Low progesterone receptor levels in high-grade DCIS correlate with HER2 upregulation and the presence of invasive components.

Objective: In this study, we investigated pivotal molecular markers in human high-grade breast ductal carcinoma in situ (DCIS). Expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2) was measured among various subtypes (Luminal (Lum) A, LumB HER2-, LumB HER2+, HER2-enriched and triple-negative). Methods: In total, 357 DCIS cases were classified into respective subtypes, according to the 2013 St. Gallen guidelines. Each subtype was categorized into three subcategories: "Pure" (those without an invasive component), "W/invasive" (those with an invasive component), and "All" (the entire group of the given subtype). ER and PR expression were registered as intervals. Equivocal HER2 immunohistochemistry (IHC) cases (2+) were further investigated using dual-color in situ hybridization. Results: The majority of patients (71%) were over the age of 50. We discovered no significant differences in the proportion of age between the "Pure" and "W/invasive" groups. There was no significant difference in ER/PR expression between "Pure" luminal subtypes of DCIS and "W/invasive" cases. We compared the HER2 IHC scores of "0", "1+", and "2+" among LumA and LumB HER2 subtypes and identified no statistically significant differences between "Pure" and "W/invasive" (p = 0.603). ER and PR expression ≥ 50% cutoff value was present in > 90% of all LumA cases. The incidences of cases with ER expression at cutoff values of < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). The proportion of cases with PR expression < 20% showed significant differences in the various luminal subtypes. In luminal B subtypes, low PR expression (< 20%) was significantly associated with both strong HER2 expression (3+) and the presence of an invasive component (p = 0.0001 and p = 0.0365, respectively). Conclusions: ER and PR expression at ≥ 50% cutoff values were found in more than 90% of LumA cases. Samples with ER < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). Low PR expression in high-grade DCIS was strongly associated with HER2 overexpression (3+) and an invasive component (p = 0.0001 and p = 0.0365, respectively).

Subtypes of high-grade breast ductal carcinoma in situ (DCIS): incidence and potential clinical impact.

OBJECTIVE: The purpose of this study was to investigate and classify the molecular subtypes of high-grade ductal carcinoma in situ (DCIS) and identify possible high-risk subtypes. The heterogenicity of DCIS with variable clinical and histopathological presentations has been recognized. Nevertheless, only histopathological grading and diameter are currently implemented in clinical decision-making following the diagnosis of DCIS. The molecular subtypes of DCIS and their IHC surrogate markers have not been defined in conventional treatment guidelines and recommendations. We applied the definitions of molecular subtypes according to the IHC surrogate markers defined for IBC and subclassified high-grade DCIS, accordingly. METHODS: Histopathological specimens were collected, revised, and regraded from 494 patients diagnosed with DCIS between 1996 and 2018. Other in situ and papillary lesions observed in breast biopsies were excluded from this study. 357 high-grade DCIS cases were submitted to IHC analysis. The markers investigated were ER, PR, HER2, and Ki67. RESULTS: 45 cases were classified as grade 1, 19 as grade 2, and 430 as grade 3. Sixty patients with high-grade DCIS had an additional invasive component in the surgical specimen. Thirty-three patients were diagnosed with recurrent DCIS or invasive cancer (minimum one year after their primary DCIS diagnosis). The proportions of luminal A and luminal B HER2-negative subtypes varied depending on whether 2011 or 2013 St. Gallen Consensus Conference guidelines were adopted. Luminal A was the most prevalent subtype, according to both classifications. The luminal B HER2-positive subtype was found in 22.1% of cases, HER2-enriched subtype in 21.8%, and TPN subtype in 5.6%. There were strong indications that HER2-enriched subtype was significantly more frequent among DCIS with invasive component (p = 0.0169). CONCLUSIONS: High-grade DCIS exhibits all the molecular subtypes previously identified in IBC, but with a somewhat different distribution in our cohort. HER2-enriched subtype is substantially related to the presence of an invasive component in DCIS; consequently, it is regarded as a high-risk entity.

Accuracy of breast MRI in patients receiving neoadjuvant endocrine therapy: comprehensive imaging analysis and correlation with clinical and pathological assessments.

