Semi-Supervised Deep Learning-Based Image Registration Method with Volume Penalty for Real-Time Breast Tumor Bed Localization.

Breast-conserving surgery requires supportive radiotherapy to prevent cancer recurrence. However, the task of localizing the tumor bed to be irradiated is not trivial. The automatic image registration could significantly aid the tumor bed localization and lower the radiation dose delivered to the surrounding healthy tissues. This study proposes a novel image registration method dedicated to breast tumor bed localization addressing the problem of missing data due to tumor resection that may be applied to real-time radiotherapy planning. We propose a deep learning-based nonrigid image registration method based on a modified U-Net architecture. The algorithm works simultaneously on several image resolutions to handle large deformations. Moreover, we propose a dedicated volume penalty that introduces the medical knowledge about tumor resection into the registration process. The proposed method may be useful for improving real-time radiation therapy planning after the tumor resection and, thus, lower the surrounding healthy tissues' irradiation. The data used in this study consist of 30 computed tomography scans acquired in patients with diagnosed breast cancer, before and after tumor surgery. The method is evaluated using the target registration error between manually annotated landmarks, the ratio of tumor volume, and the subjective visual assessment. We compare the proposed method to several other approaches and show that both the multilevel approach and the volume regularization improve the registration results. The mean target registration error is below 6.5 mm, and the relative volume ratio is close to zero. The registration time below 1 s enables the real-time processing. These results show improvements compared to the classical, iterative methods or other learning-based approaches that do not introduce the knowledge about tumor resection into the registration process. In future research, we plan to propose a method dedicated to automatic localization of missing regions that may be used to automatically segment tumors in the source image and scars in the target image.

Breast cancer in women aged 75 years and older - tumour characteristics and treatment options.

INTRODUCTION: An optimal approach to older women with breast cancer is still a major challenge. In this paper, we present a retrospective analysis of treatment in patients aged 75 years and older who were treated at the Holycross Cancer Centre in 2015-2019. MATERIAL AND METHODS: The analysed group consisted of 259 women. For estimation of the general status of patients, we used the Geriatric 8 questionnaire. For every patient, an individual treatment plan was established. Survival analysis was performed; disease-free survival (DFS), cancer-specific survival, and overall survival (OS) were calculated by the Kaplan-Meier method. For DFS and OS, the Cox proportional-hazard regression was applied. RESULTS: The mean age in the analysed group was 80 years. Stage I and II cancer accounted for over 80% of patients. Radical mastectomy was performed in 56% and breast-conserving surgery in over 34% of patients. Sentinel lymph node biopsy was used in 114 patients. Preoperative systemic treatment was applied in 34 and postoperative chemotherapy in 51 patients, respectively. Trastuzumab was used in 23 patients. Postoperative hormonal therapy was applied in 205 and radiotherapy in 178 patients. During the observation after the treatment 32 patients died, while 227 survived. In multivariate analysis for DFS hormonotherapy was statistically significant for OS clinical stage and hormonotherapy. CONCLUSIONS: The treatment plan for older women consisted of surgery and radiation therapy, and systemic treatment should be always considered. The decision should be made by the breast cancer team.

Nipple-sparing mastectomy with immediate breast reconstruction - early complications and outcomes of the treatment.

AIM OF THE STUDY: To assess the early complications and outcomes of the treatment of patients undergoing nipple-sparing mastectomy (NSM) with immediate breast reconstruction. MATERIAL AND METHODS: A retrospective study was performed on 120 patients who underwent 130 NSM (10 bilateral) procedures between 1.01.2015 and 31.12.2017 in two oncology centers in Poland. In 80 patients a breast cancer was recognized. Sixteen patients underwent operations on the basis of being carriers of the BRCA1 mutation. The follow-up period ranged from 10 to 34 months. The NSM procedures were performed with or without skin reduction and a free nipple-areola complex (NAC) transplant, with 130 prosthetic devices inserted subpectorally. Breast cancer patients followed the standard protocol for adjuvant therapy. RESULTS: The patients for risk-reducing mastectomies were younger. Prevalent histology was no special type (NST) in 60 out of 80 patients, mean tumor - NAC distance was 43.3 mm. The prevalent biological subtype was Luminal B HER2-negative. Adjuvant management consisted of chemotherapy in 61 and radiotherapy in 35 patients. We noted 14 cases of complications, 13 in the cancer group, and 1 in the non-cancer group. Skin necrosis was the most common. The mean time for the appearance of the complications was 2.8 months. No local recurrences were observed. CONCLUSIONS: NSM is a safe and effective surgical option for qualified patients with breast cancer and in risk-reducing mastectomies.

