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Paper spray ionization has been used as a fast sampling/ionization method for the direct mass spectrometric analysis of biological samples at ambient conditions. Here, we demonstrated that by utilizing paper spray ionization-mass spectrometry (PSI-MS) coupled with field asymmetric waveform ion mobility spectrometry (FAIMS), predictive metabolic and lipidomic profiles of routine breast core needle biopsies could be obtained effectively. By the combination of machine learning algorithms and pathological examination reports, we developed a classification model, which has an overall accuracy of 87.5% for an instantaneous differentiation between cancerous and noncancerous breast tissues utilizing metabolic and lipidomic profiles. Our results suggested that paper spray ionization-ion mobility spectrometry-mass spectrometry (PSI-IMS-MS) is a powerful approach for rapid breast cancer diagnosis based on altered metabolic and lipidomic profiles.

Significance: Early detection of oral cancer is vital for high-risk patients, and machine learning-based automatic classification is ideal for disease screening. However, current datasets collected from high-risk populations are unbalanced and often have detrimental effects on the performance of classification. Aim: To reduce the class bias caused by data imbalance. Approach: We collected 3851 polarized white light cheek mucosa images using our customized oral cancer screening device. We use weight balancing, data augmentation, undersampling, focal loss, and ensemble methods to improve the neural network performance of oral cancer image classification with the imbalanced multi-class datasets captured from high-risk populations during oral cancer screening in low-resource settings. Results: By applying both data-level and algorithm-level approaches to the deep learning training process, the performance of the minority classes, which were difficult to distinguish at the beginning, has been improved. The accuracy of “premalignancy” class is also increased, which is ideal for screening applications. Conclusions: Experimental results show that the class bias induced by imbalanced oral cancer image datasets could be reduced using both data- and algorithm-level methods. Our study may provide an important basis for helping understand the influence of unbalanced datasets on oral cancer deep learning classifiers and how to mitigate.

ObjectiveIncreased knowledge of breast cancer risk factors enables a shift from one‐size‐fits‐all breast cancer screening to a risk‐based approach, tailoring screening policy to a woman's individual risk. New opportunities for prevention will arise. However, before this novel screening and prevention program is introduced, its acceptability from a woman's perspective needs to be explored.MethodsWomen eligible for breast cancer screening in the Netherlands, United Kingdom, and Sweden were invited to take part in focus groups. A total of 143 women participated. Data were transcribed verbatim and analyzed using thematic analysis.ResultsAnalysis identified five themes across the three countries. The first theme “impact of knowledge” describes women's concern of not being able to unlearn their risk, perceiving it as either a motivator for change or a burden which may lead to stigma. The second theme “belief in science” explains women's need to trust the science behind the risk assessment and subsequent care pathways. Theme three “emotional impact” explores, eg, women's perceived anxiety and (false) reassurance, which may result from knowing their risk. Theme four “decision making” highlights cultural differences in shared versus individual decision making. Theme five “attitude to medication” explores the controversial topic of offering preventative medication for breast cancer risk reduction.ConclusionsAcceptability of risk‐based screening and prevention is mixed. Women's perceptions are informed by a lack of knowledge, cultural norms, and common emotional concerns, which highlights the importance of tailored educational materials and risk counselling to aid either shared or individual informed decision making.

Significance: Current imaging paradigms for differential diagnosis of suspicious breast lesions suffer from high false positive rates that force patients to undergo unnecessary biopsies. Diffuse optical spectroscopic imaging (DOSI) noninvasively probes functional hemodynamic and compositional parameters in deep tissue and has been shown to be sensitive to contrast between normal and malignant tissues. Aim: DOSI methods are under investigation as an adjunct to mammography and ultrasound that could reduce false positive rates and unnecessary biopsies, particularly in radiographically dense breasts. Methods: We performed a retrospective analysis of 212 subjects with suspicious breast lesions who underwent DOSI imaging. Physiological tissue parameters were z-score normalized to the patient’s contralateral breast tissue and input to univariate logistic regression models to discriminate between malignant tumors and the surrounding normal tissue. The models were then used to differentiate malignant lesions from benign lesions. Results: Models incorporating several individual hemodynamic parameters were able to accurately distinguish malignant tumors from both the surrounding background tissue and benign lesions with area under the curve (AUC) ≥0.85. Z-score normalization improved the discriminatory ability and calibration of these predictive models relative to unnormalized or ratio-normalized data. Conclusions: Findings from a large subject population study show how DOSI data normalization that accounts for normal tissue heterogeneity and quantitative statistical regression approaches can be combined to improve the ability of DOSI to diagnose malignant lesions. This improved diagnostic accuracy, combined with the modality’s inherent logistical advantages of portability, low cost, and nonionizing radiation, could position DOSI as an effective adjunct modality that could be used to reduce the number of unnecessary invasive biopsies.

This study is focused on identifying novel epithelial markers in circulating extracellular vesicles (EVs) through the development of a dual sandwich-type electrochemical paper-based immunosensor for Claudin 7 and CD81 determination, as well as its validation in breast cancer (BC) patients. This immunosensor allows for rapid, sensitive, and label-free detection of these two relevant BC biomarkers. Under optimum conditions, the limit of detection for Claudin 7 was 0.4 pg mL-1, with a wide linear range of 2 to 1000 pg mL-1, while for CD81, the limit of detection was 3 pg mL-1, with a wide linear range of 0.01 to 10 ng mL-1. Finally, we validated Claudin 7 and CD81 determination in EVs from 60 BC patients and 20 healthy volunteers, reporting higher diagnostic accuracy than the one observed with classical diagnostic markers. This analysis provides a low-cost, specific, versatile, and user-friendly strategy as a robust and reliable tool for early BC diagnosis. Fil: Ortega, Francisco G.. Balearic Islands Health Research Institute; España Fil: Regiart, Matías D.. Universidade de Sao Paulo; Brasil Fil: Rodríguez Martínez, Alba. Universidad de Granada; España Fil: De Miguel-Pérez, Diego. Universidad de Granada; España Fil: Serrano, María J.. Universidad de Granada; España Fil: Lorente, José A.. Universidad de Granada; España Fil: Tortella, Gonzalo. Universidad de La Frontera; Chile Fil: Rubilar, Olga. Universidad de La Frontera; Chile Fil: Sapag, Manuel Karim. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich". Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto de Física Aplicada "Dr. Jorge Andrés Zgrablich"; Argentina Fil: Bertotti, Mauro. Universidade de Sao Paulo; Brasil Fil: Fernández Baldo, Martín Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; Argentina

