Nipple-Areola Complex Reconstruction Using FixNip NRI Implant after Mastectomy: An Innovative Technique.

BACKGROUND: Nipple-areolar complex reconstruction is the final stage of breast reconstruction, and it improves quality of life in patients with post-mastectomy breast cancer. We present a case of a patient with breast cancer underwent breast reconstruction and subsequent nipple-areolar complex reconstruction with an innovative biocompatible smooth silicone implant specially designed for a long-lasting restoration of the nipple-areola complex called FixNip NRI. However, to our knowledge, nipple-areolar complex reconstruction with FixNip was not previously reported. INNOVATIVE TECHNIQUE: We present an emerging technique applied on a patient with breast cancer treated with skin-sparing mastectomy and with immediate breast reconstruction using an expander and then exchanged expander to breast implant. FixNip nipple reconstruction implant is implanted for the reconstruction of the areola-nipple complex with local-regional anaesthesia. She did not develop any postoperatively short-term or long-term complications, and her nipple slowly underwent to a gradual and better definition of its profile. CONCLUSION: This new approach regarding the reconstruction of the nipple-areola complex seems to be very promising in relation to both the degree of aesthetic satisfaction of patients and the ease of use by surgeons. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

BRAFV600E;K601Q metastatic melanoma patient-derived organoids and docking analysis to predict the response to targeted therapy.

The V600E mutation in BRAF is associated with increased phosphorylation of Erk1/2 and high sensitivity to BRAFi/MEKi combination in metastatic melanoma. In very few patients, a tandem mutation in BRAF, V600 and K601, causes a different response to BRAFi/MEKi combination. BRAFV600E;K601Q patient-derived organoids (PDOs) were generated to investigate targeted therapy efficacy and docking analysis was used to assess BRAFV600E;K601Q interactions with Vemurafenib. PDOs were not sensitive to Vemurafenib and Cobimetinib given alone and sensitive to their combination, although not as responsive as BRAFV600E PDOs. The docking analysis justified such a result showing that the tandem mutation in BRAF reduced the affinity for Vemurafenib. Tumor analysis showed that BRAFV600E;K601Q displayed both increased phosphorylation of Erk1/2 at cytoplasmic level and activation of Notch resistance signaling. This prompted us to inhibit Notch signaling with Nirogacestat, achieving a greater antitumor response and providing PDOs-based evaluation of treatment efficacy in such rare metastatic melanoma.

Cryopreservation of adipose tissue with and without cryoprotective agent addition for breast lipofilling: A cytological and histological study.

In the second reconstructive phase of the breast after mastectomy, lipofilling is often necessary. Currently, lipofilling occurs immediately after autologous adipose tissue harvesting procedure, but most of the patients, usually, require multiple sessions to obtain a satisfactory result. Therefore, the need of repeated surgical harvesting outputs implies high risk of patients' morbidity and discomfort as well as increasing medical time and costs. The aim of our pilot study was to find out a feasible method to cryopreserve adipose tissue, in order to avoid reiterated liposuctions. Lipoaspirates samples have been harvested from 10 women and preserved by three methods: (1) the first one, using 10% Me2SO and 20% human albumin from human plasma as cryoprotective agents; (2) the second one, adding 5% Me2SO as cryoprotective agent; 3) the last one, without any cryoprotective agent. Fresh and cryopreserved fat samples, obtained through the aforementioned processes, have been analyzed ex vivo. The efficiency of the cryopreservation methods used was determined by adipocyte viability and the expression of adipocytes surface markers. Lipoaspirates stored at -196 °C for 3 months, after thawing, retained comparable adipocyte viability and histology to fresh tissue and no significant differences were found between the three methods used. Although the current results, differences between the methodologies in terms of viability may not become evident until breast lipofilling using frozen-thawed cryopreserved tissue.

Explainable 3D CNN based on baseline breast DCE-MRI to give an early prediction of pathological complete response to neoadjuvant chemotherapy.