Retrospective evaluation of the effectiveness of radiotherapy in patients with plantar fascitis (heel spurs).

AIM: The aim of the study was the evaluation of the effectiveness of radiotherapy in patients with the feet pain caused by heel spurs. BACKGROUND: Treatment options for patients reporting these symptoms include use of suitable orthopedic footwear, the use of general or topical non-steroidal anti-inflammatory drugs or steroids, physiotherapy, manual therapy, shock wave or appropriate surgical procedures. Radiotherapy is one of the method used in patients with chronic pain syndrome. MATERIALS AND METHODS: The material consisted of 47 patients treated in Radiotherapy Department at the Holycross Cancer Center. The time of follow-up ranged from 1 to 129 months. After treatment patients were observed. RESULTS: During the first follow-up visit a complete relief of symptoms was observed in 37 patients, and the pain was felt by 10 patients for 4 months after the treatment. One patient was re-irradiated 6 months after treatment because of persistent pain. At 16 and 17 months after the onset of treatment, pain was reported by two patients. These patients were re-irradiated. One patient had recurrence of pain 48 months after completion of radiation. After the second irradiation the pain was relieved. The remaining patients, with the exception of two, experienced remission of pain, which has been documented. Tolerance of the treatment was very good. No complications of radiation were observed. CONCLUSIONS: Radiotherapy remains an attractive treatment for patients with inflammation of the heel fascia.

Subtype of breast cancer influences sentinel lymph node positivity.

Introduction: The purpose of the study was to determine the correlation between biological subtype of breast cancer and the risk of its metastasis to a sentinel lymph node. Material and methods: In the analysed group there were 1018 women with breast cancer, clinically node negative, untreated previously. Luminal A subtype was recognised in 57% of patients. A positive sentinel lymph node was detected in 26.5% of women. Results: In the multivariate analysis only age and tumour size proved to be significant for the entire group, respectively: OR = 0.59, p = 0.0004; OR = 1.96; p < 0.0001. For Luminal A subtype values were OR = 0.51, p = 0.0007; OR = 1.78, p = 0.0045, respectively. For Luminal B patients, in women over 61 years, the risk of sentinel node metastasis probability decreases by 67% and for tumours over 21 mm the probability of positive sentinel node metastasis increases by 117%. Conclusions: According to our analysis luminal breast cancers are most numerous subtypes, and in these cases we expect more frequent instances of metastasis to a sentinel node. Following the most updated and modern procedures of breast cancer patients' treatment a procedure of sentinel lymph node biopsy is used, replacing an aggressive treatment in the axilla region. In regards to our analysis we should be more vigilant in estimation of regional lymph nodes in luminal patients under sixty with high grade tumours and the tumour diameter more than 20 mm.

Kaiso Protein Expression Correlates with Overall Survival in TNBC Patients.

Triple-negative breast cancers (TNBCs) are histologically heterogenic invasive carcinomas of no specific type that lack distinctive histological characteristics. The prognosis for women with TNBC is poor. Regardless of the applied treatments, recurrences and deaths are observed 3-5 years after the diagnosis. Thus, new diagnostic markers and targets for personalized treatment are needed. The subject of our study-the Kaiso transcription factor has been found to correlate with the invasion and progression of breast cancer. The publicly available TCGA breast cancer cohort containing Illumina HiSeq RNAseq and clinical data was explored in the study. Additionally, Kaiso protein expression was assessed in formalin-fixed and paraffin-embedded tissue archive specimens using the tissue microarray technique. In this retrospective study, Kaiso protein expression (nuclear localization) was compared with several clinical factors in the cohort of 103 patients with TNBC with long follow-up time. In univariate and multivariate analysis, high Kaiso protein but not mRNA expression was correlated with better overall survival and disease-free survival, as well as with premenopausal age. The use of radiotherapy was correlated with better disease-free survival (DFS) and overall survival (OS). However, given the heterogeneity of TNBC and context-dependent molecular diversity of Kaiso signaling in cancer progression, these results must be taken with caution and require further studies.

