Evaluation of robustness in hybrid intensity-modulated radiation therapy plans generated by commercial software for automated breast planning.

This study aimed to evaluate the robustness against geometric uncertainties in the hybrid intensity-modulated radiation therapy (IMRT) plans generated by commercially available software for automated breast planning (ABP). The ABP plans were compared with commonly used forward-planned field-in-field (FIF) technique plans. The planning computed tomography datasets of 20 patients who received left-sided breast-conserving surgery were used for both the ABP and FIF plans. Geometric uncertainties were simulated by shifting beam isocenters by 2, 3, 5, and 10 mm in the six directions: anterior/posterior, left/right, and superior/inferior. A total of 500 plans (20 patients and 25 scenarios, including the original plan) were created for each of the ABP and FIF plans. The homogeneity index of the target volume in the ABP plans was significantly better (p < 0.001) than the value in the FIF plans in the scenarios of shifting beam isocenters by 2, 3, and 5 mm. Mean heart dose and percentage volume of lungs receiving a dose more than 20 Gy were clinically acceptable in all scenarios. The hybrid IMRT plans generated by commercially available ABP software provided better robustness against geometric uncertainties than forward-planned FIF plans.

Finite element modeling of Non-Fourier heat transfer in a cancerous tissue with an injected fat layer during hyperthermia treatment.

Hyperthermia technique has received much attention over the last decade being less invasive among the others. Laser therapy is among the most commonly investigated types of ablative hyperthermia for treatment of cancer. In this method an external heat source provided by a laser fiber leads the cancerous tissue to the necrosis stage. For its simulation a cylindrical geometry of a breast tissue containing a tumor is acted upon by a Gaussian form of laser radiation. Then the feasibility of a fat layer injection around the tumor during the therapy is investigated numerically. In order to consider the finite speed of heat transfer, dual phase lag (DPL) model is implemented for prediction of the thermal results. The therapy is addressed with and without the presence of a fat layer around the breast tumor. Results show that the temperature in the tumor increases up to 15 % by the injection of a fat layer. Also, the presence of a fat layer around the tumor shows that the irreversible ablation happens at a faster rate.

Evaluation of a generalized knowledge-based planning performance for VMAT irradiation of breast and locoregional lymph nodes-Internal mammary and/or supraclavicular regions.

PURPOSE: To evaluate the performance of eleven Knowledge-Based (KB) models for planning optimization (RapidPlantm (RP), Varian) of Volumetric Modulated Arc Therapy (VMAT) applied to whole breast comprehensive of nodal stations, internal mammary and/or supraclavicular regions. METHODS AND MATERIALS: Six RP models have been generated and trained based on 120 VMAT plans data set with different criteria. Two extra-structures were delineated: a PTV for the optimization and a ring structure. Five more models, twins of the previous models, have been created without the need of these structures. RESULTS: All models were successfully validated on an independent cohort of 40 patients, 30 from the same institute that provided the training patients and 10 from an additional institute, with the resulting plans being of equal or better quality compared with the clinical plans. The internal validation shows that the models reduce the heart maximum dose of about 2 Gy, the mean dose of about 1 Gy and the V20Gy of 1.5 Gy on average. Model R and L together with model B without optimization structures ensured the best outcomes in the 20% of the values compared to other models. The external validation observed an average improvement of at least 16% for the V5Gy of lungs in RP plans. The mean heart dose and for the V20Gy for lung IPSI were almost halved. The models reduce the maximum dose for the spinal canal of more than 2 Gy on average. CONCLUSIONS: All KB models allow a homogeneous plan quality and some dosimetric gains, as we saw in both internal and external validation. Sub-KB models, developed by splitting right and left breast cases or including only whole breast with locoregional lymph nodes, have shown good performances, comparable but slightly worse than the general model. Finally, models generated without the optimization structures, performed better than the original ones.

Estimation of glandular dose in mammography based on artificial neural networks.

