Multiparametric MRI Features of Breast Cancer Molecular Subtypes.

Background and Objectives: Breast cancer (BC) molecular subtypes have unique incidence, survival and response to therapy. There are five BC subtypes described by immunohistochemistry: luminal A, luminal B HER2 positive and HER2 negative, triple negative (TNBC) and HER2-enriched. Multiparametric breast MRI (magnetic resonance imaging) provides morphological and functional characteristics of breast tumours and is nowadays recommended in the preoperative setting. Aim: To evaluate the multiparametric MRI features (T2-WI, ADC values and DCE) of breast tumours along with breast density and background parenchymal enhancement (BPE) features among different BC molecular subtypes. Materials and Methods: This was a retrospective study which included 344 patients. All underwent multiparametric breast MRI (T2WI, ADC and DCE sequences) and features were extracted according to the latest BIRADS lexicon. The inter-reader agreement was assessed using the intraclass coefficient (ICC) between the ROI of ADC obtained from the two breast imagers (experienced and moderately experienced). Results: The study population was divided as follows: 89 (26%) with luminal A, 39 (11.5%) luminal B HER2 positive, 168 (48.5%) luminal B HER2 negative, 41 (12%) triple negative (TNBC) and 7 (2%) with HER2 enriched. Luminal A tumours were associated with special histology type, smallest tumour size and persistent kinetic curve (all p-values < 0.05). Luminal B HER2 negative tumours were associated with lowest ADC value (0.77 × 10−3 mm2/s2), which predicts the BC molecular subtype with an accuracy of 0.583. TNBC were associated with asymmetric and moderate/marked BPE, round/oval masses with circumscribed margins and rim enhancement (all p-values < 0.05). HER2 enriched BC were associated with the largest tumour size (mean 37.28 mm, p-value = 0.02). Conclusions: BC molecular subtypes can be associated with T2WI, ADC and DCE MRI features. ADC can help predict the luminal B HER2 negative cases.

Melatonin, an ubiquitous metabolic regulator: functions, mechanisms and effects on circadian disruption and degenerative diseases.

The last four decades, we assist to an increasing scientific interest on melatonin, a circadian hormone, a metabolic regulator which influences not only plants' metabolism and their defense against pathogens but mostly the animals and humans' metabolic pathways, their response to circadian disruption, stress and burnout syndrome. In humans, as a hormonal regulator, produced in the pineal grand as well in mitochondria, melatonin is involved in different, complex intracellular signaling pathways, with antioxidant and immune stimulating effects, proving to act as a circadian synchronizer, as a preventive and therapeutic agent in many degenerative diseases, and especially in hormone-dependent cancers. Preclinical or clinical studies showed recently the mechanisms involved in regulating the cellular activity, its role in aging and circadian disturbances and impact on degenerative diseases. Melatonin proved to have an anti-inflammatory, antiapoptotic and powerful antioxidant effect by subtle mechanisms in mitochondrial metabolic pathways. This overview includes recent and relevant literature data related to the impact of endogenous and exogeneous melatonin on the prevention of cancer progression and treatment of various degenerative diseases. Metabolomics, an emerging new omics' technology, based on high performance liquid chromatography coupled with mass spectrometry is presented as an encouraging technique to fingerprint and realize a precise evaluation and monitoring of the turnover of melatonin and its metabolites in different pathological circumstances.

Whole-Tumor ADC Texture Analysis Is Able to Predict Breast Cancer Receptor Status.

There are different breast cancer molecular subtypes with differences in incidence, treatment response and outcome. They are roughly divided into estrogen and progesterone receptor (ER and PR) negative and positive cancers. In this retrospective study, we included 185 patients augmented with 25 SMOTE patients and divided them into two groups: the training group consisted of 150 patients and the validation cohort consisted of 60 patients. Tumors were manually delineated and whole-volume tumor segmentation was used to extract first-order radiomic features. The ADC-based radiomics model reached an AUC of 0.81 in the training cohort and was confirmed in the validation set, which yielded an AUC of 0.93, in differentiating ER/PR positive from ER/PR negative status. We also tested a combined model using radiomics data together with ki67% proliferation index and histological grade, and obtained a higher AUC of 0.93, which was also confirmed in the validation group. In conclusion, whole-volume ADC texture analysis is able to predict hormonal status in breast cancer masses.

Copy Number Variations (CNVs) Account for 10.8% of Pathogenic Variants in Patients Referred for Hereditary Cancer Testing.

