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Introduction Magnetic resonance imaging (MRI) has shown the potential to improve the screening effectiveness among women with dense breasts. The introduction of fast abbreviated protocols (AP) makes MRI more feasible to be used in a general population. We aimed to investigate the cost-effectiveness of AP-MRI in women with dense breasts (heterogeneously/extremely dense) in a population-based screening program. Methods A previously validated model (SiMRiSc) was applied, with parameters updated for women with dense breasts. Breast density was assumed to decrease with increased age. The base scenarios included six biennial AP-MRI strategies, with biennial mammography from age 50–74 as reference. Fourteen alternative scenarios were performed by varying screening interval (triennial and quadrennial) and by applying a combined strategy of mammography and AP-MRI. A 3% discount rate for both costs and life years gained (LYG) was applied. Model robustness was evaluated using univariate and probabilistic sensitivity analyses. Results The six biennial AP-MRI strategies ranged from 132 to 562 LYG per 10,000 women, where more frequent application of AP-MRI was related to higher LYG. The optimal strategy was biennial AP-MRI screening from age 50–65 for only women with extremely dense breasts, producing an incremental cost-effectiveness ratio of € 18,201/LYG. At a threshold of € 20,000/LYG, the probability that the optimal strategy was cost-effective was 79%. Conclusion Population-based biennial breast cancer screening with AP-MRI from age 50–65 for women with extremely dense breasts might be a cost-effective alternative to mammography, but is not an option for women with heterogeneously dense breasts., Highlights • AP-MRI can be cost-effective for screening women with extremely dense breast. • The more frequent the use of AP-MRI, the more life years will be gained. • Biennial AP-MRI for women with extremely dense breast up to age 65 is optimal.

Increased implementation of proven prevention strategies is required to combat rising breast cancer incidence. We assessed use of risk reducing medication (RRMed) by Australian women at elevated breast cancer risk. Only 2.4% had ever used RRMed. Higher breast cancer risk was statistically significantly associated with use of RRMed (OR 1.82, 95%CI: 1.08–3.07, p = 0.02 for ≥30% lifetime risk compared with 16%–29% lifetime risk), but parity, education level and family history of breast cancer were not. Breast cancer prevention medications are underutilised. Efforts are needed to incorporate breast cancer risk assessment and risk management discussions into routine health assessments for women., Highlights • Risk-reducing medication is infrequently used by Australian women at increased risk of breast cancer. • Higher breast cancer risk is associated with greater uptake of risk reducing medication, but not with adherence. • Routine breast cancer risk assessment may increase risk reducing medication use.

Background Female-to-male (FtM) transsexuals may use testosterone therapy for masculinization, which potentially influences the risk of breast cancer development. Guided by our case report, we aimed to investigate the evidence regarding the risk of testosterone therapy on breast malignancy in female-to-male transsexuals and evaluate breast cancer screening in this subgroup. Methods We conducted a systematic literature search according to the PRISMA checklist in June 2020 in PubMed/MEDLINE and Ovid/EMBASE. Reference lists of included articles were screened to find additional articles that met the inclusion criteria. All cohort studies and case reports evaluating breast cancer in FtM transsexuals after testosterone therapy were included. Results We found 23 cases of FtM transsexuals who developed breast cancer after testosterone therapy, including our own case. Moreover, we evaluated ten retrospective cohort studies investigating breast malignancy in the transsexual population. The cohort studies showed no elevated risk in FtM transsexuals compared to natal women. Including our own case, nine cases were described in which breast malignancy was incidentally found during routine histological examination after mastectomy. High-level evidence for a correlation between testosterone therapy and breast malignancy is missing. Conclusion Few cases are described of FtM transsexuals with breast malignancy. However, cases such as these make physicians aware of the possibility of breast cancer in FtM transsexuals. Radiological screening of FtM transsexuals for breast cancer prior to mastectomy and histological screening of the mammalian tissue after mastectomy should be considered; physicians should decide together with every individual FtM transsexual if screening is necessary., Highlights • Breast cancer malignancy after testosterone therapy in female to male (FtM) transsexuals is very rare, including our own case, we found 23 of such cases reported in literature. • Based on current evidence, it is not possible to conclude associations between FtM transsexuals using testosterone therapy and breast cancer. • Radiological screening FtM transsexuals for breast cancer prior to mastectomy and histological screening of the mammalian tissue after mastectomy should be considered; physician should decide together with every individual FtM transsexual if screening is necessary.