This work proposes using artificial neural networks (ANNs) for the regression of the dosimetric quantities employed in mammography. The data were generated by Monte Carlo (MC) simulations using a modified and validated version of the PENELOPE (v. 2014) + penEasy (v. 2015) code. A breast model of a homogeneous mixture of adipose and glandular tissue was adopted. The ANNs were constructed using the Keras and scikit-learn libraries for mean glandular dose (MGD) and air kerma (Kair ) regressions, respectively. In total, seven parameters were considered, including the incident photon energies (from 8.25 to 48.75 keV), breast geometry, breast glandularity and Kair acquisition geometry. Two ensembles of five ANNs each were formed to calculate MGD and Kair . The normalized glandular dose coefficients (DgN) were calculated using the ratio of the ensemble outputs for MGD and Kair . Polyenergetic DgN values were calculated by weighting monoenergetic values by the spectrum bin probabilities. The results indicate a very good ANN prediction performance when compared to the validation data, with median errors on the order of the average simulation uncertainties (≈ 0.2%). Moreover, the predicted DgN values are in good agreement compared with previously published works, with mean (maximum) differences up to 2.2% (9.4%). Therefore, it is shown that ANNs could be a complementary or alternative technique to tables, parametric equations and polynomial fits to estimate DgN values obtained via MC simulations.

ANALYSIS OF STRUCTURAL AND FUNCTIONAL PARAMETERS OF THE THYROID GLAND IN PATIENTS WITH MALIGNANT BREAST TUMORS, WHO SUFFERED FROM THE CHORNOBYL ACCIDENT. / ANALIZ STRUKTURNYKh I FUNKTsIONAL'NYKh POKAZNYKIV ShchYTOPODIBNOÏ ZALOZY U PATsIIeNTIV ZI ZLOIaKISNYMY NOVOUTVORENNIaMY MOLOChNOÏ ZALOZY, IaKI POSTRAZhDALY VID AVARIÏ NA ChAES.

OBJECTIVE: Study the nature of structural and functional changes in the thyroid gland in patients with malignant tumors of the mammary glands that have suffered from the Chornobyl accident. MATERIALS AND METHODS: Examination of 80 patients with malignant tumors of the mammary glands at the age of 27-85 years. In 78 patients were diagnosed with breast cancer with different stages of the spread of the tumor process. The participants in the aftermath of the accident were 12 people, living in radioactive contaminated areas - 68. Mammography was performed with the help of mammographs Senographe 700 T and 800 Tsm. Echo- graphic study of the structure of the mammary gland and the thyroid gland was performed on the ultrasound devices Nemio XG SSA-580. Computed tomography was performed on a multi-detector computed tomography 64 КТ «LightSpeed VCT¼. MRI was performed on a magnetic resonance imager «Magnetom Vision Plus 1,5 T¼. For trepan biopsies, special needles were used in combination with a biopsy system gun «Magnum¼. The functional state of the thyroid gland was studied by studying the level of the thyroid hormone in peripheral venous blood. RESULTS: The results of the ultrasound study on the structural changes in the thyroid gland (TG) and markers that characterize the functional state of the TG in women with breast cancer, show that 60 out of 80 patients who asked for help with various forms of breast cancer and examined in the clinic, revealed the presence of structural changes in the thyroid gland, which is 75 %.Сonclusions. Structural changes in the thyroid gland in patients with breast cancer, who are considered victims of the Chornobyl Nuclear Power Plant accident, were diagnosed in 75 %, of which 71.25 % of patients did not know about the presence of pathological changes in the thyroid gland before the examination in the clinic. In the struc- ture of the identified pathological changes in the thyroid gland, 47.5 % accounted for the nodular goiter, 10 % for small hydrophilic and small fibrous areas, 3.75 % for previously undergone surgery for thyroid removal, 3.75 % for chronic thyroiditis, 7.5 % - CAIT, 2.5 % - cystic changes in the thyroid gland, 3.75 % - nodular goiter and CAIT.

Doses in eye lens, thyroid, salivary glands, mammary glands, and gonads, due to radiation scattered in dental orthopantomography.

In the aim to support treatments and diagnostics in Dentistry the most common radiographies are the periapical radiography and the dental panoramic. In the dental panoramic the X-ray beam is addressed into a large zone of the face obtaining the image of the upper and lower jaw. In this procedure part of the X-rays are scattered reaching some other parts of the patient body. In this work the absorbed dose in the eye lens, thyroid, salivary glands, mammary glands, and gonads, was measured in patients undergoing a dental orthopantomography. Measurements were carried out with thermolmuminiscent dosimeters. With the absorbed doses the Effective dose were calculated. The highest dose was obtained in the salivary glands (30.4 µSv) and the lowest dose was obtained in thyroid (3.8 µSv).