BACKGROUND/AIM: Germline copy number variation (CNV) is a type of genetic variant that predisposes significantly to inherited cancers. Today, next-generation sequencing (NGS) technologies have contributed to multi gene panel analysis in clinical practice. MATERIALS AND METHODS: A total of 2,163 patients were screened for cancer susceptibility, using a solution-based capture method. A panel of 52 genes was used for targeted NGS. The capture-based approach enables computational analysis of CNVs from NGS data. We studied the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and of the non-commercial tool panelcn.MOPS. Additionally, we tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA). RESULTS: Pathogenic/likely pathogenic variants (P/LP) were identified in 464 samples (21.5%). CNV accounts for 10.8% (50/464) of pathogenic variants, referring to deletion/duplication of one or more exons of a gene. In patients with breast and ovarian cancer, CNVs accounted for 10.2% and 6.8% of pathogenic variants, respectively. In colorectal cancer patients, CNV accounted for 28.6% of pathogenic/likely pathogenic variants. CONCLUSION: In silico CNV detection tools provide a viable and cost-effective method to identify CNVs from NGS experiments. CNVs constitute a substantial percentage of P/LP variants, since they represent up to one of every ten P/LP findings identified by NGS multigene analysis; therefore, their evaluation is highly recommended to improve the diagnostic yield of hereditary cancer analysis.

Unconventional Treatment of Breast Abscess: Case Report.

We describe the case of two lactating mothers with breast abscesses who refused invasive interventions. In the first case, a mother developed a 10 mm abscess and refused needle aspiration. Under ultrasonography (US) follow-up she was treated with antibiotics until the abscess disappeared on the US scan, while fully breastfeeding. In the second case, a woman with a large abscess refused invasive interventions. We followed the recommendations in case of breast Adenitis, first to nurse the baby from the affected breast and then squeezing regularly the lump to drain the pus. In this study, we demonstrate that this procedure is also beneficial in the case of breast abscesses. Under antibiotic treatment, the abscess was completely resolved on the US scan after 23 days. In conclusion, when invasive intervention is refused in the case of breast abscess, successful treatment can be applied by using effective breast drainage, US follow-up, and aggressive antibiotic therapy.

Are Mutation Carrier Patients Different from Non-Carrier Patients? Genetic, Pathology, and US Features of Patients with Breast Cancer.

The purpose of this study is to evaluate the relationship between the pathogenic/likely pathogenic mutations, US features, and histopathologic findings of breast cancer in mutation carriers compared to non-carrier patients. Methods: In this retrospective study, we identified 264 patients with breast cancer and multigene panel testing admitted to our clinic from January 2018 to December 2020. Patient data US findings, US assessment of the axilla, multigene panel tests, histopathology, and immunochemistry reports were reviewed according to the BI-RADS lexicon. Results: The study population was comprised of 40% pathogenic mutation carriers (BRCA1, BRCA2, CHEK2, ATM, PALB, TP 53, NBN, MSH, BRIP 1 genes) and 60% mutation-negative patients. The mean patient age was 43.5 years in the carrier group and 44 years in the negative group. Carrier patients developed breast cancer with benign morphology (acoustic enhancement, soft elastography appearance) compared to non-carriers (p < 0.05). A tendency towards specific US features was observed for each mutation. BRCA1 carriers were associated with BC with microlobulated margins, hyperechoic rim, and soft elastography appearance (p < 0.05). Estrogen receptor (ER)-negative tumors were associated with BRCA1, TP53, and RAD mutations, while BRCA2 and CHEK2 were associated with ER-positive tumors. Conclusions: Patients with pathogenic mutations may exhibit BC with benign US features compared to negative, non-carrier patients. BRCA1, TP53, and RAD carriers account for up to one third of the ER tumors from the carrier group. Axillary US performed worse in depicting involved lymph nodes in carrier patients, compared to negative patients.

The Role of US in Depicting Axillary Metastasis in High-Risk Breast Cancer Patients.

