusted risks of mortality between the three groups were not significantly different. In 363 patients with T3-4, N2-3, M0 TNBCs, BCT was associated with highest 5-year RSR (94.1%, 95% CI: 81.3-99.4%), followed by mastectomy with radiotherapy (62.7%, 95% CI: 54.3-70.1%), and mastectomy only (58.6%, 95% CI: 43.5-71.6%). Following multivariable adjustment, BCT and mastectomy with radiotherapy remained significantly associated with lower mortality risk compared to mastectomy only. Overall, adjuvant radiotherapy was associated with higher survival in women aged <40 years, but not in older women. Adjuvant radiotherapy appears to be independently associated with a survival gain in locally advanced as well as in very young TNBC.

Adjuvant radiotherapy for primary breast cancer in BRCA1 and BRCA2 mutation carriers and risk of contralateral breast cancer with special attention to patients irradiated at younger age.

The purpose of this study was to estimate the influence of adjuvant radiotherapy for primary breast cancer (BC) on the risk of contralateral BC (CBC) in BRCA1 or BRCA2 (BRCA1/2) mutation carriers, with special attention to patients irradiated at age younger than 40 years. Additionally, tendencies in locoregional treatments and rates of contralateral risk-reducing mastectomy over time were explored. In this retrospective cohort study, 691 BRCA1/2-associated BC patients treated between 1980 and 2013 were followed from diagnosis until CBC or censoring event including ipsilateral BC recurrence, distant metastasis, contralateral risk-reducing mastectomy, other invasive cancer diagnosis, death, or loss to follow up. Hazard ratios (HR) for CBC associated with radiotherapy were estimated using Cox regression. Median follow-up time was 8.6 years [range 0.3­34.3 years]. No association between radiotherapy for primary BC and risk of CBC was found, neither in the total population (HR 0.82, 95 % CI 0.45­1.49) nor in the subgroup of patients younger than 40 years at primary diagnosis (HR 1.36, 95 % CI 0.60­3.09). During follow-up, the number of patients at risk decreased substantially since a large proportion of patients were censored after contralateral risk-reducing mastectomy or BC recurrence. Over the years, increasing preference for mastectomy without radiotherapy compared to breast-conserving surgery with radiotherapy was found ranging from less than 30 % in 1995 to almost 50 % after 2010. The rate of contralateral risk-reducing mastectomy increased over the years from less than 40 % in 1995 to more than 60 % after 2010. In this cohort of BRCA1/2-associated BC patients, no association between radiotherapy for primary BC and risk of CBC was observed in the total group, nor in the patients irradiated before the age of 40 years. The number of patients at risk after 10 and 15 years of follow-up, however, was too small to definitively exclude harmful effects of adjuvant radiotherapy.

Radiation Nanomedicine for EGFR-Positive Breast Cancer: Panitumumab-Modified Gold Nanoparticles Complexed to the ß-Particle-Emitter, (177)Lu.