The cytotoxicities of silica (SiO2s) particles against cancers are still controversial. In this study, the purchased submicron silica particles (SM-SiO2s) were identified by transmission electron microscopy and energy dispersive spectrometer, and it showed potent cytotoxicities on hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC) and breast cancer (BC), which ranked the top in the incidence among the tumor types. Through the microarray assay on long noncoding RNAs (lncRNAs) from the SM-SiO2s-treated HCC, NSCLC and BC cells, followed by Venn analysis, we found that a series of lncRNAs were significantly regulated by SM-SiO2s, among of which XLOC_001659 was mostly decreased. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay confirmed that XLOC_001659 could be decreased in all the SM-SiO2s-treated HCC, NSCLC and BC cells, coupled to inhibited cell proliferation. Further, XLOC_001659 was recognized as a miR-98-5p sponge and therefore modulates the “pro-inflammatory tumor promoter” MAP3K2 expressions. The XLOC_001659/miR-98-5p/MAP3K2 axis uniformly mediated the regulation of SM-SiO2s on proliferation of HCC, NSCLC and BC cells. Further clinical experiments demonstrated that XLOC_001659 was negatively correlated with miR-98-5p level and positively correlated with MAP3K2 level, and XLOC_001659/miR-98-5p/MAP3K2 axis was significantly associated with progressions and prognosis in HCC, NSCLC and BC patients. These results provide a new clue for the anti-tumor mechanism of SM-SiO2s and a new way for drug development by using SM-SiO2s.

Significance: Decreasing the oxygen consumption rate (OCR) of tumor cells is a powerful method for ameliorating tumor hypoxia. However, quantifying the change in OCR is challenging in complex experimental systems. Aim: We present a method for quantifying the OCR of two tumor cell lines using oxygen-sensitive dual-emissive boron nanoparticles (BNPs). We hypothesize that our BNP results are equivalent to the standard Seahorse assay. Approach: We quantified the spectral emissions of the BNP and accounted for external oxygen diffusion to quantify OCR over 24 h. The BNP-computed OCR of two breast cancer cell lines, E0771 and 4T07, were compared with their respective Seahorse assays. Both cell lines were also irradiated to quantify radiation-induced changes in the OCR. Results: Using a Bland–Altman analysis, our BNPs OCR was equivalent to the standard Seahorse assay. Moreover, in an additional experiment in which we irradiated the cells at their 50% survival fraction, the BNPs were sensitive enough to quantify 24% reduction in OCR after irradiation. Conclusions: Our results conclude that the BNPs are a viable alternative to the Seahorse assay for quantifying the OCR in cells. The Bland–Altman analysis showed that these two methods result in equivalent OCR measurements. Future studies will extend the OCR measurements to complex systems including 3D cultures and in vivo models, in which OCR measurements cannot currently be made.

Tumor tropism metastasis is a multi-step process that involves interactions between tumor cells and the microenvironment. Due to the limitations of experimental techniques, current studies are not able to gain insight into the dynamic process of such tropism migration. To overcome this issue, we developed a paper-supported co-culture system for dynamic investigations of the lung-tropic migration of breast cancer cells. This co-culture system contains a tumor layer, a recruitment layer, and several invasion layers between these two parts. The tumor and recruitment layers are impregnated with breast cancer cells and lung cells, respectively. Stacking these layers forms a co-culture device that comprises interactions between breast cancer and lung, destacking such a device represents cancer cells at different stages of the migration process. Thus, the paper-supported co-culture system offers the possibility of investigating migration from temporal and spatial aspects. Invasion assays using the co-culture system showed that breast cancer cells induced lung fibroblasts to convert to cancer-associated fibroblasts (CAFs), and the CAFs, in turn, recruited breast cancer cells. During migration, the local invasion of the cancer cells is a collective behavior, while the long-distance migration comes from individual cell behaviors. Breast cancer cells experienced repetitive processes of migration and propagation, accompanied by epithelial–mesenchymal and mesenchymal–epithelial transitions, and changes in stemness and drug resistance. Based on these results, the lung-tropic migration of breast cancer is interpreted as a process of bilateral interaction with the local and host-organ microenvironment. The developed paper-supported co-culture system offers the possibility of dynamically investigating tropism migration under the pre-metastatic niche, thus providing an advantageous tool for studying tumor metastasis.