Long-term primary culture of mammalian cells has been always difficult due to unavoidable senescence. Conventional methods for generating immortalized cell lines usually require manipulation of genome which leads to change of important biological and genetic characteristics. Recently, conditional reprogramming (CR) emerges as a novel next generation tool for long-term culture of primary epithelium cells derived from almost all origins without alteration of genetic background of primary cells. CR co-cultures primary cells with inactivated mouse 3T3-J2 fibroblasts in the presence of RHO-related protein kinase (ROCK) inhibitor Y-27632, enabling primary cells to acquire stem-like characteristics while retain their ability to fully differentiate. With only a few years’ development, CR shows broad prospects in applications in varied areas including disease modeling, regenerative medicine, drug evaluation, drug discovery as well as precision medicine. This review is thus to comprehensively summarize and assess current progress in understanding mechanism of CR and its wide applications, highlighting the value of CR in both basic and translational researches and discussing the challenges faced with CR., Graphical abstract Conditional reprogramming is a new tool for next generation primary cell culture, which has broad prospect in applications in both basic science and translational medicine.Image 1

The diagnostic performance difference between digital breast tomosynthesis (DBT) and conventional full-field digital mammography (FFDM) for breast suspicious calcifications from various populations is unclear. The objective of this study is to determine whether DBT exhibits the diagnostic advantage for breast suspicious calcifications from various populations compared with FFDM. Three hundred and five patients were enrolled (of which seven patients with bilateral lesions) and 312 breasts images were retrospectively analyzed by three radiologists independently. The postoperative pathology of breast calcifications was the gold standard. Breast cancer was diagnosed utilizing DBT and FFDM with sensitivities of 92.9% and 88.8%, specificities of 87.9% and 75.2%, positive predictive values of 77.8% and 62.1%, negative predictive values of 96.4% and 93.6%, respectively. DBT exhibited significantly higher diagnostic accuracy for benign calcifications compared with FFDM (87.9% vs 75.2%), and no advantage in the diagnosis of malignant calcifications. DBT diagnostic accuracy was notably higher than FFDM in premenopausal (88.4% vs 78.8%), postmenopausal (90.2% vs 77.2%), and dense breast cases (89.4% vs 81.9%). There was no significant difference in non-dense breast cases. In our study, DBT exhibited a superior advantage in dense breasts and benign calcifications cases compared to FFDM, while no advantage was observed in non-dense breasts or malignant calcifications cases. Thus, in the breast cancer screening for young women with dense breasts, DBT may be recommended for accurate diagnosis. Our findings may assist the clinicians in applying the optimal techniques for different patients and provide a theoretical basis for the update of breast cancer screening guideline., Graphical Abstract Unlabelled Image, Highlights • DBT exhibits higher diagnostic accuracy for benign calcifications compared to FFDM • DBT exhibits higher diagnostic accuracy in dense breast cases than FFDM • DBT exhibits higher diagnostic accuracy in premenopausal and postmenopausal cases • DBT has no advantage in non-dense breasts and malignant calcifications cases

Breast cancer is one of the leading causes of mortality worldwide being the most common cancer among women. Despite the significant progress obtained during the past years in the understanding of breast cancer pathophysiology, women continue to die from it. Novel tools and technologies are needed to develop better diagnostic and therapeutic approaches, and to better understand the molecular and cellular players involved in the progression of this disease. Typical methods employed by the pharmaceutical industry and laboratories to investigate breast cancer etiology and evaluate the efficiency of new therapeutic compounds are still based on traditional tissue culture flasks and animal models, which have certain limitations. Recently, tumor-on-chip technology emerged as a new generation of in vitro disease model to investigate the physiopathology of tumors and predict the efficiency of drugs in a native-like microenvironment. These microfluidic systems reproduce the functional units and composition of human organs and tissues, and importantly, the rheological properties of the native scenario, enabling precise control over fluid flow or local gradients. Herein, we review the most recent works related to breast tumor-on-chip for disease modeling and drug screening applications. Finally, we critically discuss the future applications of this emerging technology in breast cancer therapeutics and drug development., Graphical abstract Unlabelled Image, Highlights • Breast cancer is one of the leading causes of mortality among women. • Microfluidics can address the challenges related to breast cancer progression. • Breast cancer physiopathology can be replicated using tumor-on-chip technology. • Tumor biomarkers can be precisely identified and analyzed. • Drug screening and discovery can be accelerated with microfluidics.