Radiation-induced circulating microRNAs linked to echocardiography parameters after radiotherapy.

Introduction: Patients treated with radiotherapy to the chest region are at risk of cardiac sequelae, however, identification of those with greatest risk of complications remains difficult. Here, we sought to determine whether short-term changes in circulating miRNA expression are related to measures of cardiac dysfunction in follow-up. Materials and methods: Two parallel patient cohorts were enrolled and followed up for 3 years after completion of RT to treat left-sided breast cancer. In the primary group (N=28) we used a a panel of 752 miRNAs to identify miRNAs associated with radiation and cardiac indices at follow up. In the second, independent cohort (N=56) we validated those candidate miRNAs with a targeted qPCR panel. In both cohorts. serum samples were collected before RT, 24h after the last dose and 1 month after RT; cardiac echocardiography was performed 2.5-3 year after RT. Results: Seven miRNAs in the primary group showed marked changes in serum miRNAs immediately after RT compared to baseline and associations with cardiopulmonary dose-volume histogram metrics. Among those miRNAs: miR-15b-5p, miR-22-3p, miR-424-5p and miR-451a were confirmed to show significant decrease of expression 24 hours post-RT in the validation cohort. Moreover, miR-29c, miR-451 and miR-424 were correlated with the end-diastolic diameter of the left ventricle, which was also confirmed in multivariable analysis adjusting for RT-associated factors. Conclusion: We identified a subset of circulating miRNAs predictive for cardiac function impairment in patients treated for left-sided breast cancer, although longer clinical observation could determine if these can be used to predict major clinical endpoints.

Evaluation of Complete Pathological Regression after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients with BRCA1 Founder Mutation Aided Bayesian A/B Testing Approach.

The aim of this study was to evaluate the probability of pathologic complete regression (pCR) by the BRCA1 gene mutation status in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy. The study involved 143 women (mean age 55.4 ± 13.1 years) with TNBC. The BRCA1 mutation was observed in 17% of the subjects. The most commonly used (85.3%) chemotherapy regimen was four cycles of adriamycine and cyclophosphamide followed by 12 cycles of paclitaxel (4AC + 12T). The differences between clinico-pathological factors by BRCA1 status were estimated. Odds ratios and 95% confidence intervals for pCR vs. non-pCR were calculated using logistic regression. The probability distribution of pCR based on BRCA1 status was estimated using beta distributions. The presence of T3-T4 tumours, cancer in stages II and III, lymphovascular invasion, and the use of chemotherapy schedules other than 4AC + 12T significantly decreased the odds of pCR. It was established that there was a 20% chance that pCR in patients with the BRCA1 mutation was 50% or more times as frequent than in patients without the mutation. Thus, the BRCA1 mutation can be a predictive factor for pCR in patients with TNBC.

Two-year follow-up cohort study focused on gender-specific associations between socioeconomic status and body weight changes in overweight and obese middle-aged and older adults.

OBJECTIVE: As overall spread of obesity in populations is generally acknowledged to result from unhealthy lifestyles rather than individual genetic makeup, this study aimed to gain specific insights into its determinants through assessing the prevalent associations between individual socioeconomic status (SES) and weight loss in overweight and obese men and women. METHODS: A prospective, 2-year follow-up study covered 3362 (38.0% men) respondents, aged 43-64 years, body mass index ≥25 kg/m2. Changes in body weight were estimated as a percentage of initial weight. Three categories of changes were defined: gained ≥3%, stable (gained <3% or lost <3%), lost ≥3%. Body weight loss was determined against three categories: lost ≥3 to <5%, lost ≥5 to <10%, lost ≥10%. Select SES variables (ie, gender, age, education, marital status, occupational activity and income) were determined in line with the Health Status Questionnaire. The associations between SES and body weight changes were analysed with the aid of logistic regression models. The results were presented as ORs with 95% CIs. RESULTS: Only 18% of the respondents had complied with the medical recommendations on weight loss. Significant differences were encountered between the gender, age and occupational activity variables and the weight loss one. Multifactorial models were used to determine the following gender-specific associations between SES and weight loss. Men with moderate income had significantly higher odds for weight loss (≈75%), as compared with the higher earners, whereas women with low income, occupationally inactive, had significantly higher odds (≈30% and ≈50%, respectively), as compared with the high earners and occupationally active ones. CONCLUSIONS: Lower education, male gender, lower income per household, older age and unemployment status were the established factors predisposing to obesity. While aiming to ensure effectiveness of the measures specifically aimed at preventing obesity, population groups deemed most at risk of potential weight gain must prior be identified.