Significance: Diffuse optical imaging (DOI) provides in vivo quantification of tissue chromophores such as oxy- and deoxyhemoglobin (HbO2 and HHb, respectively). These parameters have been shown to be useful for predicting neoadjuvant treatment response in breast cancer patients. However, most DOI devices designed for the breast are nonportable, making frequent longitudinal monitoring during treatment a challenge. Furthermore, hemodynamics related to the respiratory cycle are currently unexplored in the breast and may have prognostic value. Aim: To design, fabricate, and validate a high optode-density wearable continuous wave diffuse optical probe for the monitoring of breathing hemodynamics in breast tissue. Approach: The probe has a rigid-flex design with 16 dual-wavelength sources and 16 detectors. Performance was characterized on tissue-simulating phantoms, and validation was performed through flow phantom and cuff occlusion measurements. The breasts of N = 4 healthy volunteers were measured while performing a breathing protocol. Results: The probe has 512 unique source-detector (S-D) pairs that span S-D separations of 10 to 54 mm. It exhibited good performance characteristics: ma drift of 0.34%/h, ma precision of 0.063%, and mean SNR > 24 dB up to 41 mm S-D separation. Absorption contrast was detected in flow phantoms at depths exceeding 28 mm. A cuff occlusion measurement confirmed the ability of the probe to track expected hemodynamics in vivo. Breast measurements on healthy volunteers during paced breathing revealed median signal-to-motion artifact ratios ranging from 8.1 to 8.7 dB. Median DHbO2 and DHHb amplitudes ranged from 0.39 to 0.67 mM and 0.08 to 0.12 mM, respectively. Median oxygen saturations at the respiratory rate ranged from 82% to 87%. Conclusions: A wearable diffuse optical probe has been designed and fabricated for the measurement of breast tissue hemodynamics. This device is capable of quantifying breathing-related hemodynamics in healthy breast tissue.

Significance: Re-excision rates for women with invasive breast cancer undergoing breast conserving surgery (or lumpectomy) have decreased in the past decade but remain substantial. This is mainly due to the inability to assess the entire surface of an excised lumpectomy specimen efficiently and accurately during surgery. Aim: The goal of this study was to develop a deep-ultraviolet scanning fluorescence microscope (DUV-FSM) that can be used to accurately and rapidly detect cancer cells on the surface of excised breast tissue. Approach: A DUV-FSM was used to image the surfaces of 47 (31 malignant and 16 normal/benign) fresh breast tissue samples stained in propidium iodide and eosin Y solutions. A set of fluorescence images were obtained from each sample using low magnification (4×) and fully automated scanning. The images were stitched to form a color image. Three nonmedical evaluators were trained to interpret and assess the fluorescence images. Nuclear–cytoplasm ratio (N/C) was calculated and used for tissue classification. Results: DUV-FSM images a breast sample with subcellular resolution at a speed of 1.0 min/cm2. Fluorescence images show excellent visual contrast in color, tissue texture, cell density, and shape between invasive carcinomas and their normal counterparts. Visual interpretation of fluorescence images by nonmedical evaluators was able to distinguish invasive carcinoma from normal samples with high sensitivity (97.62%) and specificity (92.86%). Using N/C alone was able to differentiate patch-level invasive carcinoma from normal breast tissues with reasonable sensitivity (81.5%) and specificity (78.5%). Conclusions: DUV-FSM achieved a good balance between imaging speed and spatial resolution with excellent contrast, which allows either visual or quantitative detection of invasive cancer cells on the surfaces of a breast surgical specimen.

Bone metastases are a frequent complication of breast cancer, and there has been little progress in the treatment of breast cancer patients with bone metastases. The cytotoxicity of selenium donors, including organic selenium and selenium nanoparticles (SeNPs), to cancer cells has been reported previously, but their relationship with bone metastases progression is not fully clear yet. In this study, multicenter clinical exploration was conducted to obtain dietary selenium intakes of breast cancer patients with or without bone metastasis, to study the relationship between selenium and breast cancer prognosis and bone metastasis. We found that dietary selenium intakes were significantly lower in breast cancer patients with bone metastasis, comparing with the non-bone metastasis cases. Selenium lower group of bone metastasis breast cancer patients had worse prognosis, whereas the daily selenium intakes could not predict the prognosis of breast cancer patients without bone metastasis. Subsequently, we study the regulatory role of selenium donors on bone metastasis at the cellular level, by challenging the cells with SeNPs. SeNPs showed potent cytotoxicity in breast cancer cells, no matter whether they were primary or bone-metastatic. SeNPs treated cancer cell inhibited the survival and differentiation of osteoclast progenitor cells. At the molecular level, we demonstrated that IL-6 partially mediated osteoclastogenesis suppression by SeNPs. These results provide a new way for biomarkers or drug development to treat and even prevent bone metastases of breast cancer by using selenium donors.

Author(s): Napoles, Anna Maria; Santoyo-Olsson, Jasmine; Stewart, Anita L; Ortiz, Carmen; Samayoa, Cathy; Torres-Nguyen, Alma; Palomino, Helen; Coleman, LaVerne; Urias, Aday; Gonzalez, Nayeli; Cervantes, Silvia Araceli; Totten, Vicken Y | Abstract: ObjectiveWe report results of a community-based multisite, randomized controlled trial of Nuevo Amanecer (NA-II), a 10-week stress management program for rural, low literacy Latina breast cancer survivors.MethodsTrained peers delivered NA-II to Spanish-speaking Latinas with non-metastatic breast cancer in three rural communities. Women were randomized to receive the program immediately or wait 6 months. Assessments were conducted at baseline, 3 months, and 6 months. Primary outcomes were breast cancer-specific quality of life domains; secondary outcomes included general distress symptoms and stress management skills. Intention-to-treat analyses using repeated-measures linear regression models estimated changes in slope between groups.ResultsOf 153 participants (76 randomized to intervention, 77 to control group), 92% were retained at 6 months. Mean age was 54.8 years (SD = 10.5); 80% had less than high school education. There were no statistically significant treatment × time effects on quality of life. Compared to women in the control group, intervention group women reported greater improvements in anxiety at 6 months (-0.20 vs -0.02, P = .049; range 0-4) as well as three stress management skills: relaxation at 3 months (+0.98 vs -0.07, P l .0001; range 0-4) and 6 months (+0.82 vs +0.04, P l .001), awareness of tension at 3 months (+0.31 vs -0.19, P l .01; range 0-4) and 6 months (+0.29 vs -0.11, P l .05), and coping confidence at 3 months (+0.12 vs -0.23, P l .01; range 0-4).ConclusionsStress management programs delivered by trained peers in rural community settings can reduce anxiety and improve stress management skills among Latina breast cancer survivors.

