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Melinda Csenki, Dóra Újhidy, Adrienn Cserháti, Zsuzsanna Kahán, Zoltán Varga Department of Oncotherapy, University of Szeged, Szeged, Hungary Background: Prone positioning for breast radiotherapy is preferable when the aim is a reduction of the dose to the ipsilateral lung or the heart in certain left-sided cases. Materials and methods: In 100 breast cancer cases awaiting postoperative whole-breast radiotherapy, conformal radiotherapy plans were prospectively generated in both prone and supine positions. The axillary nodal region (levels I–III) and internal mammary (IM) lymph-node region in the upper three intercostal spaces were retrospectively contoured. The mean doses to the nodal regions and the volume receiving 25 Gy (V25Gy), V45Gy, and V47.5Gy were compared between the two treatment positions. Results: In most cases, the doses to axillary levels I–III and the IM lymph nodes were inadequate, regardless of the treatment position. The nodal doses were significantly lower in the prone than in the supine position. The radiation doses to levels II–III and IM nodes were especially low. The V45Gy and V47.5Gy of the level I axillary lymph nodes were 54.6% and 40.2%, respectively, in the supine, and 3.0% and 1.7%, respectively, in the prone position. In the supine position, only 17 patients (17%) received a mean dose of 45 Gy to the axillary level I nodes. Conclusion: The radiation dose to the axillary and IM lymph nodes during breast radiotherapy is therapeutically insufficient in most cases, and is significantly lower in the prone position than in the supine position. Keywords: axillary lymph nodes, breast radiotherapy, internal mammary nodes, prone positioning, supine positioning

Histological grade is a validated prognostic factor of breast cancer but may show alterations following neoadjuvant chemotherapy (NACT). Its reporting after NACT is recommended by several guidelines, but evidence of its retained prognostic impact is scarce. Patients treated with NACT followed by surgery and having sufficient residual tumour for the determination of grade were analysed for the survival effects of posttreatment grade (yG). Kaplan-Meier analyses and the log-rank test were applied, followed by the univariable and multivariable Cox proportional hazards models. The cohort comprised 355 patients with known yG, and 320 of them had also a pretreatment grade available. Pretreatment grade changed in 99/320 (31 %) cases following NACT, and downgrading was more common (n=78/320, 24 %) than upgrading (21/320, 7 %). Among 355 breast cancer patients, those with yG3 (poorly differentiated) tumours (n=155) had worse 5-year relapse-free and overall survival estimates than those with yG2 (n=169) or yG1 (n=31) tumours. This was also substantiated by univariable analysis; however, yG lost its significance in the multivariable model. Post-NACT histological grade has a prognostic impact, but does not seem to be an independent prognosticator in the post-NACT setting; however, these results lend support for its reporting by pathologists after primary systemic treatment., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest. This is also expressed as part of the manuscript., (Copyright © 2024. Published by Elsevier GmbH.)

Radiation-induced heart disease (RIHD), a common side effect of chest irradiation, is a primary cause of mortality among patients surviving thoracic cancer. Thus, the development of novel, clinically applicable cardioprotective agents which can alleviate the harmful effects of irradiation on the heart is of great importance in the field of experimental oncocardiology. Biglycan and decorin are structurally related small leucine-rich proteoglycans which have been reported to exert cardioprotective properties in certain cardiovascular pathologies. Therefore, in the present study we aimed to examine if biglycan or decorin can reduce radiation-induced damage of cardiomyocytes. A single dose of 10 Gray irradiation was applied to induce radiation-induced cell damage in H9c2 cardiomyoblasts, followed by treatment with either biglycan or decorin at various concentrations. Measurement of cell viability revealed that both proteoglycans improved the survival of cardiac cells post-irradiation. The cardiocytoprotective effect of both biglycan and decorin involved the alleviation of radiation-induced proapoptotic mechanisms by retaining the progression of apoptotic membrane blebbing and lowering the number of apoptotic cell nuclei and DNA double-strand breaks. Our findings provide evidence that these natural proteoglycans may exert protection against radiation-induced damage of cardiac cells.