Effect of internal mammary vessels radiation dose on outcomes of free flap breast reconstruction.

To assess the impact of internal mammary (IM) vessels radiation dose on autologous free-flap based breast reconstruction outcomes. We retrospectively evaluated the medical records of breast cancer patients who underwent mastectomy and free-flap breast reconstruction after postoperative radiation therapy (RT) to the breast/chest wall with (n = 9) or without (n = 11) electively including the IM lymph nodes. Twenty patients were included. Median age at diagnosis was 50 years (range, 33-63). The median time interval between the start of RT and reconstructive surgery was 16 months (range, 6-45). The maximal IM vessels dose was not associated with the risk of all complications (P = 0.44) or fat necrosis (P = 0.31). The mean IM vessels dose was not significant for the risk of all complications (P = 0.13) but was significant for fat necrosis (P = 0.04). A high mean IM vessels dose was related to the occurrence of fat necrosis.

Mean glandular dose in digital mamography in women with breast implants.

PURPOSE: Mean Glandular Dose (MGD) is the quantity related to the risk of radiation-induced breast cancer. This study aimed to evaluate the MGD in screening mammography for women with breast implants. METHODS: This retrospective study used data of 2680 mammographies of 335 asymptomatic women with mammary implants examined in a digital direct x-ray unit. Each woman had a total of eight images: four in standard views and four with posterior displacement of the implant (ID). Data on kV, mAs, target/filter combination, compressed breast thickness and MGD were obtained from the DICOM header of the stored images. Quantitative variables were presented through descriptive statistics for median (5th-95th percentiles); and the qualitative variables were presented by numbers and percentages. Mean glandular doses of standard views and ID views were compared and statistical analysis was used to assess the influence of implant position, breast glandularity and thickness on mean glandular doses. RESULTS: Median MGD for standard views were 3.30 (2.60-4.00) mGy for CC and 3.31 (2.70-4.20) mGy for MLO. For ID views, median were 1.20 (0.90-2.20) mGy and 1.40 (0.97-3.74) mGy for CC and MLO views, respectively. Median MGD for the whole examination of women with breast implants was 9.60 (7.92-12.07) mGy, ranging from 6.25 to 21.50 mGy. When comparing MGD median for standard and ID views it was found a statistically significant difference (p < 0.05), with higher doses for the standard views due to the greater compressed breast thickness in these views. It was observed that, in the standard views, MGD decreases with increasing breast thickness due to the manual radiographic techniques used to expose the women. It was also observed that implant position does not affect MGD in breast augmentation mammography. CONCLUSION: Mammography of women with mammary implants gives higher radiation doses when compared with those without implants. For more accurate dose assessment in augmented breast mammography, it is necessary that specific conversion factors for the calculation of MGD based on air kerma at entrance of breasts with implants are made available.

Functionalized MoS2-nanosheets for targeted drug delivery and chemo-photothermal therapy.

Molybdenum disulfide (MoS2) has been extensively explored for biomedical applications due to its excellent photothermal conversion ability. In this paper, we report a nanoplatform based on folic acid (FA) targeted dual-stimuli responsive MoS2 nanosheets and explore this for the treatment of FA-receptor positive human breast cancer. The nanocomposites generated had a uniform diameter (ca. 133 nm), and could be loaded with the anti-cancer drug doxorubicin (DOX) to a high capacity (151.4 mg/g). The release of DOX was greatly accelerated at pH 5.0 as compared to pH 7.4. In addition, it was found that drug release is enhanced under near infrared laser (NIR) irradiation, showing that the composites can be used as dual responsive systems, with DOX release controllable through pH or NIR irradiation. MTT assays and confocal experiments showed that the MoS2-based nanoplatform could selectively target and kill FA-positive MDA-MB-231 cells (a human breast cancer cell line). The platform also allowed the combination of chemotherapy and photothermal therapy, which led to synergistic effects superior to either monotherapy. The functionalized MoS2 nanoplatform developed in this work hence could be a potent system for targeted drug delivery and synergistic chemo-photothermal cancer therapy.