BACKGROUND: So far, baseline Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) has played a key role for the application of sophisticated artificial intelligence-based models using Convolutional Neural Networks (CNNs) to extract quantitative imaging information as earlier indicators of pathological Complete Response (pCR) achievement in breast cancer patients treated with neoadjuvant chemotherapy (NAC). However, these models did not exploit the DCE-MRI exams in their full geometry as 3D volume but analysed only few individual slices independently, thus neglecting the depth information. METHOD: This study aimed to develop an explainable 3D CNN, which fulfilled the task of pCR prediction before the beginning of NAC, by leveraging the 3D information of post-contrast baseline breast DCE-MRI exams. Specifically, for each patient, the network took in input a 3D sequence containing the tumor region, which was previously automatically identified along the DCE-MRI exam. A visual explanation of the decision-making process of the network was also provided. RESULTS: To the best of our knowledge, our proposal is competitive than other models in the field, which made use of imaging data alone, reaching a median AUC value of 81.8%, 95%CI [75.3%; 88.3%], a median accuracy value of 78.7%, 95%CI [74.8%; 82.5%], a median sensitivity value of 69.8%, 95%CI [59.6%; 79.9%] and a median specificity value of 83.3%, 95%CI [82.6%; 84.0%], respectively. The median and CIs were computed according to a 10-fold cross-validation scheme for 5 rounds. CONCLUSION: Finally, this proposal holds high potential to support clinicians on non-invasively early pursuing or changing patient-centric NAC pathways.

A Machine Learning Approach for Predicting Capsular Contracture after Postmastectomy Radiotherapy in Breast Cancer Patients.

In recent years, immediate breast reconstruction after mastectomy surgery has steadily increased in the treatment pathway of breast cancer (BC) patients due to its potential impact on both the morpho-functional and aesthetic type of the breast and the quality of life. Although recent studies have demonstrated how recent radiotherapy techniques have allowed a reduction of adverse events related to breast reconstruction, capsular contracture (CC) remains the main complication after post-mastectomy radio-therapy (PMRT). In this study, we evaluated the association of the occurrence of CC with some clinical, histological and therapeutic parameters related to BC patients. We firstly performed bivariate statistical tests and we then evaluated the prognostic predictive power of the collected data by using machine learning techniques. Out of a sample of 59 patients referred to our institute, 28 patients (i.e., 47%) showed contracture after PMRT. As a result, only estrogen receptor status (ER) and molecular subtypes were significantly associated with the occurrence of CC after PMRT. Different machine learning models were trained on a subset of clinical features selected by a feature importance approach. Experimental results have shown that collected features have a non-negligible predictive power. The extreme gradient boosting classifier achieved an area under the curve (AUC) value of 68% and accuracy, sensitivity, and specificity values of 68%, 64%, and 74%, respectively. Such a support tool, after further suitable optimization and validation, would allow clinicians to identify the best therapeutic strategy and reconstructive timing.

Analyzing breast cancer invasive disease event classification through explainable artificial intelligence.

Introduction: Recently, accurate machine learning and deep learning approaches have been dedicated to the investigation of breast cancer invasive disease events (IDEs), such as recurrence, contralateral and second cancers. However, such approaches are poorly interpretable. Methods: Thus, we designed an Explainable Artificial Intelligence (XAI) framework to investigate IDEs within a cohort of 486 breast cancer patients enrolled at IRCCS Istituto Tumori "Giovanni Paolo II" in Bari, Italy. Using Shapley values, we determined the IDE driving features according to two periods, often adopted in clinical practice, of 5 and 10 years from the first tumor diagnosis. Results: Age, tumor diameter, surgery type, and multiplicity are predominant within the 5-year frame, while therapy-related features, including hormone, chemotherapy schemes and lymphovascular invasion, dominate the 10-year IDE prediction. Estrogen Receptor (ER), proliferation marker Ki67 and metastatic lymph nodes affect both frames. Discussion: Thus, our framework aims at shortening the distance between AI and clinical practice.

A machine learning ensemble approach for 5- and 10-year breast cancer invasive disease event classification.

Designing targeted treatments for breast cancer patients after primary tumor removal is necessary to prevent the occurrence of invasive disease events (IDEs), such as recurrence, metastasis, contralateral and second tumors, over time. However, due to the molecular heterogeneity of this disease, predicting the outcome and efficacy of the adjuvant therapy is challenging. A novel ensemble machine learning classification approach was developed to address the task of producing prognostic predictions of the occurrence of breast cancer IDEs at both 5- and 10-years. The method is based on the concept of voting among multiple models to give a final prediction for each individual patient. Promising results were achieved on a cohort of 529 patients, whose data, related to primary breast cancer, were provided by Istituto Tumori "Giovanni Paolo II" in Bari, Italy. Our proposal greatly improves the performances returned by the baseline original model, i.e., without voting, finally reaching a median AUC value of 77.1% and 76.3% for the IDE prediction at 5-and 10-years, respectively. Finally, the proposed approach allows to promote more intelligible decisions and then a greater acceptability in clinical practice since it returns an explanation of the IDE prediction for each individual patient through the voting procedure.