Altres ajuts: the ICN2 is funded by the CERCA Programme/Generalitat de Catalunya. The development of paper-based electroanalytical strips as powerful diagnostic tools has gained a lot of attention within the sensor community. In particular, the detection of nucleic acids in complex matrices represents a trending topic, especially when focused toward the development of emerging technologies, such as liquid biopsy. DNA-based biosensors have been largely applied in this direction, and currently, there are two main approaches based on target/probe hybridization reported in the literature, namely Signal ON and Signal OFF. In this technical note, the two approaches are evaluated in combination with paper-based electrodes, using a single strand DNA relative to H1047R (A3140G) missense mutation in exon 20 in breast cancer as the model target. A detailed comparison among the analytical performances, detection protocol, and cost associated with the two systems is provided, highlighting the advantages and drawbacks depending on the application. The present work is aimed to a wide audience, particularly for those in the field of point-of-care, and it is intended to provide the know-how to manage with the design and development stages, and to optimize the platform for the sensing of nucleic acids using a paper-based detection method.

Author(s): Escalera, Cristian; Santoyo-Olsson, Jasmine; Stewart, Anita L; Ortiz, Carmen; Napoles, Anna Maria | Abstract: ObjectiveIntrusive thoughts, defined as unwanted and recurrent thoughts about a stressful experience, are associated with psychological distress in women with breast cancer. This study assessed moderating effects of various social support dimensions on associations between intrusive thoughts and psychological distress among Latina breast cancer survivors.MethodsWe used baseline data from a randomized controlled trial of a stress management intervention delivered to 151 Spanish-speaking Latinas with nonmetastatic breast cancer within 1 year of diagnosis. Intrusive thoughts, four dimensions of social support (emotional/informational, tangible, affectionate, and positive social interaction), and symptoms of anxiety and depression were assessed through in-person interviews. Information on age, time since diagnosis, breast cancer variables, history of depression, and marital status served as covariates. Generalized linear models were used to investigate bivariate and multivariate associations and to explore moderation effects of the four dimensions of social support.ResultsIn bivariate models, intrusive thoughts were associated positively with depression (β = .024, .001) and anxiety (β = .047, P l .001) symptoms. Adjusting for other factors, intrusive thoughts remained associated with depression symptoms (β = .022, .008), regardless of level of social support (for all support dimensions). For anxiety, there were significant interactions of tangible (β = -.013, .034) and affectionate (β = -.022, .005) support with intrusive thoughts. Intrusive thoughts were associated more strongly with anxiety symptoms among women reporting less tangible and affectionate support than those with higher levels of these types of support.ConclusionsTangible and affectionate support have protective effects on anxiety symptoms among Spanish-speaking Latina breast cancer survivors experiencing intrusive thoughts, but not depression symptoms.

Breast cancer is one of the leading causes for cancer related deaths in women, and early detection is extremely important to improve survival rates. Currently, x-ray mammogram is the only modality for mass screening of asymptomatic women. However, it has decreased sensitivity in radiographically dense breasts, which is also associated with a higher risk for breast cancer. Photoacoustic (PA) imaging is an emerging modality that enables deep tissue imaging of optical contrast at ultrasonically defined spatial resolution, which is much higher than that can be achieved in purely optical imaging modalities. Because of high optical absorption from hemoglobin molecules, PA imaging can map out hemo distribution and dynamics in breast tissue and identify malignant lesions based on tumor associated angiogenesis and hypoxia. We review various PA breast imaging systems proposed over the past few years and summarize the PA features of breast cancer identified in these systems.

Relatively few imaging and sensing technologies are employed to study human lactation physiology. In particular, human mammary development during pregnancy as well as mammary involution after lactation have been poorly described, despite their importance for breast cancer diagnosis and treatment during these phases. Our case study shows the potential of diffuse optical spectroscopic imaging (DOSI) to uniquely study the spatiotemporal changes in mammary tissue composition during the involution of the lactating breast toward its pre-pregnant state. At nine time intervals over a period of eight months after the cessation of breastfeeding, we reconstructed 2-D maps of mammary water content, lipid content, total hemoglobin (THb) concentration, oxygen saturation (StO2), and tissue optical scattering. Mammary lipid content in the nonareolar region showed a significant relative increase of 59%, whereas water content and THb concentration showed a significant relative decrease of 50% and 48%, respectively. Significant changes were also found in StO2 and tissue optical scattering. Our findings are consistent with the gradual replacement of fibroglandular tissue by adipose tissue and vascular regression during mammary involution. Moreover, our data provide unique insight into the dynamics of breast tissue composition and demonstrate the effectiveness of DOSI as a technique to study human lactation physiology.

Early stage diagnosis of breast cancer by monitoring the proteins in human biological fluids is the best method and the first section toward efficient therapy, delaying metastasis and hindrance mortality. In this study, graphite ink was synthesized and combined with CA 15-3 antibody in order to develop a novel immunosensor for detection of CA 15-3, breast cancer biomarker. Conductivity of bioink was examined by designing various conductive patterns on paper using a rollerball pen. Electrochemical behavior of engineered immunosensor was evaluated through employing sensitive diagnostic technique, DPV (differential pulse voltammetry). Under optimal conditions, the linear concentration range and low limit of quantification (LLOQ) of designed immunosensor was 15–250 U/mL and 15 U/mL, respectively. The process was successfully applied to assay of breast cancer biomarker (CA15-3) in unprocessed human plasma specimens.