Our objective was to construct a novel radiation nanomedicine for treatment of breast cancer (BC) expressing epidermal growth factor receptors (EGFR), particularly triple-negative tumors (TNBC). Gold nanoparticles (AuNP; 30 nm) were modified with polyethylene glycol (PEG) chains (4 kDa) derivatized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the ß-emitter, (177)Lu and with PEG chains (5 kDa) linked to panitumumab for targeting BC cells expressing EGFR. The AuNP were further coated with PEG chains (2 kDa) to stabilize the particles to aggregation. The binding and internalization of EGFR-targeted AuNP ((177)Lu-T-AuNP) into BC cells was studied and compared to nontargeted (177)Lu-NT-AuNP. The cytotoxicity of (177)Lu-T-AuNP and (177)Lu-NT-AuNP was measured in clonogenic assays using BC cells with widely different EGFR densities: MDA-MB-468 (10(6) receptors/cell), MDA-MB-231 (10(5) receptors/cell), and MCF-7 cells (10(4) receptors/cell). Radiation absorbed doses to the cell nucleus of MDA-MB-468 cells were estimated based on subcellular distribution. Darkfield and fluorescence microscopy as well as radioligand binding assays revealed that (177)Lu-T-AuNP were specifically bound by BC cells dependent on their EGFR density whereas the binding and internalization of (177)Lu-NT-AuNP was significantly lower. The affinity of binding of (177)Lu-T-AuNP to MDA-MB-468 cells was reduced by 2-fold compared to (123)I-labeled panitumumab (KD = 1.3 ± 0.2 nM vs 0.7 ± 0.4 nM, respectively). The cytotoxicity of (177)Lu-T-AuNP was dependent on the amount of radioactivity incubated with BC cells, their EGFR density and the radiosensitivity of the cells. The clonogenic survival (CS) of MDA-MB-468 cells overexpressing EGFR was reduced to <0.001% at the highest amount of (177)Lu-T-AuNP tested (4.5 MBq; 6 × 10(11) AuNP per 2.5 × 10(4)-1.2 × 10(5) cells). (177)Lu-T-AuNP were less effective for killing MDA-MB-231 cells or MCF-7 cells with moderate or low EGFR density (CS = 33.8 ± 1.6% and 25.8 ± 1.2%, respectively). Because the ß-particles emitted by (177)Lu have a 2 mm range, (177)Lu-NT-AuNP were also cytotoxic to BC cells due to a cross-fire effect but (177)Lu-T-AuNP were significantly more potent for killing MDA-MB-468 cells overexpressing EGFR than (177)Lu-NT-AuNP at all amounts tested. The cross-fire effect of the ß-particles emitted by (177)Lu may be valuable for eradicating BC cells in tumors that have low or moderate EGFR expression or cells that are not targeted by (177)Lu-T-AuNP as a consequence of heterogeneous intratumoral distribution. The radiation dose to the nucleus of a single MDA-MB-468 cell was 73.2 ± 6.7 Gy, whereas (177)Lu-NT-AuNP delivered 5.6 ± 0.6 Gy. We conclude that (177)Lu-T-AuNP is a promising novel radiation nanomedicine with potential application for treatment of TNBC, in which EGFR are often overexpressed.

Full-thickness closure in breast-conserving surgery: the impact on radiotherapy target definition for boost and partial breast irradiation. A multimodality image evaluation.

BACKGROUND: During breast-conserving surgery (BCS), surgeons increasingly perform full-thickness closure (FTC) to prevent seroma formation. This could potentially impair precision of target definition for boost and accelerated partial breast irradiation (APBI). The purpose of this study was to investigate the precision of target volume definition following BCS with FTC among radiation oncologists, using various imaging modalities. METHODS: Twenty clinical T1-2N0 patients, scheduled for BCS involving clip placement and FTC, were included in the study. Seven experienced breast radiation oncologists contoured the tumor bed on computed tomography (CT), magnetic resonance imaging (MRI) and fused CT-MRI datasets. A total of 361 observer pairs per image modality were analyzed. A pairwise conformity among the generated contours of the observers and the distance between their centers of mass (dCOM) were calculated. RESULTS: On CT, median conformity was 44 % [interquartile range (IQR) 28-58 %] and median dCOM was 6 mm (IQR 3-9 mm). None of the outcome measures improved when MRI or fused CT-MRI were used. In two patients, superficial closure was performed instead of FTC. In these 14 image sets and 42 observer pairs, median conformity increased to 70 %. CONCLUSIONS: Localization of the radiotherapy target after FTC is imprecise, on both CT and MRI. This could potentially lead to a geographical miss in patients at increased risk of local recurrence receiving a radiation boost, or for those receiving APBI. These findings highlight the importance for breast surgeons to clearly demarcate the tumor bed when performing FTC.

Decisional support throughout the cancer journey for older women diagnosed with early stage breast cancer: a single institutional study.