A Cost Decision Model Supporting Treatment Strategy Selection in BRCA1/2 Mutation Carriers in Breast Cancer.

In this paper, a cost decision-making model that compares the healthcare costs for diverse treatment strategies is built for BRCA-mutated women with breast cancer. Moreover, this model calculates the cancer treatment costs that could potentially be prevented, if the treatment strategy with the lowest total cost, along the entire lifetime of the patient, is chosen for high-risk women with breast cancer. The benchmark of the healthcare costs for diverse treatment strategies is selected in the presence of uncertainty, i.e., considering, throughout the lifetime of the patient, the risks and complications that may arise in each strategy and, therefore, the costs associated with the management of such events. Our results reveal a clear economic advantage of adopting the cost decision-making model for benchmarking the healthcare costs for various treatment strategies for BRCA-mutated women with breast cancer. The cost savings were higher when all breast cancer patients underwent counseling and genetic testing before deciding on any diagnostic-therapeutic path, with a probability of obtaining savings of over 75%.

Radiomic Feature Reduction Approach to Predict Breast Cancer by Contrast-Enhanced Spectral Mammography Images.

Contrast-enhanced spectral mammography (CESM) is an advanced instrument for breast care that is still operator dependent. The aim of this paper is the proposal of an automated system able to discriminate benign and malignant breast lesions based on radiomic analysis. We selected a set of 58 regions of interest (ROIs) extracted from 53 patients referred to Istituto Tumori "Giovanni Paolo II" of Bari (Italy) for the breast cancer screening phase between March 2017 and June 2018. We extracted 464 features of different kinds, such as points and corners of interest, textural and statistical features from both the original ROIs and the ones obtained by a Haar decomposition and a gradient image implementation. The features data had a large dimension that can affect the process and accuracy of cancer classification. Therefore, a classification scheme for dimension reduction was needed. Specifically, a principal component analysis (PCA) dimension reduction technique that includes the calculation of variance proportion for eigenvector selection was used. For the classification method, we trained three different classifiers, that is a random forest, a naïve Bayes and a logistic regression, on each sub-set of principal components (PC) selected by a sequential forward algorithm. Moreover, we focused on the starting features that contributed most to the calculation of the related PCs, which returned the best classification models. The method obtained with the aid of the random forest classifier resulted in the best prediction of benign/malignant ROIs with median values for sensitivity and specificity of 88.37% and 100%, respectively, by using only three PCs. The features that had shown the greatest contribution to the definition of the same were almost all extracted from the LE images. Our system could represent a valid support tool for radiologists for interpreting CESM images.

Early prediction of neoadjuvant chemotherapy response by exploiting a transfer learning approach on breast DCE-MRIs.

The dynamic contrast-enhanced MR imaging plays a crucial role in evaluating the effectiveness of neoadjuvant chemotherapy (NAC) even since its early stage through the prediction of the final pathological complete response (pCR). In this study, we proposed a transfer learning approach to predict if a patient achieved pCR (pCR) or did not (non-pCR) by exploiting, separately or in combination, pre-treatment and early-treatment exams from I-SPY1 TRIAL public database. First, low-level features, i.e., related to local structure of the image, were automatically extracted by a pre-trained convolutional neural network (CNN) overcoming manual feature extraction. Next, an optimal set of most stable features was detected and then used to design an SVM classifier. A first subset of patients, called fine-tuning dataset (30 pCR; 78 non-pCR), was used to perform the optimal choice of features. A second subset not involved in the feature selection process was employed as an independent test (7 pCR; 19 non-pCR) to validate the model. By combining the optimal features extracted from both pre-treatment and early-treatment exams with some clinical features, i.e., ER, PgR, HER2 and molecular subtype, an accuracy of 91.4% and 92.3%, and an AUC value of 0.93 and 0.90, were returned on the fine-tuning dataset and the independent test, respectively. Overall, the low-level CNN features have an important role in the early evaluation of the NAC efficacy by predicting pCR. The proposed model represents a first effort towards the development of a clinical support tool for an early prediction of pCR to NAC.

A Clinical Decision Support System for Predicting Invasive Breast Cancer Recurrence: Preliminary Results.