Stromal PTEN determines mammary epithelial response to radiotherapy.

The importance of the tumor-associated stroma in cancer progression is clear. However, it remains uncertain whether early events in the stroma are capable of initiating breast tumorigenesis. Here, we show that in the mammary glands of non-tumor bearing mice, stromal-specific phosphatase and tensin homolog (Pten) deletion invokes radiation-induced genomic instability in neighboring epithelium. In these animals, a single dose of whole-body radiation causes focal mammary lobuloalveolar hyperplasia through paracrine epidermal growth factor receptor (EGFR) activation, and EGFR inhibition abrogates these cellular changes. By analyzing human tissue, we discover that stromal PTEN is lost in a subset of normal breast samples obtained from reduction mammoplasty, and is predictive of recurrence in breast cancer patients. Combined, these data indicate that diagnostic or therapeutic chest radiation may predispose patients with decreased stromal PTEN expression to secondary breast cancer, and that prophylactic EGFR inhibition may reduce this risk.

Clinical and diagnosis characteristics of breast cancers in women with a history of radiotherapy in the first 30years of life: A French multicentre cohort study.

PURPOSE: Irradiation (>3Gy) to the breast or axillae before 30years of age increases the risk of secondary breast cancer (SBC). The purpose of this article is to describe the clinical characteristics of SBC and the way of diagnosis in young women (before the age of national screening) in France who had received previous radiotherapy for a childhood or a young adulthood cancer. PATIENTS AND METHODS: This retrospective, multicentre study reviewed the medical records of women with SBC before the age of the national screening who had received irradiation (≥3Gy) on part or all of the breast before 30years of age, for any type of tumour except BC. RESULTS: A total of 121 SBC were detected in 104 women with previous radiotherapy. Twenty percent of SBC were detected during regular breast screening and 16% of the women had a regular radiological follow-up. CONCLUSION: Our results points out that the main proportion of childhood cancer survivors did not benefit from the recommended breast cancer screening. This result is comparable to other previously published studies in other countries. A national screening programme is necessary and should take into account the patient's age, family history, personal medical history and previous radiotherapy to reduce the number of SBC diagnosed at an advanced stage.

Melanin of the nipple areola complex.

Biological pigments or biochromes are ubiquitous in animals, plants, and simpler organisms such as fungi and bacteria. They serve a wide spectrum of functions from photosynthesis, camouflage, mimicry, photo protection from the environment to attracting mates. The human female nipple areola complex (NAC) is a highly-pigmented area. Currently, the prevailing theory as to the evolution of the pigmented human NAC is based on infant recognition of breast feeding latching zone; however, due to the protruding shape of the nipple and surrounding breast, the authors of this letter believe that the evolutionary advantage of the pigmented NAC has a direct physiological function, namely the initiation of involution at the end of the infant lactation period.

Localisation Microscopy of Breast Epithelial ErbB-2 Receptors and Gap Junctions: Trafficking after γ-Irradiation, Neuregulin-1ß, and Trastuzumab Application.

In cancer, vulnerable breast epithelium malignance tendency correlates with number and activation of ErbB receptor tyrosine kinases. In the presented work, we observe ErbB receptors activated by irradiation-induced DNA injury or neuregulin- 1 ß application, or alternatively, attenuated by a therapeutic antibody using high resolution fluorescence localization microscopy. The gap junction turnover coinciding with ErbB receptor activation and co-transport is simultaneously recorded. DNA injury caused by 4 Gray of 6 MeV photon γ -irradiation or alternatively neuregulin- 1 ß application mobilized ErbB receptors in a nucleograde fashion-a process attenuated by trastuzumab antibody application. This was accompanied by increased receptor density, indicating packing into transport units. Factors mobilizing ErbB receptors also mobilized plasma membrane resident gap junction channels. The time course of ErbB receptor activation and gap junction mobilization recapitulates the time course of non-homologous end-joining DNA repair. We explain our findings under terms of DNA injury-induced membrane receptor tyrosine kinase activation and retrograde trafficking. In addition, we interpret the phenomenon of retrograde co-trafficking of gap junction connexons stimulated by ErbB receptor activation.

Exuberant Squamous Metaplasia with Calcification Following Intraoperative Radiotherapy for Breast Carcinoma: Report of an Unusual Case and Retrospective Review of Cases from a Single Institution.