To determine if older women with early stage breast cancer have sufficient decisional support during their breast cancer journey, a questionnaire-based study was conducted at the Sunnybrook Odette Cancer Centre, in Toronto, Ontario, Canada. Women with stages I and II breast cancer, ≥60 years, were contacted upon completion of their adjuvant treatment. A questionnaire was developed based on focus groups, the literature, and consultation with patients and a multidisciplinary team of experts. The questionnaire was divided into six domains as follows: (1) information support surrounding diagnosis, (2) impact of cancer diagnosis on the patient, (3) quality of interaction with healthcare team, (4) decisional support from the healthcare team, (5) additional information needs surrounding treatment decision, and (6) information support during radiation treatment. Ninety-two of 137 patients approached were included in the analysis. Ninety percent were > 60 years at the time of diagnosis and 65% had stage I invasive breast cancer. The majority of women received adequate decisional support during their cancer journey. Approximately 90% of women indicated that they received a high level of support during their cancer diagnosis. We found no significant differences in overall decisional support based on age at diagnosis, education level, ethnicity, or the presence of co-morbidities. However, participants desired additional educational resources such as a worksheet, consultation summary, or workbook to assist in making a treatment decision. The majority of participants felt that they had sufficient support while making a treatment decision for breast cancer.

A generalized model for monitor units determination in ocular proton therapy using machine learning: A proof-of-concept study.

Objective.Determining and verifying the number of monitor units is crucial to achieving the desired dose distribution in radiotherapy and maintaining treatment efficacy. However, current commercial treatment planning system(s) dedicated to ocular passive eyelines in proton therapy do not provide the number of monitor units for patient-specific plan delivery. Performing specific pre-treatment field measurements, which is time and resource consuming, is usually gold-standard practice. This proof-of-concept study reports on the development of a multi-institutional-based generalized model for monitor units determination in proton therapy for eye melanoma treatments.Approach.To cope with the small number of patients being treated in proton centers, three European institutes participated in this study. Measurements data were collected to address output factor differences across the institutes, especially as function of field size, spread-out Bragg peak modulation width, residual range, and air gap. A generic model for monitor units prediction using a large number of 3748 patients and broad diversity in tumor patterns, was evaluated using six popular machine learning algorithms: (i) decision tree; (ii) random forest, (iii) extra trees, (iv) K-nearest neighbors, (v) gradient boosting, and (vi) the support vector regression. Features used as inputs into each machine learning pipeline were: Spread-out Bragg peak width, range, air gap, fraction and calibration doses. Performance measure was scored using the mean absolute error, which was the difference between predicted and real monitor units, as collected from institutional gold-standard methods.Main results.Predictions across algorithms were accurate within 3% uncertainty for up to 85.2% of the plans and within 10% uncertainty for up to 98.6% of the plans with the extra trees algorithm.Significance.A proof-of-concept of using machine learning-based generic monitor units determination in ocular proton therapy has been demonstrated. This could trigger the development of an independent monitor units calculation tool for clinical use.

Long-term results of hypofractionated radiation therapy for breast cancer.

BACKGROUND: The optimal fractionation schedule for whole-breast irradiation after breast-conserving surgery is unknown. METHODS: We conducted a study to determine whether a hypofractionated 3-week schedule of whole-breast irradiation is as effective as a 5-week schedule. Women with invasive breast cancer who had undergone breast-conserving surgery and in whom resection margins were clear and axillary lymph nodes were negative were randomly assigned to receive whole-breast irradiation either at a standard dose of 50.0 Gy in 25 fractions over a period of 35 days (the control group) or at a dose of 42.5 Gy in 16 fractions over a period of 22 days (the hypofractionated-radiation group). RESULTS: The risk of local recurrence at 10 years was 6.7% among the 612 women assigned to standard irradiation as compared with 6.2% among the 622 women assigned to the hypofractionated regimen (absolute difference, 0.5 percentage points; 95% confidence interval [CI], -2.5 to 3.5). At 10 years, 71.3% of women in the control group as compared with 69.8% of the women in the hypofractionated-radiation group had a good or excellent cosmetic outcome (absolute difference, 1.5 percentage points; 95% CI, -6.9 to 9.8). CONCLUSIONS: Ten years after treatment, accelerated, hypofractionated whole-breast irradiation was not inferior to standard radiation treatment in women who had undergone breast-conserving surgery for invasive breast cancer with clear surgical margins and negative axillary nodes. (ClinicalTrials.gov number, NCT00156052.)