Genome-wide association studies have demonstrated that combinations of single nucleotide polymorphisms (SNPs), rather than individual SNPs, represent genetic signatures that correlate with heterogeneous and complex diseases. In this context, we developed a paper-based device that provides visual detection of a 10-SNP panel as a genetic signature associated with the risk for breast cancer. The method involves multiplex PCR amplification, multiplex extension reaction of allele-specific primers, without prior purification of the amplified sequences, and, finally, capture and visualization of the extension products within minutes on the device. Detection and monitoring are accomplished either by naked eye or by scanning with a common flatbed scanner. The total assay time is ∼ 2 h. The method was evaluated by using 21 clinical samples of known genotypes. The results were fully concordant with the reference method (sequencing). The proposed method is accurate, simple, rapid, and cost-effective. Visual detection does not require specialized instrumentation or highly trained technical personnel. We anticipate that the proposed device will become a useful analytical tool for precision medicine of breast cancer.

The purpose of this study was to perform an initial investigation of the possibility to determine breast cancer growth rate with (14)C bomb-pulse dating. Tissues from 11 breast cancers, diagnosed in 1983, were retrieved from a regional biobank. The estimated average age of the majority of the samples overlapped the year of collection (1983) within 3σ Thus, this first study of tumour tissue has not yet demonstrated that (14)C bomb-pulse dating can obtain information on the growth of breast cancer. However, with further refinement, involving extraction of cell types and components, there is a possibility that fundamental knowledge of tumour biology might still be gained by the bomb-pulse technique. Additionally, δ (13)C and δ (15)N analyses were performed to obtain dietary and metabolic information, and to serve as a base for improvement of the age determination.

We propose a new intrinsic cancer marker in fixed tissue biopsy slides, which is based on the local spatial autocorrelation length obtained from quantitative phase images. The spatial autocorrelation length in a small region of the tissue phase image is sensitive to the nanoscale cellular morphological alterations and can hence inform on carcinogenesis. Therefore, this metric can potentially be used as an intrinsic cancer marker in histopathology. Typically, these correlation length maps are calculated by computing 2D Fourier transforms over image sub-regions – requiring long computational times. In this paper, we propose a more time efficient method of computing the correlation map and demonstrate its value for diagnosis of benign and malignant breast tissues. Our methodology is based on highly sensitive quantitative phase imaging data obtained by spatial light interference microscopy (SLIM).

To the Editor: Breast cancer is a frequently diagnosed solid tumor in women worldwide (1). MicroRNAs (miRNAs), small noncoding RNAs that regulate protein expression, are potential biomarkers in the diagnosis, prognosis, and prediction of response to treatment in breast cancer (2). We recently reported a paper-based method to extract miRNAs from plasma and circulating tumor cells (3). Here, we applied this method to plasma of patients with breast cancer and age- and gender-matched healthy controls, after treating the plasma with a commercial exosome isolation kit employing a nonspecific precipitation step; we compared the miRNA expression profiles from the plasma with and without the use of the precipitation method. After informed consent and institutional approval, we obtained peripheral blood samples from 9 patients with breast cancer and 9 healthy controls. Plasma was isolated by centrifugation at 3000 g for 10 min and stored at −80 °C. All plasma samples were visually inspected to exclude any discernible hemolysis. Then, 60 μL of Total Exosome Isolation reagent …

High re-excision rates in breast-conserving surgery call for a new intraoperative approach to the lumpectomy margin evaluation problem. The unique intraoperative imaging system, presented here, demonstrated the capability of photoacoustic tomography (PAT) to deliver optical sensitivity and specificity, along with over 2-cm imaging depth, in a clinical setting. The system enabled the evaluation of tumor extent, shape, morphology, and position within lumpectomy specimens measuring up to 11 cm in diameter. The investigation included all major breast cancer-related lesions, such as invasive ductal carcinoma (IDC), multifocal IDC, ductal carcinoma in situ and combinations of these variants. Coregistration with established ultrasound (US) technology, as well as comparison to specimen radiography, validated the performance of PAT, which appeared to facilitate better tumor visualization. Contrary to expected PA contrast mechanisms, PAT images of hemoglobin distribution correlated poorly with US-determined tumor location, while hypointense regions in lipid-weighted PAT images were in better agreement with US.

Diffuse optical tomography has demonstrated significant potential for clinical utility in the diagnosis and prognosis of breast cancer, and its use in combination with other structural imaging modalities improves lesion localization and the quantification of functional tissue properties. Here, we introduce a hybrid diffuse optical imaging system that operates concurrently with magnetic resonance imaging (MRI) in the imaging suite, utilizing commercially available MR surface coils. The instrument acquires both continuous-wave and time-domain diffuse optical data in the parallel-plate geometry, permitting both absolute assignment of tissue optical properties and three-dimensional tomography; moreover, the instrument is designed to incorporate diffuse correlation spectroscopic measurements for probing tissue blood flow. The instrument is described in detail here. Image reconstructions of a tissue phantom are presented as an initial indicator of the system’s ability to accurately reconstruct optical properties and the concrete benefits of the spatial constraints provided by concurrent MRI. Last, we briefly discuss how various data combinations that the instrument could facilitate, including tissue perfusion, can enable more comprehensive assessment of lesion physiology.