Intraoperative radiotherapy (IORT) is a novel and increasingly utilized radiation technique in the treatment of breast carcinoma. There are few reports on the histologic changes seen in breast tissue from patients who have undergone IORT. We sought to evaluate the histologic changes observed in specimens received following IORT, as well as report an unusual case which prompted our study. A retrospective review of patients who received IORT and subsequently had breast tissue histologically evaluated at our institution was performed. Fifteen post-IORT specimens from 12 patients, including the patient from the reported case, were studied. We report a case of a 77-year-old woman found to have mammographic microcalcifications at the lumpectomy site 6 months following lumpectomy and IORT for ductal carcinoma in situ (DCIS). A stereotactic biopsy showed abundant desquamated anucleate squamous cells with calcification and keratin material associated with squamous metaplasia of ducts. Carcinoma was not present. The predominant findings in the post-IORT specimens were fat necrosis and scar (n = 5), recurrent invasive carcinoma (n = 5), surgical site changes (n = 3), abscess (n = 1), and exuberant squamous metaplasia with calcification (n = 1). Five of fifteen (33%) post-IORT specimens showed squamous metaplasia, all of which were collected within 6 months of IORT delivery. The morphologic changes observed after IORT are similar to those seen after external beam radiotherapy. Exuberant squamous metaplasia is an uncommon consequence of IORT; however, pathologists should be aware of this phenomenon and review a history of prior intraoperative radiation before raising concern for malignancy.

Two-year Follow-up of Volumetric-modulated Arc Therapy for Treating Internal Mammary Nodes in Locally Advanced Breast Cancer.

BACKGROUND/AIM: We evaluated dosimetric and clinical results of volumetric-modulated arc therapy (VMAT) treating internal mammary nodes (IMNs) in patients with locally advanced breast cancer. PATIENTS AND METHODS: Between July 2012 and December 2013, treatment outcomes of 31 patients with stage III breast cancer treated with postoperative radiotherapy including the IMN field using VMAT were analyzed. RESULTS: The median follow-up was 25.2 months. VMAT showed good homogeneity and improved conformity. The incidence of lung toxicity of grade 2 or more was 3.2%, and cardiac toxicity was not observed. No patient developed local recurrence. CONCLUSION: VMAT appears safe for the treatment of locally advanced breast cancer including the IMN field.

Assessment of the mean glandular dose using LiF:Mg,Ti, LiF:Mg,Cu,P, Li2B4O7:Mn and Li2B4O7:Cu TL detectors in mammography radiation fields.

The aim of this paper is the characterization of four thermoluminescence detectors (TLD), namely, LiF:Mg,Ti, LiF:Mg,Cu,P, Li2B4O7:Mn and Li2B4O7:Cu for the measurement of the entrance surface air kerma (ESAK) and estimation of the mean glandular dose (MGD) in digital mammography examinations at hospitals and clinics. Low-energy x-ray beams in the typical energy ranges of mammography, produced with a tungsten target and additional 60 µm molybdenum filtration were implemented and characterized at the Laboratory of Metrology of Ionizing Radiation at Instituto Superior Técnico. These beams were used for the characterization of the TLDs in terms of sensitivity, linearity, reproducibility, energy dependence and fading at 40 °C. The energy dependence test was further extended using clinical beams produced by mammography units at hospitals and clinics. The method proposed by the International Atomic Energy Agency was used for the measurement of ESAK and assessment of MGD. The combined standard uncertainty for the measurement of ESAK (and MGD) was determined in accordance to the Guide to the expression of uncertainty in measurement. The x-ray beams generated in the 23-40 kVp range presented HVL values from 0.36 to 0.46 mm Al. The beam produced at 28 kVp (HVL 0.39 mm Al) was considered as reference. The radiation field defined a circle with 84 mm diameter with a maximum variation of the beam intensity of less than 1% at the top flat (plateau) within 4 cm of the central axis. The estimated total uncertainty for the measurement of air kerma was 0.42%. All the TL detectors tested showed good performance except the commercial Li2B4O7:Mn (or TLD-800) which was excluded due to its poor sensitivity in our experimental set up. Both lithium fluorides showed better linearity and reproducibility as well as lower energy dependence and fading when compared to lithium borates. The stable behaviour of LiF:Mg,Ti and LiF:Mg,Cu,P detectors is reflected in the low combined standard uncertainty of ±5.6% and ±4.3% respectively (or ±5.1% and ±3.6% if fading is neglected). In general a total combined uncertainty lower than ±10% for the measurement of ESAK was obtained for the four TL materials studied.