Molecularly targeted gold nanoparticles enhance the radiation response of breast cancer cells and tumor xenografts to X-radiation.

The purpose of this study was to evaluate the effect of molecularly targeted gold nanoparticles (AuNPs) on tumor radiosensitization both in vitro and in vivo. Human Epidermal Growth Factor Receptor-2 (HER-2)-targeted AuNPs (Au-T) were synthesized by conjugating trastuzumab (Herceptin) to 30 nm AuNPs. In vitro, the cytotoxicity of Au-T or non-targeted AuNPs (Au-P) was assessed by γ-H2AX immunofluorescence microscopy for DNA damage and clonogenic survival assays. In vivo, athymic mice bearing subcutaneous MDA-MB-361 xenografts were treated with a single dose of 11 Gy of 100 kVp X-rays 24 h after intratumoral injection of Au-T (~0.8 mg of Au) or no X-radiation. Normal tissue toxicity was determined by hematology or biochemistry parameters. The combination of Au-P or Au-T with X-ray exposure increased the formation of γ-H2AX foci by 1.7 (P = 0.054) and 3.3 (P = 0.024) fold in comparison to X-radiation alone, respectively. The clonogenic survival of cells exposed to Au-T and X-rays was significantly lower from that of cells exposed to X-radiation alone, which translated to a dose enhancement factor of 1.6. In contrast, survival of cells exposed to Au-P and X-rays versus X-radiation alone were not significantly different. In vivo, the combination of Au-T and X-radiation resulted in regression of MDA-MB-361 tumors by 46 % as compared to treatment with X-radiation (16.0 % increase in tumor volume). No significant normal tissue toxicity was observed. Radiosensitization of breast cancer to X-radiation with AuNPs was successfully achieved with an optimized therapeutic strategy of molecular targeting of HER-2 and intratumoral administration.

Role of antibody-mediated tumor targeting and route of administration in nanoparticle tumor accumulation in vivo.

In this study, we have looked at enhancing tumor uptake and intracellular delivery of gold nanoparticles (AuNPs) while reducing the systemic exposure by systematic evaluation of the impact of targeting and route of administration on organ distribution. High-resolution microSPECT/CT imaging was used to track the in vivo fate of (111)In-labeled nontargeted and human epidermal growth factor receptor-2 (HER-2) targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and nonspecific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to nontargeted AuNPs. I.T. injections with HER-2 targeted AuNPs resulted in high tumor retention with low systemic exposure and represents an attractive delivery strategy. Our results provide a strategy for optimizing tumor delivery and quantifying organ distribution of this widely studied class of nanomaterial.

Comparison of visibility of iodinated hydrogel and gadolinium-modified hyaluronic acid spacer gels on computed tomography and onboard imaging.

BACKGROUND AND PURPOSE: In accelerated partial breast irradiation (APBI), accurate definition of the tumour bed is crucial to reduce the risk of local recurrence and the volume of healthy tissue irradiated. Recently, hydrogels have been proposed to improve visibility of the lumpectomy cavity for APBI. The aim of this study was to alter two commercially available hyaluronic acid (HA) gels, with gadopentenate dimeglumine (GD), a magnetic resonance imaging (MRI) contrast agent. We hypothesize that after injection in the surgical cavity, the mixtures will be visible with computed tomography (CT) for improved treatment planning, cone-beam CT (CBCT) for improved patient setup and planar kilovoltage (kV) x-ray for real-time tracking during treatment. MATERIALS AND METHODS: In this ex vivo study, GD was mixed with the two HA gels, and 1 mL of each mixture was injected into fatty and muscular tissue of a pork phantom. Visibility with CT, CBCT and planar x-ray imaging was assessed. Contrast-to-noise ratios (CNR) were measured and compared to commercially available iodinated polyethylene glycol (PEG). RESULTS: The gel mixtures showed increased visibility over HA gels without GD. When comparing CNR of the gel mixtures to that of iodinated PEG on CT, there was a 4-fold increase in muscle for both mixtures and a 1.6-fold to 3.6-fold increase in fat, depending on the HA gel. Gel mixtures showed better visibility with planar kV imaging over iodinated PEG. CONCLUSION: Addition of GD to HA gels increases visibility with CT, CBCT and planar x-ray imaging, indicating potential for improved delineation and positioning in APBI.