Introduction: Deep-inspirational breath hold (DIBH) is an option for heart protection in breast radiotherapy; we intended to study its individual benefit., Materials and Methods: 3DCRT treatment planning was performed in a cohort of 103 patients receiving radiotherapy of the whole breast (WBI)/chest wall (CWI) ± nodal regions (NI) both under DIBH and free breathing (FB) in the supine position, and in the WBI only cases prone (n = 45) position, too. A series of patient-related and heart dosimetry parameters were analyzed., Results: The DIBH technique provided dramatic reduction of all heart dosimetry parameters the individual benefit, however, varied. In the whole population the best predictor of benefit was the ratio of ipsilateral lung volume (ILV)FB and ILVDIBH. In the WBI cohort 9-11 patients and 5-8 patients received less dose to selected heart structures with the DIBH and prone positioning, respectively; based on meeting various dose constraints DIBH was the only solution in 6-13 cases, and prone positioning in 5-6 cases. In addition to other excellent predictors, a small ILVFB or ILVDIBH with outstanding predicting performance (AUC ≥ 0.90) suggested prone positioning. Detailed analysis consistently indicated the outstanding performance of ILVFB and ILVDIBH in predicting the benefit of one over the other technique in lowering the mean heart dose (MHD), left anterior descending coronary artery (LAD) mean dose and left ventricle(LV)-V5Gy. The preference of prone positioning was further confirmed by anatomical parameters measured on a single CT scan at the middle of the heart. Performing spirometry in a cohort of 12 patients, vital capacity showed the strongest correlation with ILVFB and ILVDIBH hence this test could be evaluated as a clinical tool for patient selection., Discussion: Individual lung volume measures estimated by spirometry and anatomical data examined prior to acquiring planning CT may support the preference of DIBH or prone radiotherapy for optimal heart protection., (© 2024 The Authors.)

A limited number of studies have focused on the mutational landscape of breast cancer in different ethnic populations within Europe and compared the data with other ethnic groups and databases. We performed whole-genome sequencing of 63 samples from 29 Hungarian breast cancer patients. We validated a subset of the identified variants at the DNA level using the Illumina TruSight Oncology (TSO) 500 assay. Canonical breast-cancer-associated genes with pathogenic germline mutations were CHEK2 and ATM . Nearly all the observed germline mutations were as frequent in the Hungarian breast cancer cohort as in independent European populations. The majority of the detected somatic short variants were single-nucleotide polymorphisms (SNPs), and only 8% and 6% of them were deletions or insertions, respectively. The genes most frequently affected by somatic mutations were KMT2C (31%), MUC4 (34%), PIK3CA (18%), and TP53 (34%). Copy number alterations were most common in the NBN , RAD51C , BRIP1 , and CDH1 genes. For many samples, the somatic mutational landscape was dominated by mutational processes associated with homologous recombination deficiency (HRD). Our study, as the first breast tumor/normal sequencing study in Hungary, revealed several aspects of the significantly mutated genes and mutational signatures, and some of the copy number variations and somatic fusion events. Multiple signs of HRD were detected, highlighting the value of the comprehensive genomic characterization of breast cancer patient populations.