Highlights • Weight and the BMI are inadequate proxies for adiposity that do not distinguish between muscle and adipose tissue or different specific deposits of adipose tissue (visceral and subcutaneous), which have different physiological effects. • Patients with the same BMI are likely to have different anatomical distribution of adipose and muscle tissue. • To our knowledge, only few studies have investigated the association between fat and muscle tissue distribution of the body, and response to neoadjuvant chemotherapy., Purpose To compare the adipose and muscle tissue areas in patients who responded differently to neoadjuvant chemotherapy. Methods One hundred and eighty six patients diagnosed with breast cancer who underwent neoadjuvant chemotherapy between January 2015- October 2019 and were operated after the treatment were retrospectively included in the study. Pathological results were divided into five groups using the Miller-Payne grading systems. Grade 1 indicating no significant reduction in malignant cells; Grade 2: a minor loss of malignant cells (≤ 30 %); Grade 3: reduction in malignant cells between 30 % and 90 %; Grade 4: disappearance of malignant cells >90 %; Grade 5: no malignant cells identifiable. Pre-treatment PET CT scans were evaluated, and calculation of body composition parameters were performed on a single axial section passing through the L3 vertebrae. Spearman’s correlation test was used to analyze the correlation between SAT, VAT, MT parameters and pathological responses. Results There was no strong correlation between the 5 groups separated according to neoadjuvant chemotherapy treatment response and tissue distributions. However, that there was a very low correlation found between superficial adipose tissue and pathological response (r=, 156). Conclusion In conclusion, our results have provided a very low correlation between SAT and more than 30 % response. More research is required to evaluate the role of the body fat and muscle parameters in response to neoadjuvant chemotherapy in larger patient populations.

Background During the COVID-19 pandemic, surgical delays have been common for patients with ductal carcinoma in situ (DCIS) and early-stage estrogen receptor-positive (ER+) breast cancer, often in favor of neoadjuvant endocrine therapy (NET). To understand possible ramifications of these delays, we examined the association between time to operation and pathologic staging and overall survival (OS). Study Design Patients with DCIS or ER+ cT1-2N0 breast cancer treated from 2010 through 2016 were identified in the National Cancer Database. Time to operation was recorded. Factors associated with pathologic upstaging were examined using logistic regression analyses. Cox proportional hazard models were used to analyze OS. Analyses were stratified by disease stage and initial treatment strategy. Results There were 378,839 patients identified. Among those undergoing primary surgical procedure, time to operation was within 120 days in > 98% in all groups. Among cT1-2N0 patients selected for NET, operations were performed within 120 days in 59.6% of cT1N0 and 30.9% of cT2N0 patients. Increased time to operation was associated with increased odds of pathologic upstaging in DCIS patients (ER+: 60 to 120 days: odds ratio 1.15; 95% CI, 1.08 to 1.22; more than 120 days: odds ratio 1.44; 95% CI, 1.24 to 1.68; ER–: 60 to 120 days: NS; more than 120 days: odds ratio 1.36; 95% CI, 1.01 to 1.82; 60 days or less: reference), but not in patients with invasive cancer, irrespective of initial treatment strategy. No difference in OS was seen by time to operation in DCIS or NET patients. Conclusions Increased time to operation was associated with a small increase in pathologic upstaging in DCIS patients, but did not impact OS. In patients with cT1-2N0 disease, NET use did not impact stage or OS, supporting the safety of delay strategies in ER+ breast cancer patients during the pandemic., Graphical abstract

This study aimed to identify the characteristics of the vascular network in the superficial subcutaneous layer of the breast and to analyze differences between breasts with cancer and contralateral unaffected breasts using vessel branching points (VBPs) detected by three-dimensional photoacoustic imaging with a hemispherical detector array. In 22 patients with unilateral breast cancer, the average VBP counts to a depth of 7 mm below the skin surface were significantly greater in breasts with cancer than in the contralateral unaffected breasts (p