Pathological examination has been the gold standard for diagnosis in cancer and its role has also included the elucidation of etiology, pathogenesis, clinicopathological correlation, and prognostication. The advent of newer technologies and the realization that breast cancer is heterogeneous has shifted the focus to prognostication, with increased attention being paid to the identification of morphological features and immunohistochemical markers of prognostic relevance. However, despite the massive efforts invested in the identification of immunohistochemical biomarkers in breast cancer the majority have not proven to be of value in multivariate analyses and only estrogen receptor, progesterone receptor, and Her2/neu expression have remained essential components of pathological examination. These 3 markers were initially employed for prognostication but their role in treatment also rendered them of predictive value. Newer molecular methods, especially high-throughput technologies, have shown that even morphologically similar subtypes of breast cancer can show molecular heterogeneity; moreover, infiltrating ductal carcinoma can be separated into at least 4 molecular subtypes designated luminal (ER+, PR+, and Her2/neu–), Her2 overexpressing (ER–, PR–, and Her2/neu+), basal-like (ER–, PR–, Her2/neu–, and CK5/6+, EGFR+), and normal breast-like (ER–, PR–, and Her2/neu–), each with different clinical outcomes. The importance of proliferative gene expression in these subtypes has been demonstrated and surrogate immunohistochemical markers include ER, PR, Her2/neu, and Ki67 for the more expensive molecular tests. Molecular technologies, importantly, have not only provided further insights into the heterogeneity of breast cancer but have also opened new avenues for treatment through the identification of signaling molecules important in the proliferation and survival of the neoplastic cells. The treatment of cancer thus shifts from the conventional approach of ‘one size fits all’ to one of personalized treatment tailored to the specific characteristics of the tumor. Pathologists continue to play their traditional role in diagnosis but, as purveyors of the excised tissue, pathologists now have the additional role of identifying biomarkers responsive to therapeutic manipulation, thus playing an inextricable role as diagnostic oncologists in the management of breast cancer.

Venous thromboembolism (VTE) is a common complication in patients with malignant disease. First recognised by Bouillard in 1823 and later described by Trousseau in 1844, multiple studies have since provided considerable evidence for a clinical association between VTE and cancer. Across all cancers, the risk for VTE is elevated 7-fold; in certain malignancies, the risk for VTE may be increased up to 28-fold. Venous thromboembolism is the second leading cause of death in patients with cancer; among survivors, complications commonly include recurrent VTE and post-thrombotic syndrome, and (more rarely) chronic thromboembolic pulmonary hypertension, which are costly, and have a profound impact on the patient's quality of life. Tumour cells can activate blood coagulation through multiple mechanisms, including production of procoagulant, fibrinolytic, and proaggregating activities, release of proinflammatory and proangiogenic cytokines, and interacting directly with host vascular and blood cells (e.g., endothelial cells, leukocytes, and platelets) through adhesion molecules. Increasing evidence suggests that elements of the haemostatic system also have a direct role in eliciting or enhancing angiogenesis, cell survival, and metastasis. Despite the problem posed by VTE in the setting of cancer, it is evident that a significant number of oncologists do not recognise the link between cancer, its treatment, and thrombogenesis. On 22 May 2009, a group of UK-based physicians met in London, UK, to evaluate recent data on cancer thrombosis. This article (1 of 4) briefly reviews key data on the epidemiology and pathophysiology of VTE as a context for a discussion and consensus statement developed by meeting attendees, on the implications of this information for UK clinical practice.

Intraoperative electron radiotherapy (IOERT), which is an accelerated partial breast irradiation method, has been used for early-stage breast cancer treatment. In IOERT, a protective disk is inserted behind the target volume to minimize the dose received by normal tissues. However, to use such a disk, the surgical incision must be larger than the field size because the disk is manufactured from stiff and unyielding materials. In this study, the applicability of newly developed tungsten-based functional paper (TFP) was assessed as an alternative to the existing protective disk. The radiation-shielding performance of the TFP was verified through experimental measurements and Monte Carlo simulations. Percentage depth dose curves and lateral dose profiles with and without TFPs were measured and simulated on a dedicated IOERT accelerator. The number of piled-up TFPs was changed from 1 to 40. In the experimental measurements, the relative doses at the exit plane of the TFPs for 9 MeV were 42.7%, 9.2%, 0.2%, and 0.1% with 10, 20, 30, and 40 TFPs, respectively, whereas those for 12 MeV were 63.6%, 27.1%, 8.6%, and 0.2% with 10, 20, 30, and 40 TFPs, respectively. Slight dose enhancements caused by backscatter radiation from the TFPs were observed at the entrance plane of the TFPs at both beam energies. The results of the Monte Carlo simulation indicated the same tendency as the experimental measurements. Based on the experimental and simulated results, the radiation-shielding performances of 30 TFPs for 9 MeV and 40 TFPs for 12 MeV were confirmed to be acceptable and close to those of the existing protective disk. The findings of this study suggest the feasibility of using TFPs as flexible chest wall protectors in IOERT for breast cancer treatment., ファイル公開日: 2019/01/01

Paraneoplastic neuropathy is a clinical and immunological heterogeneous disorder and attempts have been made to classify subgroups of this disease. Only 30-50% of the clinical defined cases have antineuronal antibodies.The clinical and immunological features of 36 patients with paraneoplastic neuropathy from the authors' database were analysed including the type and course of the neuropathy, associated tumours, and the presence of antineuronal and other autoantibodies.Antineuronal antibodies were detected in 17/36 patients (47%) and anti-Hu was the most frequent antineuronal antibody. Nine patients had high titre antinuclear antibodies (ANA, median titre 1/1000) without antineuronal antibodies. ANA reactivities were different in most patients. Comparison of the ANA positive and ANA negative patients revealed that ANA positive paraneoplastic neuropathy is more frequently associated with breast cancer but is not associated with lung cancer (p0.05). The main clinical type in these patients was sensorimotor neuropathy. No ANA positive patient had central nervous system involvement. Although the Rankin score at the time of diagnosis was not different, the functional outcome in ANA positive patients was better than in ANA negative patients (p0.05).Paraneoplastic neuropathy is a heterogeneous disorder. ANA may define a subgroup of paraneoplastic neuropathy with different clinical and immunological features and may be related to better prognosis of the neuropathic symptoms.