Follow-up includes ongoing contact with and health education of the patient, surveillance and control of the adverse effects of surgery, oncological therapies or radiotherapy, screening of metachronous cancers, and comprehensive (physical, psychological and social) patient rehabilitation, which may be enhanced by a healthy lifestyle. Primary attention should be paid to early detection and, when needed, curative treatment of local/regional tumour recurrences. Similarly, with the hope of curative solution, it is important to recognize the entity of a low-mass and relatively indolent recurrence or metastasis (oligometastasis); however, there is still no need to investigate distant metastases by routine diagnostic imaging or assess tumour markers. Below there is a list of possible sources of support, with respect to adjuvant hormone therapy continued during long-term care, social support resources, pivotal points and professional opportunities for physical and mental rehabilitation. Individual solutions for specific issues (breast cancer risk/genetic mutation, pregnancy) are provided by constantly widening options. Ideally, a complex breast cancer survivorship programme is practised by a specially trained expert supported by a cooperative team of oncologists, surgeons, breast radiologists, social workers, physiotherapists, psycho-oncologists and psychiatrists. The approach of follow-up should be comprehensive and holistic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kahán, Szántó, Dudás, Kapitány, Molnár, Koncz and Mailáth.)

Background: The aim of the study was to individualize accelerated partial breast irradiation based on optimal dose distribution, protect risk organ and predict most advantageous technique., Materials and Methods: 138 breast cancer patients receiving postoperative APBI were enrolled. APBI plans were generated using 3D-conformal (3D-CRT), sliding window intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT). In the case of superficial tumours, additional plans were developed by adding electron beam. To planning target volume (PTV) 37.5 Gy/10 fractions, 1 fraction/day was prescribed. A novel plan quality index (PQI) served as the basis for comparisons., Results: IMRT was the most advantageous technique regarding homogeneity. VMAT provided best conformity, 3D-CR T - the lowest lung and heart exposure. PQI was the best in 45 (32.61%) VMAT, 13 (9.42%) IMRT, 9 (6.52%) 3D-CRT plans. In 71 cases (51.45%) no difference was detected. In patients with large PTV, 3D-CRT was the most favourable. Additional electron beam improved PQI of 3D-CRT plans but had no meaningful effect on IMRT or VMAT. IMRT was superior to VMAT if the tumour was superficial (p < 0.001), situated in the medial (p = 0.032) or upper quadrant (p = 0.046)., Conclusions: In half of all cases, individually selected teletherapy techniques provide superior results over others; relevance of a certain technique may be predicted by volume and PTV localization., Competing Interests: Conflicts of interest None declared., (© 2021 Greater Poland Cancer Centre.)

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-β/SMAD signaling pathway in our RIHD model.

Circulating tumor DNA (ctDNA) is increasingly employed in the screening, follow-up, and monitoring of the continuously evolving tumor; however, most ctDNA assays validated for clinical use cannot maintain the right balance between sensitivity, coverage, sample requirements, time, and cost. Here, we report our BC-monitor, a simple, well-balanced ctDNA diagnostic approach using a gene panel significant in breast cancer and an optimized multiplex PCR-based NGS protocol capable of identifying allele variant frequencies below 1% in cell-free plasma DNA. We monitored a cohort of 45 breast cancer patients prospectively enrolled into our study receiving neoadjuvant chemotherapy or endocrine therapy or palliative therapy for metastatic diseases. Their tumor mutation status was examined in the archived tumor samples and plasma samples collected before and continuously during therapy. Traceable mutations of the used 38-plex NGS assay were found in approximately two-thirds of the patients. Importantly, we detected new pathogenic variants in follow-up plasma samples that were not detected in the primary tumor and baseline plasma samples. We proved that the BC-monitor can pre-indicate disease progression four-six months earlier than conventional methods. Our study highlights the need for well-designed ctDNA monitoring during treatment and follow-up, integrated into a real-time treatment assessment, which could provide information on the active tumor DNA released into the blood.