Diagnosis of breast ductal carcinoma in situ (DCIS) presents a challenge since we cannot yet distinguish those cases that would remain indolent and not require aggressive treatment from cases that may progress to invasive ductal cancer (IDC). The purpose of this study is to determine the role of Rap1Gap, a GTPase activating protein, in the progression from DCIS to IDC. Immunohistochemistry (IHC) analysis of samples from breast cancer patients shows an increase in Rap1Gap expression in DCIS compared to normal breast tissue and IDCs. In order to study the mechanisms of malignant progression, we employed an in vitro three-dimensional (3D) model that more accurately recapitulates both structural and functional cues of breast tissue. Immunoblotting results show that Rap1Gap levels in MCF10.Ca1D cells (a model of invasive carcinoma) are reduced compared to those in MCF10.DCIS (a model of DCIS). Retroviral silencing of Rap1Gap in MCF10.DCIS cells activated extracellular regulated kinase (ERK) mitogen-activated protein kinase (MAPK), induced extensive cytoskeletal reorganization and acquisition of mesenchymal phenotype, and enhanced invasion. Enforced reexpression of Rap1Gap in MCF10.DCIS-Rap1GapshRNA cells reduced Rap1 activity and reversed the mesenchymal phenotype. Similarly, introduction of dominant negative Rap1A mutant (Rap1A-N17) in DCIS-Rap1Gap shRNA cells caused a reversion to nonmalignant phenotype. Conversely, expression of constitutively active Rap1A mutant (Rap1A-V12) in noninvasive MCF10.DCIS cells led to phenotypic changes that were reminiscent of Rap1Gap knockdown. Thus, reduction of Rap1Gap in DCIS is a potential switch for progression to an invasive phenotype. The Graphical Abstract summarizes these findings., Graphical abstract Down-regulation of Rap1Gap: A switch from DCIS to IDC via ERK/MAPK activation. The confocal immunofluorescence images (collapsed z-stacks; 40x magnification) are of in vitro 3D culture models of MCF10.DCIS. Green and blue represent F-actin cytoskeleton and nuclei, respectively. When Rap1Gap is reduced by shRNA, ERK is activated and there is acquisition of an invasive phenotype. Conversely, when Rap1Gap is re-expressed in the DCIS Rap1Gap shRNA cells, there is reversion to a pre-invasive phenotype. The in vitro 3D culture model recapitulates findings from DCIS and IDC patient samples.Unlabelled Image

Excess telomere shortening has been observed in most cancer cells. The telomere quantitative polymerase chain reaction (qPCR) assay has become an important tool for epidemiological studies examining the effects of aging, stress, and other factors on the length of telomeres. Current telomere qPCR methods analyze the relative length of telomeres by amplifying telomere sequence products and normalizing with single-copy gene products. However, the current telomere qPCR does not always reflect absolute telomere length in cancer DNA. Because of genomic instability in cancer cells, we hypothesized that the use of single-copy genes (scg) is less accurate for normalizing data in cancer DNA and that new primer sets are required to better represent relative telomere length in cancer DNA. We first confirmed that cancer cells had a different copy ratio among different scg, implying that DNA is aneuploid. By using the new primer sets that amplify multiple-copy sequences (mcs) throughout the genome, the telomere qPCR results showed that the mcs primers were interchangeable with the scg primers as reference primers in normal DNA. By comparing results from the traditional southern blotting method (as kilobases) and results from monochrome multiplex qPCR using the mcs primers (as T/M ratios), we verified that the T/M ratio is highly correlated with absolute telomere length from the southern blot analysis. Together, the mcs primers were able to represent the telomere lengths accurately in cancer DNA samples. These results would allow for analyses of telomeres within cancerous DNA and the development of new, less invasive diagnostic tools for cancer.