Feasibility Study on the Radiation Dose by Radioactive Magnetic Core-Shell Nanoparticles for Open-Source Brachytherapy.

BACKGROUND: Treatment of early-stage breast cancer currently includes surgical removal of the tumor and (partial) breast irradiation of the tumor site performed at fractionated dose. Although highly effective, this treatment is exhaustive for both patient and clinic. In this study, the theoretical potential of an alternative treatment combining thermal ablation with low dose rate (LDR) brachytherapy using radioactive magnetic nanoparticles (RMNPs) containing 103-palladium was researched. METHODS: The radiation dose characteristics and emission spectra of a single RMNP were calculated, and dose distributions of a commercial brachytherapy seed and an RMNP brachytherapy seed were simulated using Geant4 Monte Carlo toolkit. RESULTS: It was found that the RMNP seeds deliver a therapeutic dose similar to currently used commercial seed, while the dose distribution shows a spherical fall off compared to the more inhomogeneous dose distribution of the commercial seed. Changes in shell thickness only changed the dose profile between 2 × 10-4 mm and 3 × 10-4 mm radial distance to the RMNP, not effecting long-range dose. CONCLUSION: The dose distribution of the RMNP seed is comparable with current commercial brachytherapy seeds, while anisotropy of the dose distribution is reduced. Because this reduces the dependency of the dose distribution on the orientation of the seed, their surgical placement is easier. This supports the feasibility of the clinical application of the proposed novel treatment modality.

From Structure to Function: Understanding Synthetic Conditions in Relation to Magnetic Properties of Hybrid Pd/Fe-Oxide Nanoparticles.

Heterostructured magnetic nanoparticles show great potential for numerous applications in biomedicine due to their ability to express multiple functionalities in a single structure. Magnetic properties are generally determined by the morphological characteristics of nanoparticles, such as the size/shape, and composition of the nanocrystals. These in turn are highly dependent on the synthetic conditions applied. Additionally, incorporation of a non-magnetic heterometal influences the final magnetic behavior. Therefore, construction of multifunctional hybrid nanoparticles with preserved magnetic properties represents a certain nanotechnological challenge. Here, we focus on palladium/iron oxide nanoparticles designed for combined brachytherapy, the internal form of radiotherapy, and MRI-guided hyperthermia of tumors. The choice of palladium forming the nanoparticle core is envisioned for the eventual radiolabeling with 103Pd to enable the combination of hyperthermia with brachytherapy, the latter being beyond the scope of the present study. At this stage, we investigated the synthetic mechanisms and their effects on the final magnetic properties of the hybrid nanoparticles. Thermal decomposition was applied for the synthesis of Pd/Fe-oxide nanoparticles via both, one-pot and seed-mediated processes. The latter method was found to provide better control over morphology of the nanoparticles and was therefore examined closely by varying reaction conditions. This resulted in several batches of Pd/Fe-oxide nanoparticles, whose magnetic properties were evaluated, revealing the most relevant synthetic parameters leading to promising performance in hyperthermia and MRI.

Improving organs-at-risk sparing for choroidal melanoma patients: A CT-based two-beam strategy in ocular proton therapy with a dedicated eyeline.