Background: Studying the clinical utility of deep-inspirational breath-hold (DIBH) in left breast cancer radiotherapy (RT) was aimed at focusing on dosimetry and feasibility aspects., Methods: In this prospective trial all enrolled patients went through planning CT in supine position under both DIBH and free breathing (FB); in whole breast irradiation (WBI) cases prone CT was also taken. In 3-dimensional conformal radiotherapy (3DCRT) plans heart, left anterior descending coronary artery (LAD), ipsilateral lung and contralateral breast doses were analyzed. The acceptance of DIBH technique as reported by the patients and the staff was analyzed; post-RT side-effects including radiation lung changes (visual scores and lung density measurements) were collected., Results: Among 130 enrolled patients 26 were not suitable for the technique while in 16, heart or LAD dose constraints were not met in the DIBH plans. Among 54 and 34 patients receiving WBI and postmastectomy/nodal RT, respectively with DIBH, mean heart dose (MHD) was reduced to < 50%, the heart V 25 Gy to < 20%, the LAD mean dose to < 40% and the LAD maximum dose to about 50% as compared to that under FB; the magnitude of benefit was related to the relative increase of the ipsilateral lung volume at DIBH. Nevertheless, heart and LAD dose differences (DIBH vs. FB) individually varied. Among the WBI cases at least one heart/LAD dose parameter was more favorable in the prone or in the supine FB plan in 15 and 4 cases, respectively; differences were numerically small. All DIBH patients completed the RT, inter-fraction repositioning accuracy and radiation side-effects were similar to that of other breast RT techniques. Both the patients and radiographers were satisfied with the technique., Conclusions: DIBH is an excellent heart sparing technique in breast RT, but about one-third of the patients do not benefit from that otherwise laborious procedure or benefit less than from an alternative method., Trial Registration: retrospectively registered under ISRCTN14360721 (February 12, 2021).

Purpose: The neoadjuvant use of pertuzumab and trastuzumab with chemotherapy improves the pathologic complete response (pCR) in early HER2+ breast cancer. The aim of this study was to determine the pCR rate obtained with dual HER2 blockade in routine clinical practice. The secondary and tertiary objective was to investigate the impact of neoadjuvant systemic therapy (NST) on performing breast-conserving surgery and survival data. Methods: This was a multicentre, retrospective, observational study in patients with stage II and III HER2+ early breast cancer who received pertuzumab and trastuzumab-based NST. Data were collected from patients' medical records. Results: Eighty-two patients were included in the study treated in 8 cancer centers in Hungary between March 2015 and January 2020. The study included women with a median age of 50.3 years. The majority of the patients (95%) received a sequence of anthracycline-based chemotherapy followed by docetaxel. pCR was achieved in 54% of the cases. As a result of NST a significant increase of conservative breast surgeries (33% vs. 3.6% planned, p = 0.0001) was observed. Ki67 expression and neutrophil-to-lymphocyte ratio (NLR) significantly predicted pCR. None of the variables were independent predictors of DFS. Conclusion: The pCR rate achieved in our study demonstrates the reproducibility of trial data in a real-world population. The rate of breast-conserving surgery was significantly increased., Competing Interests: The authors declare that there are no known conflicts of interest associated with this publication and there was no significant financial support for this work that could have influenced its outcome. The authors state that the following financial relationships were not in any respect related to the present study. KB received consulting fees from Pfizer, Novartis, Eli Lilly, and Roche. ZH has received speaker honorarium from Roche, Pfizer, Eli-Lilly, Novartis, AstraZeneca, Amgen, Swixx, Bayer, Sandoz, Merck, Abbvie, Amicus, Egis, TEVA, Boeringer, BMS, Med-Gen Sol, and Oncompass. ZK received consulting fees from AstraZeneca EGIS, Pfizer, Novartis, Eli Lilly, Richter, and Roche. LL received consulting fees from Roche. GR received consulting fees from Pfizer, Novartis, Eli Lilly, and Roche. AR, TC, KM and BB declares no conflict of interest., (Copyright © 2021 Boér, Kahán, Landherr, Csőszi, Máhr, Ruzsa, Horváth, Budai and Rubovszky.)