Highlights • Ductal Carcinoma in situ in sclerosing adenosis encapsulated by a hamartoma is rare. • The diagnosis is difficult due to the appearance of these combined lesions. • Atypical appearance of a hamartoma may suggest a co-existing malignancy., Introduction Ductal Carcinoma in situ (DCIS) of the breast can develop in areas of sclerosing adenosis. The radiographic finding of sclerosing adenosis is a spiculated mass and can look like invasive ductal carcinoma. We report a patient with DCIS in sclerosing adenosis encapsulated by a hamartoma, with imaging findings quite different from the typical findings of sclerosing adenosis. Presentation of case A 73-year old woman, with no previous mammography, presented with a palpable mass in the left breast. Mammography showed a 36 mm well-defined mass with fat density in the middle outer quadrant of the left breast. Ultrasonography showed a well-defined mass in the same area which was composed of hypoechoic and hyperechoic areas. The histological diagnosis by core needle biopsy was sclerosing adenosis. We considered the patient’s age and tumor size and performed a partial mastectomy for both diagnosis and treatment. Final pathology showed DCIS in sclerosing adenosis in a hamartoma. Discussion This patient had DCIS in an area of sclerosing adenosis, encapsulated by a hamartoma. DCIS can develop in areas of sclerosing adenosis, and can appear similar to invasive ductal carcinoma, so we must avoid misdiagnosis or over-treatment. Malignant transformation of a hamartoma is rare, but can occur since it contains epithelial tissue. Definitive biopsy should be performed due to the possibility of a malignancy inside the hamartoma. Conclusions When diagnosing a hamartoma, the presence of atypical findings on imaging studies, should suggest the possibility of malignancy. Although rare, a malignant tumor may be present inside the hamartoma.

There are three main ways in which women can be identified as being at high risk of breast cancer i) family history of breast and/or ovarian cancer, which includes genetic factors ii) mammographically identified high breast density, and iii) certain types of benign breast disease. The last category is the least common, but in some ways the easiest one for which treatment can be offered, because these women have already entered into the treatment system. The highest risk is seen in women with lobular carcinoma in situ (LCIS), but this is very rare. More common is atypical hyperplasia (AH), which carries a 4–5-fold risk of breast cancer as compared to general population. Even more common is hyperplasia of the usual type and carries a roughly two-fold increased risk. Women with aspirated cysts are also at increased risk of subsequent breast cancer. Tamoxifen has been shown to be particularly effective in preventing subsequent breast cancer in women with AH, with a more than 70% reduction in the P1 trial and a 60% reduction in IBIS-I. The aromatase inhibitors (AIs) also are highly effective for AH and LCIS. There are no published data on the effectiveness of tamoxifen or the AIs for breast cancer prevention in women with hyperplasia of the usual type, or for women with aspirated cysts. Improving diagnostic consistency, breast cancer risk prediction and education of physicians and patients regarding therapeutic prevention in women with benign breast disease may strengthen breast cancer prevention efforts.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition associated with a significant social and medical cost. Patients with HS may require emergency department care and inpatient care, and a study found that these patients have greater health care utilization compared with those with psoriasis.1 The prevalence of HS in the United States has been reported as low as 0.05%2 and as high as 4%.3 It most commonly occurs in women with an average age of onset of 23 years.4 Its destructive nature can be quite debilitating, and treatment is seldom curative. The typical lesions include recurrent, painful nodules and abscesses in intertriginous areas that may form sinus tracts.5 The most common locations for HS lesions in women are the inframammary region and the groin, whereas for men they are the buttocks and the perineal area.4 HS is graded on severity based on the Hurley stages I to III. Numerous options have been investigated for the treatment of HS; however, most are ineffective in achieving complete remission. Treatment options are often chosen based on disease severity and impact of the disease on quality of life. Current treatment options include oral zinc supplementation; laser hair removal; carbon dioxide (CO2) laser ablation; oral antibiotics such as clindamycin plus rifampicin, dapsone, and tetracyclines; and surgical unroofing and more extensive surgical excision. Biologics and immunosuppressants are considered for more recalctrant and symptomatic patients with stage III disease.4 Recent research has also found that CO2 laser therapy has comparable recurrence rates to those of wide excision.6 We report the case of a female patient who had a flare of HS over the entire radiation site after treatment for ductal carcinoma in-situ (DCIS). Radiotherapy commonly causes acute skin toxicity, which may include erythema, edema, and desquamation7 but to date has not been linked to the development of HS. In the past, radiotherapy was actually used to treat early lesions of HS.4