Cisplatin Reduces the Frequencies of Radiotherapy-Induced Micronuclei in Peripheral Blood Lymphocytes of Patients with Gynaecological Cancer: Possible Implications for the Risk of Second Malignant Neoplasms.

Gynaecologic cancers are common among women and treatment includes surgery, radiotherapy or chemotherapy, where the last two methods induce DNA damage in non-targeted cells like peripheral blood lymphocytes (PBL). Damaged normal cells can transform leading to second malignant neoplasms (SMN) but the level of risk and impact of risk modifiers is not well defined. We investigated how radiotherapy alone or in combination with chemotherapy induce DNA damage in PBL of cervix and endometrial cancer patients during therapy. Blood samples were collected from nine endometrial cancer patients (treatment with radiotherapy + chemotherapy-RC) and nine cervical cancer patients (treatment with radiotherapy alone-R) before radiotherapy, 3 weeks after onset of radiotherapy and at the end of radiotherapy. Half of each blood sample was irradiated ex vivo with 2 Gy of gamma radiation in order to check how therapy influenced the sensitivity of PBL to radiation. Analysed endpoints were micronucleus (MN) frequencies, apoptosis frequencies and cell proliferation index. The results were characterised by strong individual variation, especially the MN frequencies and proliferation index. On average, despite higher total dose and larger fields, therapy alone induced the same level of MN in PBL of RC patients as compared to R. This result was accompanied by a higher level of apoptosis and stronger inhibition of cell proliferation in RC patients. The ex vivo dose induced fewer MN, more apoptosis and more strongly inhibited proliferation of PBL of RC as compared to R patients. These results are interpreted as evidence for a sensitizing effect of chemotherapy on radiation cytotoxicity. The possible implications for the risk of second malignant neoplasms are discussed.

Human papillomavirus infection predicts a better survival rate in patients with oropharyngeal cancer.

INTRODUCTION: Squamous cell carcinoma is the most common malignant tumour occurring in the head and neck region. It is now understood that (human papillomavirus (HPV)- positive and HPV-negative diseases are two very different clinical entities associated with different outcomes. We decided to assess p16 expression status in patients with oropharyngeal cancer and retrospectively evaluate the outcomes of the treatment. MATERIAL AND METHODS: The evaluated group consisted of 98 consecutive patients with squamous cell carcinoma of the oropharynx treated in a combined way in Holycross Cancer Centre in Kielce in 2006-2014. For all patients p16 status was assessed based on the biological material. In 51 patients HPV infection was diagnosed. The Kaplan-Meier method was used to produce survival curves using the log-rank test and the Cox proportional hazard model was used to determine the risk factors. The following risk factors were included: HPV status (positive, negative), sex, age, smoking, histopathological grade of the tumour, clinical stage, and systemic therapy application. For HPV-positive and HPV-negative patients independent analyses were done including aforementioned factors, excluding HPV status. RESULTS: The observation time for HPV-positive patients was significantly longer (p = 0.0008). Fifty-eight patients died, 40 patients are alive. Number of deaths in HPV-negative patients was statistically significantly higher (p = 0.0222). A statistically significant difference in the disease-free survival probability and overall survival probability between HPV-positive and HPV-negative patients was found (p = 0.0045 and p = 0.0037 respectively). For disease-free survival a statistically significant factor of the risk of recurrence was HPV infection (p = 0.0169). For HPV-positive patients, age (p = 0.0199) and smoking (p = 0.0353) were statistically significant risk factors of recurrence. For HPV-negative patients significant risk factors of recurrence were clinical stage (p = 0.0114) and systemic therapy application (p = 0.0271). For overall survival for the entire group statistically significant risk factors were absence of HPV infection (p = 0.0123), male sex (p = 0.0426), and age (p = 0.0311). For HPV-positive patients, age (p = 0.0096) and smoking (p = 0.0387) were statistically significant risk factors of death. For HPV-negative patients significant risk factors of death were clinical stage (p = 0.0120) and systemic therapy application (p = 0.0460). CONCLUSIONS: Our data show that HPV infection is a predictor of better disease-free and overall survival in patients with oropharyngeal cancer. For HPV-positive oropharyngeal cancer patients weekly given cisplatin with concurrent radiotherapy can be an alternative to three weekly given cisplatin considering effectiveness and early toxicity.