PURPOSE: To assess the accuracy of magnetic resonance imaging (MRI) measurements in locally advanced oestrogen receptor-positive and human epidermal growth factor receptor 2-negative breast tumours before, during and after neoadjuvant endocrine treatment (NET) for evaluation of tumour response in comparison with clinical and pathological assessments. METHODS: This prospective study enrolled postmenopausal patients treated neoadjuvant with letrozole and exemestane given sequentially in an intra-patient cross-over regimen. Fifty-four patients were initially recruited, but only 35 fulfilled the inclusion criteria and confirmed to participate with a median age of 77. Tumours were scanned with MRI prior to treatment, during the eighth week of treatment and prior to surgery. Additionally, changes in longest diameter on clinical examination (CE) and tumour size at pathology were determined. Pre- and post-operative measurements of tumour size were compared in order to evaluate tumour response. RESULTS: The correlation between post-treatment MRI size and pathology was moderate and higher with a correlation coefficient (r) 0.64 compared to the correlation between CE and pathology r = 0.25. Post-treatment MRI and clinical results had a negligible bias towards underestimation of lesion size. Tumour size on MRI and CE had 0.82 cm and 0.52 cm lower mean size than tumour size measured by pathology, respectively. CONCLUSIONS: The higher correlation between measurements of residual disease obtained on MRI and those obtained with pathology validates the accuracy of imaging assessment during NET. MRI was found to be more accurate for estimating complete responses than clinical assessments and warrants further investigation in larger cohorts to validate this finding.

Changes in serum estrogenic activity during neoadjuvant therapy with letrozole and exemestane.

The aromatase inhibitors (AIs), letrozole (Femar®/Femara®) and exemestane (Aromasin®), are widely used to treat estrogen receptor (ER) positive breast cancer in postmenopausal patients. In the setting of metastatic breast cancer, these drugs may be used after another causing new responses in selected patients after progressing on the first choice. The precise explanation for this "lack of cross resistance" is still missing. NEOLETEXE is a neoadjuvant, randomized, open-label, cross-over trial. Postmenopausal patients with ER-positive, HER-2 negative, locally advanced breast cancer were enrolled. All patients were randomized to treatment starting with either letrozole or exemestane for at least 2 months followed by another 2 months on the alternative AI. The total estrogenic activities in blood samples were determined using the AroER tri-screen assay developed in the Chen laboratory. Using this highly sensitive assay, estrogenic activity was detected at three time points for all patients. Importantly, a significantly higher total estrogenic activity was found during therapy with exemestane compared to letrozole in 21 out of 26 patients. When letrozole was included in the AroER tri-screen assay, the estrogenic activities in most samples collected during exemestane treatment were further reduced, suggesting that low levels of androgens remained in specimens obtained after exemestane treatment. Our results suggest the AroER tri-screen to be a very sensitive method to estimate the overall estrogen-mediated activity in human samples even during therapy with highly potent aromatase inhibitors. In the present study, serum estrogen activity was significantly higher during exemestane therapy when compared to letrozole therapy.

Remarkable Output Power Density Enhancement of Triboelectric Nanogenerators via Polarized Ferroelectric Polymers and Bulk MoS2 Composites.

Performance enhancement of triboelectric nanogenerators (TENGs) has been largely limited by the relatively low output current density. Thus, extensive research efforts have been made to increase the output current density. In this respect, this work presents a method to effectively increase output current density of TENGs by adopting polarized ferroelectric polymers and MoS2 composite. Specifically, by compositing bulk MoS2 flakes with both Nylon-11 and PVDF-TrFE, respectively, charge density of each triboelectric charging surface was significantly increased. In addition, proper polarization of both ferroelectric composite layers has also led to an additional increase in the charge density. A combination of them synergistically increases the surface charge density, generating huge output current and the power output density. By optimizing the fabrication process, the output voltage and current density up to ∼145 V and ∼350 µA/cm2 are achieved, respectively. Consequently, the TENG exhibits a recordable output power density of ∼50 mW/cm2, which is one of the highest output power densities reported to date. The method introduced in this work can greatly increase the output current density of TENGs, facilitating the development of high-performance triboelectric energy harvesting devices.

Reusable Polybenzimidazole Nanofiber Membrane Filter for Highly Breathable PM2.5 Dust Proof Mask.