Ionizing radiation-mediated premature senescence and paracrine interactions with cancer cells enhance the expression of syndecan 1 in human breast stromal fibroblasts: the role of TGF-ß.

The cell surface proteoglycan syndecan 1 (SDC1) is overexpressed in the malignant breast stromal fibroblasts, creating a favorable milieu for tumor cell growth. In the present study, we found that ionizing radiation, a well-established treatment in human breast cancer, provokes premature senescence of human breast stromal fibroblasts in vitro, as well as in the breast tissue in vivo. These senescent cells were found to overexpress SDC1 both in vitro and in vivo. By using a series of specific inhibitors and siRNA approaches, we showed that this SDC1 overexpression in senescent cells is the result of an autocrine action of Transforming Growth Factor-ß (TGF-ß) through the Smad pathway and the transcription factor Sp1, while the classical senescence pathways of p53 or p38 MAPK - NF-kB are not involved. In addition, the highly invasive human breast cancer cells MDA-MB-231 (in contrast to the low-invasive MCF-7) can also enhance SDC1 expression, both in early-passage and senescent fibroblasts via a paracrine action of TGF-ß. The above suggest that radiation-mediated premature senescence and invasive tumor cells, alone or in combination, enhance SDC1 expression in breast stromal fibroblasts, a poor prognostic factor for cancer growth, and that TGF-ß plays a crucial role in this process.

Mammary gland and radiation: Knowns and unknowns.

Effective breast cancer management and decreasing breast cancer fatalities is contingent upon reliable diagnostic procedures and treatment modalities, including those based on ionizing radiation. On the one hand, ionizing radiation is widely used for cancer diagnostics and therapy, on the other hand it is genotoxic cancer-causing agent. Here we discuss recent studies on the effects of low (diagnostic) and high (treatment) doses of ionizing radiation on healthy breast cells, breast cancer cells, and cancer cells resistant to common drug therapies.

68Ga-DOTATATE Breast Uptake and Expression in Breast Milk.

The excretion of Ga-DOTA-Octreotate (DOTATATE) and related somatostatin analogues in breast milk has not been demonstrated. We report a case of a 34-year-old woman, 7 months postpartum and breastfeeding, who was referred for DOTATATE imaging after the diagnosis of appendiceal carcinoid and subsequent appendectomy. Prominent breast uptake was noted. A breast milk sample from the patient at 90 minutes postinjection was assayed in a gamma counter and shown to have a concentration of 5.6 Bq/g per MBq administered. The excretion of DOTATATE in breast milk is important to consider when providing radiation safety advice to breastfeeding patients.

Glandular dose in breast computed tomography with synchrotron radiation.

The purpose of this work is to provide an evaluation of the mean glandular dose (MGD) for breast computed tomography (CT) with synchrotron radiation in an axial scanning configuration with a partial or total organ volume irradiation, for the in vivo program of breast CT ongoing at the ELETTRA facility (Trieste, Italy). A Geant4 Monte Carlo code was implemented, simulating the photon irradiation from a synchrotron radiation source in the energetic range from 8 to 50 keV with 1 keV intervals, to evaluate the MGD. The code was validated with literature data, in terms of mammographic normalized glandular dose coefficients (DgN) and with ad hoc experimental data, in terms of computed tomography dose index (CTDI). Simulated cylindrical phantoms of different sizes (diameter at phantom base 8, 10, 12, 14 or 16 cm, axial length 1.5 times the radius) and glandular fraction by weight (0%, 14.3%, 25%, 50%, 75% and 100%) were implemented into the code. The validation of the code shows an excellent agreement both with previously published work and in terms of DgN and CDTI measurements. The implemented simulations show a dependence of the glandular dose estimate on the vertical dimension of the irradiated zone when a partial organ irradiation was implemented. Specific normalized coefficients for calculating the MGD to the whole breast or to the single irradiated slice were reported.