Background Patients newly diagnosed with breast cancer face a series of complex decisions regarding locoregional and systemic treatment. There is a need to improve the quality of locoregional and systemic decisions for breast cancer patients, and to help patients understand the role of evaluative tests in this decision process. We are now conducting a randomized controlled trial (RCT) of an online decision tool—called iCanDecide, which we expect will help patients with these difficult decisions. Furthermore, the results of this RCT will be highly relevant to future breast cancer patients making these decisions and to their clinicians. Methods This is a two-arm randomized controlled trial with the target of 222 participants per arm. Participants are recruited from 25 surgical practices (total 40 surgeons) and 2 medical oncology practices (total 2 oncologists) in Michigan, Georgia, Tennessee, and California. Participants are newly-diagnosed female breast cancer patients between 21 and 84 years, with stage I-II invasive breast cancer or ductal carcinoma in situ (DCIS) and who are eligible for and considering either mastectomy or lumpectomy with radiation, and who may be eligible for adjuvant systemic treatment. The RCT tests an interactive, tailored website, called iCanDecide (intervention arm), compared to a static version of the website (control arm). The static control arm is designed to include the same basic content as the intervention version, but without tailoring and interactive features. The primary outcome includes the rate of making a high-quality decision. The hypothesis is that patients randomized to the interactive version of iCanDecide will have higher rates of high quality decisions (informed and values-concordant), and will appraise their decision-making process more positively, for both surgical and systemic treatment. Discussion The goal of this study is to evaluate the impact of the iCanDecide interactive website on decision-making for locoregional and systemic breast cancer treatments. The results of this study will be important for future breast cancer patients and their clinicians as we determine how to better individualize decision making across this complex treatment landscape. Trial registration ClinicalTrials.gov ID NCT01840163.

Highlights • Primary small cell neuroendocrine carcinoma of the breast is a very rare diagnosis. • It has similar features to small cell neuroendocrine carcinoma of the lung. • Diagnostic workup must exclude metastasis from another primary site. • Treatment combines approaches for more common types of lung and breast cancer. • Further studies are needed to standardized the treatment for primary SCNCB., Introduction Primary small cell neuroendocrine carcinoma of the breast (SCNCB) is a very uncommon type of breast cancer. Histology and morphology are virtually indistinguishable from small cell neuroendocrine carcinomas of the lung (SCNCL), mandating a search for a primary site elsewhere in the body. There is no standard approach to treatment as there are only a limited number of cases reported in the literature. This report summarizes a case of primary SCNCB and presents a review of the literature. Presentation of case A 65-year-old female presented to her gynecologist with a right breast mass. After biopsy, she was diagnosed with a primary SCNCB with regional lymph node involvement. She was treated with chemotherapy and radiation therapy with a good clinical response. Discussion Due to the rare nature of this tumor, no standard treatment exits. Case reports have described breast conserving therapy combined with neoadjuvant or adjuvant chemotherapy as well as chemoradiation therapy alone for metastatic disease. Both chemotherapy regimens, those used to treat SCNCL and invasive breast cancer, have been described in these reports. Conclusion Primary SCNCB is a very rare type of breast cancer with no standard treatment. Further research is needed to better understand the behavior of this rare tumor in order to develop a standard approach to treatment.

The spread of mammographic screening programmes around the world, including in developing countries, has substantially contributed to the diagnosis of small non-palpable lesions, which has increased the detection rate of DCIS (ductal carcinoma in situ). DCIS is heterogeneous in several ways, such as its clinical presentation, morphology and genomic profile. Excellent outcomes have been reported; however, many questions remain unanswered. For example, which patients groups are overtreated and could instead benefit from minimal intervention and which patient groups require a more traditional multidisciplinary approach. The development of a comprehensive integrated analysis that includes the radiological, morphological and genetic aspects of DCIS is necessary to answer these questions. This review focuses on discussing the significant findings about the morphological and molecular features of DCIS and its progression that have helped to uncover the biological and genetic heterogeneity of this disease. The knowledge gained in recent years might allow the development of tailored clinical management for women with DCIS in the future.