Ultrafine particulate matters (PMs) are an imminent threat to the human respiratory system, as their sizes are comparable to and even smaller than human tissues. To cope with this situation, researchers have developed and commercialized various personal dust proof masks. However, because of the relatively thick filter membrane to guarantee filtering efficiency, a huge pressure drop across the active filter layer is inevitable and breathing through it becomes uncomfortable. In this work, we investigated the performance of electrospun polybenzimidazole (PBI) nanofiber membrane filters that can potentially be used for dust proof masks or other high-performance filters. Thanks to its high dipole moment (6.12) as confirmed by density functional theory (DFT) calculation, the surface potential of the PBI nanofiber air filter, measured by KPFM, was higher than that of other commercially available mask filters. The filter developed in this work provides high PM filtering efficiency of ∼98.5% at much reduced pressure drop (130 Pa) in comparison to those used in commercially available masks (386 Pa) with similar filtering efficiencies. Consequently, an approximately 3-fold higher quality factor (∼0.032), evaluated for PM2.5, in comparison to that of commercial ones (∼0.011) was achieved by using PBI nanofiber. Furthermore, we developed a cleaning method effective for the filter contaminated by both inorganic and organic PMs. Even after several cycles of cleaning, the PBI filter membrane demonstrated negligible damage and retained its original performance because of its mechanical, thermal, and chemical durability.

Single- and double-gate synaptic transistor with TaO x gate insulator and IGZO channel layer.

We demonstrate single- and double-gate synaptic operations of a thin-film transistor (TFT) with double-gate stack consisting of an Al-top-gate/SiO x /TaO x /n-IGZO on a SiO2/n+-Si-bottom-gate substrate. This synaptic TFT exhibits a tunable drain current, mimicking synaptic weight modulation in the biological synapse, upon repeatedly applying gate and drain voltages. The drain current modulation features are analog, voltage-polarity dependently reversible, and strong with a dynamic range of multiple orders of magnitude (∼104). These features occur as a consequence of the changes in mobility of the IGZO channel, gate insulator capacitance, and threshold voltage. The drain current modulation responsive to the timing of the voltage application emulates synaptic potentiation, depression, paired-pulse facilitation, and memory transition behaviors depending on the voltage pulse amplitude, width, repetition number, and interval between pulses. The synaptic motions can be realized also by a double-gate operation that separately tunes the channel conductance by top-gate biasing and senses it by bottom-gate biasing. It provides the modulated synaptic weight with a wide level of synaptic weight through the read condition using a bottom-gate stack without read-disturbance. These results verify the potential application of TaO x /IGZO TFT with single- and double-gate operations to artificial synaptic devices.

An ultraviolet and electric field activated photopolymer-ferroelectric nanoparticle composite for the performance enhancement of triboelectric nanogenerators.

For the development of high performance triboelectric generators (TENGs), it is required to have facile methods to adjust the triboelectric properties of the friction surfaces. In this work, we present the surface charge density modulation of the photopolymer-ferroelectric nanoparticle composite surface by applying ultraviolet (UV) and electric field. By using the photopolymer, the triboelectric surface property was modulated by exposure to UV. In addition, lithographic surface patterning can be easily adopted to enlarge the frictional surface area as well. Furthermore, the use of the PP allows a facile integration of ferroelectric nanoparticles (NPs) in the form of a nanocomposite structure, which can effectively increase the surface charge density by spontaneous dipole coupling of NPs embedded in the PP layer. As a result, approximately 4-fold higher output power has been achieved by applying this approach. The developed TENGs have also demonstrated superior mechanical durability, generating consistent outputs during 104 cyclic frictional contacts. The approach proposed here is a simple and reliable way to enhance the output performance of TENGs.

Microneedles integrated with a triboelectric nanogenerator: an electrically active drug delivery system.

In this study, a combined system of microneedles and a triboelectric nanogenerator (TENG) has been developed for drug delivery. A triboelectric device, which converts mechanical energy into alternating current (AC), was chosen to replace the electrophoresis (EP) effect. To directly generate triboelectricity from salmon deoxyribonucleic acid (SDNA)-based microneedles, a triboelectric series of SDNA film and chargeable polymers (polyimide and Teflon) was studied. The electrical output of the two charged polymers was compared to find a material that could be highly charged with SDNA. The electrical output was also compared as a function of the concentration of a drug embedded in the SDNA film, and the results confirmed that drug intercalation affected the carrier diffusion. The mechanical strength of the microneedles was assessed by histological analysis of their penetration into porcine cadaver skin. Furthermore, the output voltage of a system incorporating microneedles and TENG in cadaver skin, and in vitro drug release into gelatin were evaluated to examine potential application as an electrically active drug delivery system. The electrical output voltage of this system was ∼95 V. The mechanism of triboelectric perturbation to the skin has also been discussed. The system developed in this work is a new, facile approach toward effective drug delivery that replaces the existing EP method and expands the application of TENGs.

Synaptic behaviors of thin-film transistor with a Pt/HfO x /n-type indium-gallium-zinc oxide gate stack.