The mortality associated to breast cancer is in many cases related to metastasization and recurrence. Personalized treatment strategies are critical for the outcomes improvement of BC patients and the Clinical Decision Support Systems can have an important role in medical practice. In this paper, we present the preliminary results of a prediction model of the Breast Cancer Recurrence (BCR) within five and ten years after diagnosis. The main breast cancer-related and treatment-related features of 256 patients referred to Istituto Tumori "Giovanni Paolo II" of Bari (Italy) were used to train machine learning algorithms at the-state-of-the-art. Firstly, we implemented several feature importance techniques and then we evaluated the prediction performances of BCR within 5 and 10 years after the first diagnosis by means different classifiers. By using a small number of features, the models reached highly performing results both with reference to the BCR within 5 years and within 10 years with an accuracy of 77.50% and 80.39% and a sensitivity of 92.31% and 95.83% respectively, in the hold-out sample test. Despite validation studies are needed on larger samples, our results are promising for the development of a reliable prognostic supporting tool for clinicians in the definition of personalized treatment plans.

Diagnostic challenges and potential early indicators of breast periprosthetic anaplastic large cell lymphoma: A case report.

RATIONALE: Anaplastic large T-cell lymphoma (BI-ALCL) is a rare primitive lymphoma described in women with breast implant prostheses, which has been arousing interest in recent years due to its potentially high social impact. The difficult diagnosis associated with the high and increasing number of prosthetic implants worldwide has led to hypothesize an underestimation of the real impact of the disease among prosthesis-bearing women. The aim of this work is to search for specific radiological signs of disease linked to the chronic inflammatory pathogenetic mechanism. PATIENT CONCERNS: This work describes a case of BI-ALCL in an American woman with no personal or family history of cancer, who underwent breast augmentation for esthetic purposes at our Institute. After about 10 years of relative well-being, the patient returned to our Institute with clear evidence of breast asymmetry due to the increase in volume of the right breast which had progressively become larger over a period of 6 months. There was no evidence of palpable axillary lymph nodes or other noteworthy signs. DIAGNOSIS: The ultrasound and magnetic resonance (MR) tests indicated the presence of seroma with amorphous material in the exudate which was confirmed by indirect signs, visible in right breast mammography. Due to suspected cold seroma, an ultrasound-guided needle aspiration was performed for the cytological analysis of the effusion which highlighted the presence of a number of large-sized atypical cells with an irregular nucleus with CD30 immunoreactivity, leucocyte common antigen (CD45) compatible with the BI-ALCL diagnosis. INTERVENTIONS: In our case, a capsulectomy was performed because the disease was limited inside the capsule and periprosthetic seroma. The final histological examination confirmed the stage. LESSONS: The patient is being monitored and shows no signs of recurrence of disease >24 months after surgery. CONCLUSION: A diagnosis of BI-ALCL can be reached using new radiological indicators, such as fibrin, which is clearly visible by MR in the form of nonvascularized debris of amorphous material hypointense in all sequences, free flowing or adhered to the external surface of the prosthesis.

Bio-Engineering tissue and V.A.C. therapy: A new method for the treatment of extensive necrotizing infection in the diabetic foot.

AIM: The aim of the study is to compare the standard care for progressive necrotizing infection in diabetic foot with a treatment protocol based on the association between autologous fibroblast grafts and vacuum-assisted closure therapy (V.A.C.). MATERIAL OF STUDY: A retrospective matched Case-Control study was carried out on 20 patients with diabetic foot infection, 10 treated with the standard care and 10 with our new protocol. Inclusion criteria were: acute diabetic foot necrosis (Wagner III and IV), ulcer size (30 to 80 cm2), tendon and bone exposure. Success in the treatment was evaluated as: percentage of healing at the 20th week, time of healing, deambulation, recurrence and major amputation rate. RESULTS: A 90% healing rate was observed after 20 weeks in the study group, compared to a 28.6% in the control group. The recurrence rate in the treated areas was 20% in the study group and 100% in the control group. None of the patients in either group required major amputations. DISCUSSION: We achieved very promising results by associating autologous fibroblasts grafts and V.A.C. therapy, in comparison with standard care. V.A.C. therapy seems to improve the growth rate of the fibroblasts, probably by sealing the wound and providing a moist environment following the fibroblast graft. The improved neoangiogenesis of the neo-dermis could explain the reduced recurrence rate of the study group. CONCLUSIONS: Despite the low number of patients involved and the retrospective nature of the analysis, this study showed a reliable, safe and cost-effective method of treating extensive infection in the diabetic foot. KEY WORDS: Bio-Engineered Tissue, Diabetic foot, Fibroblast graft, V.A.C.