PURPOSE: To investigate the potential clinical benefit of a two-beam arrangement technique using three-dimensional (3D) imaging of uveal melanoma (UM) patients treated with proton therapy and a dedicated eyeline. MATERIAL/METHODS: Retrospective CT-based treatment plans of 39 UM patients performed using a single beam (SB) were compared to plans with two beams (TB) optimized for better trade-offs in organs-at-risk sparing. The RBE-weighted prescribed dose was 60 Gy (DRBE, GTV = 60 Gy) in four fractions, assuming an RBE of 1.1. Dosimetric findings were analyzed for three patient groups based on tumor-optic nerve distance and UM staging (group GrA: ≤3 mm, T1 T2 UM; GrB: ≤3 mm, T3 UM; GrC: >3 mm, T1 T2 T3 UM). Finally, two schedules were compared on biologically effective dose (BED): both beams being delivered either the same day (TB), or on alternate days (TBalter). RESULTS: All strategies resulted in dosimetrically acceptable plans. A dose reduction to the anterior structures was achieved in 23/39 cases with the two-beam plans. D25% was significantly lowered compared to SB plans by 12.4 and 15.4 Gy RBE-weighted median dose in GrA and GrB, respectively. D2% was reduced by 18.6 and 6.0 Gy RBE-weighted median dose in GrA and GrB, respectively. A cost to the optic nerve was observed with a median difference up to 3.8 Gy RBE-weighted dose in GrB. BED differences were statistically significant for all considered parameters in favor of two beams delivered the same day. CONCLUSION: A two-beam strategy appears beneficial for posterior tumors abutting the optic nerve. This strategy might have a positive impact on the risk of ocular complications.

A comparison of postimplant dosimetry for (103)Pd versus (131)Cs seeds on a retrospective series of PBSI patients.

PURPOSE: Permanent breast seed implantation (PBSI) is an accelerated partial breast irradiation technique performed using stranded (103)Pd radioactive seeds (average energy of 21 keV, 16.97 day half-life). Since 2004, (131)Cs brachytherapy sources have become clinically available. The (131)Cs radionuclide has a higher energy (average energy of 30 keV) and a shorter half-life (9.7 days) than (103)Pd. The purpose of this study was to determine whether or not there are dosimetric benefits to using (131)Cs brachytherapy seeds for PBSI. METHODS: The prescribed dose for PBSI using (103)Pd is 90 Gy, which was adjusted for (131)Cs implants to account for the shorter half-life. A retrospective cohort of 30 patients, who have already undergone a (103)Pd implant, was used for this study. The treatments were planned using the Variseed treatment planning system. The air kerma strength of the (131)Cs seeds was adjusted in all preimplantation treatment plans so that the V(100) (the volume within the target that receives 100% or more of the prescribed dose) were equivalent at time of implantation. Two month follow-up CT scans were available for all 30 patients and each patient was reevaluated using (131)Cs seeds. The postimplant dosimetric parameters were compared using a two tailed t-test. RESULTS: The prescribed dose for (131)Cs was calculated to be 77 Gy; this dose would have the same biological effect as a PBSI implant with (103)Pd of 90 Gy. The activities of the (131)Cs sources were adjusted to an average of 2.2 ± 0.8 U for (131)Cs compared to 2.5 ± 1.1 U for (103)Pd in order to get an equivalent V(100) as the (103)Pd preimplants. While the use of (131)Cs significantly reduces the preimplant V(200) (the volume within the target that receives 200% or more of the prescribed dose) compared to (103)Pd by 13.5 ± 9.0%, the reduction observed on the 2 month postimplant plan was 12.4 ± 5.1% which accounted for seed motion, implantation inaccuracies and tissue changes. This translates into an absolute reduction of 4.1 cm(3) of tissue receiving 200% of the dose. CONCLUSIONS: This analysis of 30 early stage breast cancer patients who underwent the PBSI procedure shows that there is a theoretical dosimetric advantage to using (131)Cs. However, in a realistic implant that will have seed misplacements and tissue changes, the use of (131)Cs may not result in any clinically significant benefit.