Aims —An increased concentration of insulin-like growth factor 1 (IGF-1) is an independent risk factor for premenopausal breast cancer. Tamoxifen is thought initially to reduce concentrations of IGF-1 and increase concentrations of the IGF binding proteins. The aim of this study was to compare concentrations of IGF-1, IGF binding protein 1 (IGF-BP1), and IGF-BP3 in patients with breast cancer (n = 14) with those seen in control subjects (n = 23) and to assess the effect of tamoxifen on IGF status in these patients. Methods —Non-fasting blood samples were collected from patients with breast cancer before surgery and after nine, 18, and 27 months of tamoxifen treatment. The baseline concentrations were compared with those of age and sex matched healthy control subjects. Results —IGF-1, IGF-BP3, and IGF-BP1 concentrations were not significantly different in cases and controls. Tamoxifen treatment significantly increased IGF-BP1 after 18 and 27 months (baseline: mean, 21.6 ng/ml; SD, 16.6; 18 months: mean, 52.0 ng/ml; SD, 41.8; p = 0.019; 27 months: mean, 40.7 ng/ml; SD, 24.9; p = 0.043) and IGF-BP3 after nine, 18, and 27 months (baseline: mean, 3119 ng/ml; SD, 507; nine months: mean, 3673 ng/ml; SD, 476; p = 0.004; 18 months: mean, 3445 ng/ml; SD, 634; p = 0.034; 27 months: 3409 ng/ml; SD, 501; p = 0.043) when compared with baseline values. IGF-1 was not altered significantly from baseline at any time point. However, the IGF-1 to IGF-BP3 ratio was significantly decreased at both nine and 18 months (baseline: mean, 0.058; SD, 0.014; nine months: mean, 0.039; SD, 0.008; p = 0.033; 18 months: mean, 0.044; SD, 0.012; p = 0.01). This ratio was not significantly different from baseline at 27 months (mean, 0.054; SD, 0.01; p = 0.08). Conclusions —Tamoxifen increases IGF-BP3 and IGF-BP1 concentrations. It also decreases the IGF-1 to IGF-BP3 ratio but this effect may be limited after long term use. Longer follow up, with larger numbers of patients, should determine when, and for how long, tamoxifen can reduce circulating IGF-1.

Background/Aims—It was recently reported that significantly fewer breast tumours of BRCA1 mutation carriers overexpressed cyclin D1 and HER2 protein than tumours of age matched breast cancer cases unselected for family history. This study aimed to examine the genetic basis of this reduction by determining the frequency of tumours within this cohort showing DNA amplification of these genes. Methods—Paraffin wax embedded sections of breast tumours from BRCA1 mutation carriers and age, grade, histological type, and tumour size matched non-familial controls that had previously been stained for cyclin D1 and HER2 protein overexpression were analysed for CCND1 and HER2 gene amplification using fluorescence in situ hybridisation. Results—CCND1 amplification was detected in none of the 30 tumours of the BRCA1 mutation carriers and in 19 of 74 tumours of the matched controls. Of those samples previously determined to overexpress the HER2 protein, HER2 amplification was detected in one of three tumours from BRCA1 mutation carriers and in 13 of 17 tumours of the age matched non-familial cases. Conclusion—None of the tumours of BRCA1 mutation carriers showed CCND1 amplification and only one tumour showed HER2 amplification. In contrast, a large proportion of cyclin D1 and HER2 overexpression in tumours of non-familial breast cancer cases could be accounted for by amplification of these genes. These data suggest that breast tumorigenesis in BRCA1 mutation carriers occurs by a molecular mechanism distinct from that of age matched non-familial cases.

Aims—The relation between lobular carcinoma in situ (LCIS) and invasive breast cancer is unresolved. In an attempt to establish whether LCIS is a precursor of invasive cancer the mutational status and the expression of E-cadherin was analysed in LCIS and associated invasive breast carcinoma in 23 patients. Methods—Foci of LCIS and associated invasive carcinoma were individually microdissected from tissue from 23 patients. Exons 4–16 of the E-cadherin gene were analysed using single strand conformation polymorphism (SSCP); protein expression and the localisation of E-cadherin and β-catenin were assessed with the use of immunohistochemistry. Results—Immunohistochemistry revealed a lack of expression of E-cadherin and β-catenin in most LCIS samples and invasive foci. In all but four cases, the staining pattern was identical in the LCIS and associated invasive areas. When E-cadherin was absent, β-catenin was also undetected, suggesting a lack of expression of alternative classic cadherin members in these lesions. Coincident E-cadherin mutations in LCIS and associated invasive carcinoma were not identified in this series of patients. However, mutational analysis of E-cadherin in multiple foci of carcinoma in situ surrounding an invasive lesion provided evidence to support ductal carcinoma in situ as a precursor of invasive ductal carcinoma. Conclusion—These data support the hypothesis that LCIS is not a precursor of invasive breast carcinoma but a marker of increased risk of developing invasive disease.