Cancer management has undergone significant improvements, which led to increased long-term survival rates among cancer patients. Radiotherapy (RT) has an important role in the treatment of thoracic tumors, including breast, lung, and esophageal cancer, or Hodgkin's lymphoma. RT aims to kill tumor cells; however, it may have deleterious side effects on the surrounding normal tissues. The syndrome of unwanted cardiovascular adverse effects of thoracic RT is termed radiation-induced heart disease (RIHD), and the risk of developing RIHD is a critical concern in current oncology practice. Premature ischemic heart disease, cardiomyopathy, heart failure, valve abnormalities, and electrical conduct defects are common forms of RIHD. The underlying mechanisms of RIHD are still not entirely clear, and specific therapeutic interventions are missing. In this review, we focus on the molecular pathomechanisms of acute and chronic RIHD and propose preventive measures and possible pharmacological strategies to minimize the burden of RIHD.

Follow-up includes the permanent contact with and health education of the patient, the surveillance and control of the adverse effects of surgery, oncological therapies or radiotherapy, the screening of metachronous cancers, and the comprehensive (physical, psychological and social) rehabilitation of the patient which may be enhanced by healthy life-style. The early detection and curative management if necessary, of local/regional tumor relapse is still a priority but the routine screening of distant metastases by means of imaging studies or tumor marker tests is not justified. Supportive therapy means to endocrine therapy, available social support in Hungary, and the key issues and managing tools of physical and psychooncological care are provided. Individual solution of special issues (breast cancer risk/genetic mutation, pregnancy) may be served by widening options. Ideally, follow-up is practised by a cooperative team of oncologists, surgeons, breast radiologists, social workers, physiotherapists, psychiatrists. The follow-up approach should be comprehensive and holistic.

The radiotherapy (RT) expert panel revised and updated the RT guidelines accepted in 2016 at the 3rd Hungarian Breast Cancer Consensus Conference based on new scientific evidence. Radiotherapy after breast-conserving surgery (BCS) is indicated in ductal carcinoma in situ (St. 0), as RT decreases the risk of local recurrence (LR) by 50-60%. In early stage (St. I-II) invasive breast cancer RT remains a standard treatment following BCS. However, in elderly (≥70 years) patients with stage I, hormone receptor positive tumour hormonal therapy without RT can be considered. Hypofractionated whole breast irradiation (WBI) and for selected cases accelerated partial breast irradiation are validated treatment alternatives of conventional WBI. Following mastectomy RT significantly decreases the risk of LR and improves overall survival of patients having 1 to 3 or ≥4 positive axillary lymph nodes. In selected cases of patients with 1 to 2 positive sentinel lymph nodes axillary dissection can be substituted with axillary RT. After neoadjuvant chemotherapy (NAC) followed by BCS WBI is mandatory, while after NAC followed by mastectomy locoregional RT should be given in cases of initial stage III-IV and ypN1 axillary status.

Since the III. Breast Cancer Consensus Conference, a number of new evidence based on clinical trial results have been published which justified updating the 2016 recommendation. In addition to classical prognostic factors, some multigenic tests, which we have incorporated into the recommendation, will play an important role in therapeutic decision-making. The professional guide primarily reflects the resolutions and recommendations of the current ESMO, NCCN, ABC4, as well as the St. Gallen Consensus Conference. From a didactic point of view, the text follows first the line of early and then locally advanced breast cancer, locoregionally recurrent and metastatic breast cancer. Within these, we discuss each group according to therapeutic options.