PURPOSE: The aim of this study is to evaluate the role of US in depicting axillary nodal disease in high-risk patients with and without pathogenic mutations. Methods: The retrospective study included consecutive high-risk breast cancer (BC) patients who underwent a multigene testing panel for hereditary cancers, pre-operative axillary US and breast/axillary surgery. The group was divided into patients with pathogenic mutations (PM group) and patients without PM. Statistical analyses were performed using GraphPad Prism by applying Chi-square and Fisher exact tests, with a reference p-value < 0.05 and a CI of 95%. Results: Out of 190 patients with BC, 96 (51%) were negative and 94 (49%) were positive for PM as follows: 28 (25.5%) BRCA1, 16 (17%) BRCA2, 15 (16%) CHECK2, 14 (14%) RAD Group, 7 (7%) PALB, 6 (6%) NBN, 3 (3%) TP53 and ATM and 2 (2%) BARD1. US was positive in 88 of the patients, 36 with PM and 52 without PM. US and surgery (≥N1 stage) were both positive in 31 (62%) of PM patients and 44 (88%) of patients without genetic changes. There were 19 (61%) false negative US examinations in the PM group and 6 (13%) in the group without genetic changes, respectively. If the US is positive, there is a 2.6 times greater risk of positive nodes in PM patients (p-value < 0.000, 95% CI = 4.2-37.9), and a 6.2 times greater risk of positive nodes in patients without genetic changes (p-value < 0.000, 95%CI = 8.4-37.4). In the PM group, US compared to surgery reached a sensitivity = 62, with PPV = 86 and NPV = 67. In the BRCA1/2 subgroup, there is 2.5 greater times risk of nodal disease if the US is positive (p-value = 0.001, 95%CI = 2.6-76). In patients without PM, US compared to surgery reached a sensitivity = 88, PPV = 84 and NPV = 86. Conclusion: US is more sensitive in depicting axillary nodal disease in high-risk patients without PM compared to PM patients. Furthermore, there are more false negative US examinations in PM patients, compared to surgery patients.

Clinical Utility of Functional RNA Analysis for the Reclassification of Splicing Gene Variants in Hereditary Cancer.

BACKGROUND: Classification of splicing variants (SVs) in genes associated with hereditary cancer is often challenging. The aim of this study was to investigate the occurrence of SVs in hereditary cancer genes and the clinical utility of RNA analysis. MATERIAL AND METHODS: 1518 individuals were tested for cancer predisposition, using a Next Generation Sequencing (NGS) panel of 36 genes. Splicing variant analysis was performed using RT-PCR and Sanger Sequencing. RESULTS: In total, 34 different SVs were identified, 53% of which were classified as pathogenic or likely pathogenic. The remaining 16 variants were initially classified as Variant of Uncertain Significance (VUS). RNA analysis was performed for 3 novel variants. CONCLUSION: The RNA analysis assisted in the reclassification of 20% of splicing variants from VUS to pathogenic. RNA analysis is essential in the case of uncharacterized splicing variants, for proper classification and personalized management of these patients.

Visualization of the shear wave on gray-scale ultrasound: experience with a complex breast cyst.

Shear wave elastography (SWE) is the newer of the two methods of measuring tissue stiffness using ultrasound. We present the case of a 39-year-old patient with fibrocystic breast disease who presented with a left painful breast lump. The patient underwent a breast ultrasound that depicted a complicated cyst with a "pseudo-solid" content. When the SWE mode was turned on, the ultrasound share wave was observed on the gray-scale image, as surface undulations of the "pseudo-solid" component. To the best of our knowledge, this is the first report of the share wave visualization on a gray-scale image. The impact on patient management is discussed.

Nipple Ultrasound: A Pictorial Essay.

Ultrasound (US) is an attractive diagnostic approach to identify both common and uncommon nipple pathologies, such as duct ectasia, nipple abscess, nipple leiomyoma, nipple adenoma, fibroepithelial polyp, ductal carcinoma in situ (restricted to nipple), invasive carcinoma, and Paget's disease. US is the reliable first-line imaging technique to assess nipple pathologies. It is useful to identify and characterize nipple lesions. Additionally, we have presented the mammography and MRI outcomes correlated with histopathologic features for the relevant cases.

Invasive bilateral breast cancer and high grade serous ovarian cancer with BRCA1-germline mutation and brainstem metastasis under PARP inhibitors.

For breast cancer patients, BRCA gene mutations are predictive of a good response to chemotherapy, but are hampered by a high risk of bilateral and synchronous or metachronous ovarian cancer. Novel therapies such as PARP-inhibitors have proven effective for BRCA1/2 mutated ovarian cancer. We present the case of a 50-year-old woman, initially diagnosed with bilateral luminal B breast cancer with BRCA1 mutation. She received neoadjuvant chemotherapy, modified radical mastectomy and bilateral adnexectomy, while subsequently identifying a synchronous advanced ovarian cancer, stage FIGO IIIC, followed by adjuvant platinum chemotherapy and external radiotherapy. After a 12 months disease-free interval a brainstem tumor was discovered, for which whole-brain radiotherapy was performed. She received 6 months of PARP-inhibitors through an early access program. With only a partial at the end of treatment, the brainstem tumor was still in progression. Due to evolution of the brain metastasis, second line chemotherapy (taxanes and Bevacizumab) was administered, with complete radiologic response. The particularity of this case resides in the coexistence of a breast and ovarian cancer in the same patient with BRCA1-germline mutation who responded to a new line of therapy - the PARP inhibitors. While being unable to perform a biopsy, we speculate that the brain metastasis in this case was most likely of breast origin.