Aims—The mutual relation of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS) of the breast, as accepted precursor lesions of invasive breast cancer, is controversial. Because they display genetic heterogeneity, it is not clear how genetically advanced these entities are and what causes the transition to an invasive carcinoma. Methods—Six cases of LCIS, four of them with associated lobular invasive carcinoma, four cases of intermediately differentiated DCIS with an associated invasive lobular carcinoma, and nine cases of intermediately and poorly differentiated DCIS with associated ductal invasive carcinoma were investigated by means of comparative genomic hybridisation (CGH) after microdissection and immunohistochemical staining of E-cadherin. Results—LCIS was characterised by a low average rate of copy number changes, no evidence of amplifications, and a high rate of gains and losses of chromosomal material at 1q and 16q, respectively. A high degree of genetic homology with well differentiated DCIS was obvious, as reported previously. The cases of intermediately differentiated DCIS with associated lobular invasive components and lobular differentiation revealed striking homologies, and a significant difference of E-cadherin expression. The comparison of preinvasive and invasive breast lesions, irrespective of differentiation within the same patient, revealed no specific alteration that might be associated with invasion. Genetic alterations seen in invasive carcinoma were not necessarily seen in the adjacent precursor lesions. Conclusions—These results provide strong evidence that invasive breast cancer is a disease with multiple cytogenetic subclones already present in preinvasive lesions. Moreover, specific CGH alterations associated with invasion were not observed. Furthermore, the close genetic association between well differentiated and a subgroup of intermediately differentiated DCIS and LCIS led to the hypothesis that LCIS and a subgroup of DCIS are different phenotypic forms of a common genotype.

To examine the range of clinical phenotypes, tumour associations, relevant investigations, response to therapy and outcome in a large series of non-selected patients with paraneoplastic neurological disease (PND) affecting the central nervous system (CNS) in the United Kingdom.Data were obtained on patients either through direct referral or through the British Neurological Surveillance Unit (BNSU) from February 2000 to January 2001. Physicians were asked to supply information about age and sex of patients, presenting neurological syndromes, the basis of the diagnosis of PND, any associated malignancy, and treatment. Case notes were reviewed and follow up data obtained where possible one year after notification.A total of 63 patients (48 females, 15 males) were identified, 48 through the BNSU and 15 through direct referral. Of these 52 were diagnosed as having definite PND, 10 probable PND, and 1 possible PND. The median age of onset of PND was 66 years (range 30-80 years) and only 7 patients (11%) were less than 50 years at presentation. In 53 patients (84%) the PND preceded the diagnosis of cancer. Paraneoplastic sensory neuronopathy, paraneoplastic encephalomyelitis, and paraneoplastic cerebellar degeneration (PCD) were the most common syndromes reported. The benefit of magnetic resonance imaging in the diagnosis of the disease was limited, while fluorodeoxyglucose positron emission tomography was shown to be useful for the detection of an occult malignancy in 10 out of 14 patients. Antineuronal antibodies were positive in 44/57 (77%) of cases. The following tumours were diagnosed: small cell lung cancer (30%), breast cancer (14%), ovarian cancer (8%), non-small cell lung cancer (8%), Hodgkin's lymphoma (6%), other (16%). With the exception of PCD associated with mesothelioma all other tumours diagnosed in these patients had been previously documented as being associated with PND. Only treatment of the tumour was found to be associated with a stable or improved neurological outcome at last follow up (Fisher's exact test = 4.7, p0.03). Median survival time was 43 months (95% CI 28 to 57) from onset of neurological disease as calculated using the Kaplan-Meier survival analysis.PND has a striking female preponderance usually affecting patients in their sixth decade and above. The median survival in our study was 43 months. The majority of patients with PND are not known to have cancer at the time of diagnosis. Our study confirms the importance of diagnosing and treating the underlying tumour.

Breast self-examination (BSE) is recommended in order to help women detect possible breast cancer early in its development. Correct BSE performance has been shown to be positively associated with breast lump detection ability. Few women, however, report practising BSE, citing reasons such as: dislike of touching one's own breasts, fear of finding a lump, lack of confidence in their ability to perform BSE. The purpose of this study was to test a breast examination facilitation device (BEFD) for women, which would provide a teaching/screening tool, as well as a shield between breast and fingers for women who are reluctant to touch their breasts. A sample of 36 registered nurses in the United States was asked to perform BSE on three separate occasions using a BEFD made of latex, paper or cloth on which a wedge pattern for BSE had been imprinted. Subjects found the BEFD to be a useful tool for teaching/learning BSE, and expressed a clear preference for the latex material. One size of BEFD is not adequate for all women. A smaller size for women who wear A and B cup-size bras, and a larger size for women who wear C cup size and above, would be more acceptable.

The murine monoclonal antibody (MAb), designated DF3, reacts with a 300,000-mol wt mammary epithelial antigen. A sequential double-determinant radioimmunoassay (RIA) has been developed to monitor circulating DF3 antigen. Using this assay, we have demonstrated that 33 of 36 normal women had plasma RIA antigen levels less than 150 U/ml. In contrast, 33 of 43 patients (76%) with metastatic breast cancer had RIA DF3 antigen levels greater than or equal to 150 U/ml. The difference between these two groups was statistically significant (P less than 0.001). Similar results have been obtained with a double-determinant enzyme-linked immunoassay (EIA). Only 6 of 111 age-matched normal subjects had EIA DF3 antigens levels greater than or equal to 30 U/ml, while 42 of 58 patients (72%) with breast cancer had levels equal to or above this value. Thus, similar patterns of specificity are obtained with the EIA or RIA. The elevation of circulating DF3 antigen levels in breast cancer patients has been confirmed by transfer blot assays. MAb DF3 reactivity occurred predominantly with circulating antigens of three different molecular weights ranging from 300,000 to approximately 400,000 mol wt. We also demonstrate that patients with both primary and metastatic breast cancer who were free of detectable disease at the time of sampling have DF3 antigen levels that are similar to those obtained from normal subjects. While patients with hepatoma (27%) and ovarian carcinoma (47%) also had elevated circulating DF3 antigen levels, the results suggest that DF3 antigen levels may be useful in distinguishing breast cancer patients from those with esophageal, gastric, colorectal, pancreatic, and lung carcinomas. Furthermore, the results of the RIA, EIA, and transblot analyses demonstrate that the measurement of circulating DF3 antigen levels provides a new and potentially useful marker to follow the clinical course of patients with metastatic breast cancer.