Serum MicroRNAs as Xerostomia Biomarkers in Patients With Oropharyngeal Cancer Undergoing Radiation Therapy.

PURPOSE: Severe xerostomia is noted in the majority of patients irradiated for oropharyngeal cancer. Extracellular microRNAs (miRNAs) may serve as effective tools allowing prediction of radiation-related toxicity. The aim of this study was to create an efficient prognostic miRNA-based test for severe, patient-rated xerostomia 3 months after primary treatment. METHODS AND MATERIALS: This prospective study enrolled patients with oropharyngeal cancer treated between 2016 and 2018 in 3 centers in Poland. The primary endpoint was severe (grade ≥3) xerostomia as assessed by the European Organisation for Research and Treatment of Cancer H&N-35 questionnaires. Initially, a group of 10 patients with severe xerostomia was randomly selected and matched with a comparative group of 10 patients without severe xerostomia. Samples were collected before radiation therapy, after receiving 20 Gy, and within 24 hours after treatment completion. Quantitative real-time polymerase chain reaction arrays (QIAGEN, Hilden, Germany) were used to quantify expression levels of 752 miRNAs in the serum at all timepoints. The resulting logistic-regression based model was validated in additional 60 patients: 30 with grade >3 xerostomia and 30 without. RESULTS: Of 152 eligible patients, we successfully recruited 111 patients. Severe xerostomia 3 months after treatment was reported by 63 patients (56.8%). Mean dose delivered to parotid glands was higher in both the exploratory and validation cohort. The model based on miR-185-5p and miR-425-5p expression levels measured before the start of radiation therapy had an area under the curve of 0.96 (95% confidence interval, 0.88-1.00). The model based on the same miRNAs remained robust when parameters were measured after 20 Gy (area under the curve 0.90; 95% confidence interval, 0.75-1.00). These results were confirmed in the validation group. In the validation group, preradiation therapy model application yielded 73.3% sensitivity and 80.0% specificity. In the samples taken after 20 Gy, the same 2 miRNAs yielded 67.7% sensitivity and 72.4% specificity. The model including pretreatment miR-185-5p and miR-425-5p levels together with mean parotid dose yielded 90.0% sensitivity and 80.0% specificity. In the validation cohort, this model yielded 80.6% sensitivity and 55.2% specificity. The model based on miRNA levels measured after 20 Gy and mean parotid dose had 80.0% sensitivity and 100% specificity in the exploratory group. In the validation cohort its performance fell to 71.0% sensitivity and 58.6% specificity. CONCLUSIONS: Serum expression levels of miR-425-5p and miR-185-5p measured before the start of radiation therapy or during therapy (after 20 Gy) had significant prognostic value for the occurrence of severe xerostomia 3 months after treatment completion. The variability explained by miRNAs appears to be, at least partially, independent from that related to the dosimetric data.

Improving oncoplastic breast tumor bed localization for radiotherapy planning using image registration algorithms.