The role of imaging techniques in the diagnosis, staging and choice of therapeutic conduct in pregnancy associated breast cancer.

Breast cancer diagnosed during pregnancy is at increasing incidence due to the increased frequency of obesity, the postponement of the first pregnancy to later decades of life and the advances of diagnostic techniques. Clinical and imaging diagnosis is difficult during gestation due to adaptive changes of the maternal organism , the mammary glads in particular. Furthermore, the therapeutic approach is limited both by the possible side effects on the fetus and by the skepticism of the couple over these therapeutic regimens.The present paper aims to review the main diagnostic steps to confirm pregnancy associated breast cancer, as well as the therapeutic possibilities during this period, related to the potential adverse effects concerning pregnancy.

Blue nevus-like melanoma of the uterine cervix. Case report and review of the literature.

We present the clinical and pathological aspects of a patient diagnosed with a very rare tumor, a blue nevus-like melanoma of the uterine cervix. The patient turned to our Service for a second opinion regarding a cervical polyp causing vaginal bleeding, polyp which has been excised in another Hospital and interpreted initially as a pleomorphic sarcoma. In the presentation, we emphasize upon the stages of solving a difficult diagnosis, pathological description and treatment of these rare, aggressive tumors with poor prognosis, which represent the fundamental precondition in order to formulate the best therapeutic strategy.

Impact of Strain Elastography on BI-RADS classification in small invasive lobular carcinoma.

AIMS: The purpose of this study was to determine the impact of strain elastography (SE) on the Breast Imaging Reporting Data System (BI-RADS) classification depending on invasive lobular carcinoma (ILC) lesion size. MATERIALS AND METHODS: We performed a retrospective analysis on a sample of 152 female subjects examined between January 2010 - January 2017. SE was performed on all patients and ILC was subsequently diagnosed by surgical or ultrasound-guided biopsy. BI-RADS 1, 2, 6 and Tsukuba BGR cases were omitted. BI-RADS scores were recorded before and after the use of SE. The differences between scores were compared to the ILC tumor size using nonparametric tests and logistic binary regression. We controlled for age, focality, clinical assessment, heredo-collateral antecedents, B-mode and Doppler ultrasound examination. An ROC curve was used to identify the optimal cut-off point for size in relationship to BI-RADS classificationdifference using Youden's index. RESULTS: The histological subtypes of ILC lesions (n=180) included in the sample were luminal A (70%, n=126), luminal B (27.78%, n=50), triple negative (1.67%, n=3) and HER2+ (0.56%, n=1). The BI-RADS classification was higher when SE was performed (Z=- 6.629, p<0.000). The ROC curve identified a cut-off point of 13 mm for size in relationship to BI-RADS classification difference (J=0.670, p<0.000). Small ILC tumors were 17.92% more likely to influence BI-RADS classification (p<0.000). CONCLUSIONS: SE offers enhanced BI-RADS classification in small ILC tumors (<13 mm). Sonoelastography brings added value to B-mode breast ultrasound as an adjacent to mammography in breast cancer screening.

[Doppler ultrasound assessment of intraocular and orbital tumors]. / Ultrasonografia Doppler în patologia tumorala oculo-orbitala.

PURPOSE: To assess the role of spectral and color Doppler ultrasonography in the positive and differential diagnosis of ocular and orbital tumoral masses. MATERIAL AND METHODS: Retrospective clinical study of 153 patients with 163 ocular or / and orbital masses who were examined by spectral and color Doppler ultrasonography in the Clinic of Radiology, Cluj County Emergency Hospital, between 1997 and 2004. In all patients, the arterial impedance indices were measured by pulsed Doppler examination. The color Doppler characterization of the mass consisted in the description of intratumoral vascularity: presence, vessel number and appearance and peculiar aspects. The final diagnosis was established by histopathology in 123 tumors. In 40 tumors, the diagnosis was established by correlating the clinical findings with the results of other imaging modalities. RESULTS: The study identifies and describes peculiar ultrasonographic aspects of the vascularity in various intraocular and orbital tumors. It describes and illustrates the Doppler ultrasonographic appearance of choroidal melanoma, retinoblastoma, eyeball metastases, hemangioma, lymphangioma, optic nerve sheath glioma, inflammatory pseudotumors and tumors invading the orbit. CONCLUSIONS: The association of vascular information to the two-dimensional ultrasonographic image allows for an improved characterization of ocular and orbital tumoral masses.