Neoadjuvant therapy is a common form of treatment in locally advanced breast cancer (LABC) patients. Besides some guidelines for grading regression, a standardized general scheme is not yet available. The aim of our study was to compare the prognostic impact of different regression grading systems, namely the TR/NR, Chevallier, Sataloff, Denkert-Sinn, Miller-Payne, NSABP-B18, Residual Disease in Breast and Nodes and Residual Cancer Burden (RCB) on disease-free (DFS) and overall survival (OS). Data of 746 breast cancer patients treated in neoadjuvant setting between 1999 and 2019 have been included. The different regression grades and follow-up data were collected from medical charts. Statistical analysis included the Kaplan-Meier method, log-rank test and multivariate Cox regression. The average patient age was 55 years. The DFS and OS estimates of patients with complete pathological regression and residual in situ carcinoma have been significantly more favorable than those having partial regression or no signs of regression (pDFS<0.001, pOS < 0.001). Significant differences were found between DFS estimates of classes with partial regression and without regression defined by RCB. Concerning DFS estimates, the RCB classification (p = 0.019), while regarding OS data the y-stage (p = 0.011) and the nodal status (ypN; p = 0.045) were significant prognosticators by multivariate Cox regression. Regression grading systems help the evaluation of regression in LABC patients treated with neoadjuvant therapy. Of the several grading systems compared, the RCB classification makes the best distinction between the outcomes of the different classes, therefore we recommend the inclusion of RCB into the histopathological findings.

Germinal or somatic mutations of the BRCA genes may serve as therapeutic targets. Deficient functioning of the BRCA genes render the cancer vulnerable to such therapeutic interventions as chemotherapy with DNA-targeted agents and PARP inhibitors targeting DNA repair capacity. Although BRCA mutations may be detected in a large variety of cancers, the mentioned specific therapies are efficient in the so called BRCA-associated cancers only including ovarian, breast, pancreatic, prostate cancers and the rare uterine sarcomas. While in ovarian and prostate carcinomas both germinal and somatic, in breast and pancreatic cancers exclusively germinal, and in uterine sarcomas mostly somatic mutations specify the tumor as BRCA-dependent; platinum-sensitivity in ovarian cancer may replace BRCA testing by indicating the presence of frequent DNA repair deficiency. Platinum-based chemotherapy is frequently efficient in BRCA-dependent cancers, while PARP inhibitors yet registered for ovarian, breast and pancreatic cancers bring paradigm change in the treatment of ovarian cancer and provide an additional treatment option of the others.

Background: Chemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes. It is not known, however, whether treatment with various chemotherapeutic agents with different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in residual cancer. Methods: One hundred and twenty breast carcinoma cases with residual disease that were treated with one of three types of pre-operative chemotherapy regimens were selected for the study. The percentage of StrTIL was evaluated in pretreatment core biopsies (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL). TIL changes (ΔStrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL. Results: When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we detected significant StrTIL increase independently of the treatment applied. Based on distant metastases-free survival analysis, both post-StrTIL and ΔStrTIL was found to be independent prognostic factor in HR negative cases. Conclusions: Significant increase of StrTIL in the residual disease was observed in patients treated with the highly (platinum), moderately (cyclophosphamide) and marginally mutagenic chemotherapeutic agents (taxane, anthracycline). Increase in StrTIL in residual cancer compared to pretreatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.

Background: Radiotherapy is a standard treatment option for breast cancer, but it may lead to significant late morbidity, including radiation heart damage. Breast irradiation performed individually in the supine or prone position may aid in minimizing the irradiation dose to the heart and LAD coronary artery. A series of CT scans and therapy plans are needed in both positions for the 'gold standard' decision on the preferable treatment position. This method is expensive with respect to technology and physician workload. Our ultimate goal is to develop a predictive tool to identify the preferable treatment position using easily measurable patient characteristics. In this article, we describe the details of how model building and consequently validation of the best model are done., Methods: Different models were used: both logistic regression and multiple linear regressions were used to estimate the LAD mean dose difference (the difference between the mean dose to the LAD in the supine position versus prone position); predicted dose differences were analysed compared to the 'gold standard' values, and the best model was selected accordingly. The final model was checked by random cross-validation. In addition to generally used measures (ROC and Brier score), decision curves were employed to evaluate the performance of the models., Results: ROC analysis demonstrated that none of the predictors alone was satisfactory. Multiple logistic regression models and the linear regression model lead to high values of net benefit for a wide range of threshold probabilities. Multiple linear regression seemed to be the most useful model. We also present the results of the random cross-validation for this model (i.e. sensitivity of 80.7% and specificity of 87.5%)., Conclusions: Decision curves proved to be useful to evaluate our models. Our results indicate that any of the models could be implemented in clinical practice, but the linear regression model is the most useful model to facilitate the radiation treatment decision. In addition, it is in use in everyday practice in the Department of Oncotherapy, University of Szeged, Hungary.