Knowledge about tumor bed localization and its shape analysis is a crucial factor for preventing irradiation of healthy tissues during supportive radiotherapy and as a result, cancer recurrence. The localization process is especially hard for tumors placed nearby soft tissues, which undergo complex, nonrigid deformations. Among them, breast cancer can be considered as the most representative example. A natural approach to improving tumor bed localization is the use of image registration algorithms. However, this involves two unusual aspects which are not common in typical medical image registration: the real deformation field is discontinuous, and there is no direct correspondence between the cancer and its bed in the source and the target 3D images respectively. The tumor no longer exists during radiotherapy planning. Therefore, a traditional evaluation approach based on known, smooth deformations and target registration error are not directly applicable. In this work, we propose alternative artificial deformations which model the tumor bed creation process. We perform a comprehensive evaluation of the most commonly used deformable registration algorithms: B-Splines free form deformations (B-Splines FFD), different variants of the Demons and TV-L1 optical flow. The evaluation procedure includes quantitative assessment of the dedicated artificial deformations, target registration error calculation, 3D contour propagation and medical experts visual judgment. The results demonstrate that the currently, practically applied image registration (rigid registration and B-Splines FFD) are not able to correctly reconstruct discontinuous deformation fields. We show that the symmetric Demons provide the most accurate soft tissues alignment in terms of the ability to reconstruct the deformation field, target registration error and relative tumor volume change, while B-Splines FFD and TV-L1 optical flow are not an appropriate choice for the breast tumor bed localization problem, even though the visual alignment seems to be better than for the Demons algorithm. However, no algorithm could recover the deformation field with sufficient accuracy in terms of vector length and rotation angle differences.

Evaluation of set-up deviations during the irradiation of patients suffering from breast cancer treated with two different techniques.

PURPOSE: To compare reproducibility of set-up for two different treatment techniques for external irradiation of the breast. METHODS AND MATERIALS: In total, the analysis comprised 56 pairs of portal and simulator films for 14 consecutive patients treated following breast conserving therapy and 98 pairs of portal and simulator films for 20 consecutive patients treated after mastectomy. For the first group the tangential field technique (TF technique) was used, for the second the inverse hockey stick technique (IHS technique). Evaluation of the treatment reproducibility was performed in terms of systematic and random error calculated for the whole groups, comparison of set-up accuracy by means of comparison of cumulative distribution of the length of the displacement vector. RESULTS: In the IHS and TF techniques for medial and lateral fields, displacement larger than 5 mm occurred in 28.3, 15.8 and 25.4%, respectively. For the IHS technique, the systematic errors for lateral and cranial-caudal direction were 1.9 and 1.7 mm, respectively (1 SD), the random errors for lateral and cranial-caudal direction were 2.0 and 2.5 mm. For the TF technique, the systematic errors for ventral-dorsal and cranial-caudal direction were 2.6 and 1.3 mm for medial field and 3.7 and 0.7 mm for lateral fields, respectively, the random errors for lateral and cranial-caudal direction were 2.2 and 1.0 mm for medial field and 2.9 and 1.1 for lateral field, respectively. Rotations were negligible in the IHS technique. For the TF technique the systematic and random components amounted to about 2.0 degrees (1 SD). CONCLUSIONS: Both the inverse hockey stick and standard tangential techniques showed good reproducibility of patients' set-up with respect to cranial-caudal direction. For the TF technique, the accuracy should be improved for the medial field with respect to the ventral-dorsal direction.

Comparative analysis of three functional predictive assays in lymphocytes of patients with breast and gynaecological cancer treated by radiotherapy.

PURPOSE: There is a need to develop predictive tests that would allow identifying cancer patients with a high risk of developing side effects to radiotherapy. We compared the predictive value of three functional assays: the G(0) aberration assay, the G(2) aberration assay and the alkaline comet assay in lymphocytes of breast cancer and gynaecological cancer patients. MATERIAL AND METHODS: Peripheral blood was collected from 35 patients with breast cancer and 34 patients with gynaecological cancer before the onset of therapy. Chromosomal aberrations were scored in lymphocytes irradiated in the G(0) or G(2) phase of the cell cycle. DNA repair kinetics was performed with the alkaline comet assay following irradiation of unstimulated lymphocytes. The results were compared with the severity of early and late side effects to radiotherapy. RESULTS: No correlation was observed between the results of the assays and the severity of side effects. Moreover, each assay identified different patients as radiosensitive. CONCLUSIONS: There is no simple correlation between the in vitro sensitivity of lymphocytes and the risk of developing early and late side effects.