The Added Value of Color Parameters in Analyzing Elastographic Images of Ultrasound Detected Breast Focal Lesions.

AIMS: The purpose of the study was to determine if the color quantitative analysis obtained on elastographic images of breast lesions could improve the benign-malignant differentiation, and also to identify some of the circumstances which would benefit most from such an analysis. PATIENTS AND METHODS: The study design was a longitudinal prospective one, all data being acquired between May 2007 and September 2008. The US device used: Hitachi 8500 EUB machine with elastography option. For suspicious breast lesions histopathology was obtained by means of percutaneous biopsy or post-surgery. Studied color parameters (numeric values): average color (red, green, blue), color dispersion, average intensity, average hue, hue dispersion. Calculus modality: Image Processing Version 1.3, a program developed in collaboration with the Technical University of Cluj Napoca. RESULTS: Seventy-one (71) women were selected for the study. A hundred and six circumscribed breast lesions were detected by means of ultrasound in the studied group. Five color parameters were independently associated with the histological diagnosis (AvgBlue, AvgGreen and AvgRed; DispRed and DispIntensity) with AvgBlue parameter making the most important contribution (p<0.0001); the greater the values of AvgBlue (more than 92), the higher the chances of malignancy and the greater the values of AvgGreen (more than 88), the higher the chances for a benign lesion. CONCLUSION: High numeric values for Avg Blue (more than 92) would increase the probability of malignancy and thus recommend a more aggressive diagnostic management (biopsy), while high numeric values for AvgGreen (more than 88) would reassure the examiner to proceed conservatively with short interval or routine follow-ups.

Breast Diagnosis: Concordance Analysis Between the BI-RADS Classification and Tsukuba Sonoelastography Score.

AIMS: To establish the correlations between the ultrasound (US) BI-RADS classification and Tsukuba elastography score when assessing breast lesions. To determine which type of breast lesion (BI-RADS category) would benefit most from an elastographic assessment. PATIENTS AND METHODS: The investigated sample of imaging comprised a number of 129 images belonging to 92 subjects examined with a Hitachi 8500 US device. Each lesion was assessed according to the BI-RADS and Tsukuba elastography score. Histopathology was obtained by means of percutaneous biopsy or post-surgery. Fibroadenoma-like lesions unchanged over a period of 3 years were considered benign. RESULTS: The 1, 2 and BGR Tsukuba scores mostly correlated with BI-RADS II and III lesions such as cysts, hamartomas, lipomas, hematomas, non-palpable fibroadenomas. Palpable fibroadenomas initially included in BI-RADS IVa/b category, usually received benign elasticity scores (1 or 2), the exception being represented by a minority of cases of old, fibrotic or calcified lesions (elastic score 3 or 4). Non-specific BI-RADS IVa/b lesions, such as mastopathic nodules demonstrated rather soft, elastic properties on elastogram (score 1 or 2). The 4 and 5 Ueno-Itoh scores were predominantly correlated with BI-RADS IVc and V categories represented by high risk lesions (radial scar, papillomas, atypical epithelial ductal hyperplasia) and in situ or invasive carcinomas. CONCLUSIONS: Generally the BI-RADS classification correlates well with the Tsukuba elasticity score, the main exception being represented by fibrotic, calcified lesions which falsely appear more suspicious post-elastography. BI-RADS III and IV lesions would benefit most from an elastographic assessment, a low Tsukuba score allowing a less invasive approach, while a high score imposes histopathological evaluation.

Value of ultrasound elastography in the diagnosis and management of prostate carcinoma.

The aim of the paper is to review and illustrate the role of sonoelastography in the diagnostic and therapeutic approach of prostate cancer. The examination technique and normal appearance are presented. The paper describes and illustrates the appearance of prostate cancer and suggested diagnostic scores. Artifacts, causes for false results and limitations are discussed and also illustrated. The diagnostic influence of intraprostatic tumor location, tumor volume and Gleason score are presented. The paper also reviews the statistical diagnostic value of the method, the relation to prostate biopsy and magnetic resonance assessment. In the end, potential uses and future developments of the method are mentioned.

Doppler applications in testicular and scrotal disease.

The paper reviews the current knowledge on the use of Doppler ultrasound in disease of the testis and scrotal contents. The first part presents fundamentals on vascularization and normal Doppler appearance of the testis as well as examination technique. The review presents the applications of Doppler ultrasonography in the diagnosis of inflammation, torsion and ischemia, varicocele, venous thrombosis, tumors, hydrocele, trauma and assessing fertility disturbance.