Background: A deleterious, late-onset side effect of thoracic radiotherapy is the development of radiation-induced heart disease (RIHD). It covers a spectrum of cardiac pathology including also heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction. MicroRNA-212 (miR-212) is a crucial regulator of pathologic LVH via FOXO3-mediated pathways in pressure-overload-induced heart failure. We aimed to investigate whether miR-212 and its selected hypertrophy-associated targets play a role in the development of RIHD. Methods: RIHD was induced by selective heart irradiation (50 Gy) in a clinically relevant rat model. One, three, and nineteen weeks after selective heart irradiation, transthoracic echocardiography was performed to monitor cardiac morphology and function. Cardiomyocyte hypertrophy and fibrosis were assessed by histology at week 19. qRT-PCR was performed to measure the gene expression changes of miR-212 and forkhead box O3 (FOXO3) in all follow-up time points. The cardiac transcript level of other selected hypertrophy-associated targets of miR-212 including extracellular signal-regulated kinase 2 (ERK2), myocyte enhancer factor 2a (MEF2a), AMP-activated protein kinase, (AMPK), heat shock protein 40 (HSP40), sirtuin 1, (SIRT1), calcineurin A-alpha and phosphatase and tensin homolog (PTEN) were also measured at week 19. Cardiac expression of FOXO3 and phospho-FOXO3 were investigated at the protein level by Western blot at week 19. Results: In RIHD, diastolic dysfunction was present at every time point. Septal hypertrophy developed at week 3 and a marked LVH with interstitial fibrosis developed at week 19 in the irradiated hearts. In RIHD, cardiac miR-212 was overexpressed at week 3 and 19, and FOXO3 was repressed at the mRNA level only at week 19. In contrast, the total FOXO3 protein level failed to decrease in response to heart irradiation at week 19. Other selected hypertrophy-associated target genes failed to change at the mRNA level in RIHD at week 19. Conclusions: LVH in RIHD was associated with cardiac overexpression of miR-212. However, miR-212 seems to play a role in the development of LVH via FOXO3-independent mechanisms in RIHD. As a central regulator of pathologic remodeling, miR-212 might become a novel target for RIHD-induced LVH and heart failure.

The presence of normal tissues in the irradiated volume limits dose escalation during pelvic radiotherapy (RT) for prostate cancer. Supine and prone positions on a belly board were compared by analyzing the exposure of organs at risk (OARs) using intensity modulated RT (IMRT). The prospective trial included 55 high risk, localized or locally advanced prostate cancer patients, receiving definitive image-guided RT. Computed tomography scanning for irradiation planning was carried out in both positions. Gross tumor volume, clinical and planning target volumes (PTV) and OARs were delineated, defining subprostatic and periprostatic rectal subsegments. At the height of the largest antero-posterior (AP) diameter of the prostate, rectal diameters and distance from the posterior prostate wall were measured. IMRT plans were generated. Normal tissue exposure and structure volumes were compared between supine and prone plans using paired t-test. In the volumes of the prostate, PTV, colon and small bowel, no significant differences were found. In prone position, all rectal volumes, diameters, and rectum-prostate distance were significantly higher, the irradiated colon and small bowel volume was lower in dose ranges of 20-40 Gy, and the exposure to all rectal segments was more favorable in 40-75 Gy dose ranges. No significant difference was found in the exposure of other OARs. Prone positioning on a belly board is an appropriate positioning method aiming rectum and bowel protection during pelvic IMRT of prostate cancer. The relative reduction in rectal exposure might be a consequence of the slight departure between the prostate and rectal wall.