We report a variety of synaptic behaviors in a thin-film transistor (TFT) with a metal-oxide-semiconductor gate stack that has a Pt/HfO x /n-type indium-gallium-zinc oxide (n-IGZO) structure. The three-terminal synaptic TFT exhibits a tunable synaptic weight with a drain current modulation upon repeated application of gate and drain voltages. The synaptic weight modulation is analog, voltage-polarity dependent reversible, and strong with a dynamic range of multiple orders of magnitude (>104). This modulation process emulates biological synaptic potentiation, depression, excitatory-postsynaptic current, paired-pulse facilitation, and short-term to long-term memory transition behaviors as a result of repeated pulsing with respect to the pulse amplitude, width, repetition number, and the interval between pulses. These synaptic behaviors are interpreted based on the changes in the capacitance of the Pt/HfO x /n-IGZO gate stack, the channel mobility, and the threshold voltage that result from the redistribution of oxygen ions by the applied gate voltage. These results demonstrate the potential of this structure for three-terminal synaptic transistor using the gate stack composed of the HfO x gate insulator and the IGZO channel layer.

Synaptic characteristics with strong analog potentiation, depression, and short-term to long-term memory transition in a Pt/CeO2/Pt crossbar array structure.

A crossbar array of Pt/CeO2/Pt memristors exhibited the synaptic characteristics such as analog, reversible, and strong resistance change with a ratio of ∼103, corresponding to wide dynamic range of synaptic weight modulation as potentiation and depression with respect to the voltage polarity. In addition, it presented timing-dependent responses such as paired-pulse facilitation and the short-term to long-term memory transition by increasing amplitude, width, and repetition number of voltage pulse and reducing the interval time between pulses. The memory loss with a time was fitted with a stretched exponential relaxation model, revealing the relation of memory stability with the input stimuli strength. The resistance change was further enhanced but its stability got worse as increasing measurement temperature, indicating that the resistance was changed as a result of voltage- and temperature-dependent electrical charging and discharging to alter the energy barrier for charge transport. These detailed synaptic characteristics demonstrated the potential of crossbar array of Pt/CeO2/Pt memristors as artificial synapses in highly connected neuron-synapse network.

Digital Breast Tomosynthesis and Synthetic 2D Mammography versus Digital Mammography: Evaluation in a Population-based Screening Program.

Purpose To compare the performance of digital breast tomosynthesis (DBT) and two-dimensional synthetic mammography (SM) with that of digital mammography (DM) in a population-based mammographic screening program. Materials and Methods In this prospective cohort study, data from 37 185 women screened with DBT and SM and from 61 742 women screened with DM as part of a population-based screening program in 2014 and 2015 were included. Early performance measures, including recall rate due to abnormal mammographic findings, rate of screen-detected breast cancer, positive predictive value of recall, positive predictive value of needle biopsy, histopathologic type, tumor size, tumor grade, lymph node involvement, hormonal status, Ki-67 level, and human epidermal growth factor receptor 2 status were compared in women who underwent DBT and SM screening and in those who underwent DM screening by using χ2 tests, two-sample unpaired t tests, and tests of proportions. Results Recall rates were 3.4% for DBT and SM screening and 3.3% for DM screening (P = .563). DBT and SM screening showed a significantly higher rate of screen-detected cancer compared with DM screening (9.4 vs 6.1 cancers per 1000 patients screened, respectively; P < .001). The rate of detection of tumors 10 mm or smaller was 3.2 per 1000 patients screened with DBT and SM and 1.8 per 1000 patients screened with DM (P < .001), and the rate of grade 1 tumors was 3.3 per 1000 patients screened with DBT and SM versus 1.4 per 1000 patients screened with DM (P < .001). On the basis of immunohistochemical analyses, rates of lymph node involvement and tumor subtypes did not differ between women who underwent DBT and SM screening and those who underwent DM screening. Conclusion DBT and SM screening increased the detection rate of histologically favorable tumors compared with that attained with DM screening. © RSNA, 2018 Online supplemental material is available for this article.

Ferroelectric nanoparticle-embedded sponge structure triboelectric generators.

We report high-performance triboelectric nanogenerators (TENGs) employing ferroelectric nanoparticles (NPs) embedded in a sponge structure. The ferroelectric BaTiO3 NPs inside the sponge structure play an important role in increasing surface charge density by polarized spontaneous dipoles, enabling the packaging of TENGs even with a minimal separation gap. Since the friction surfaces are encapsulated in the packaged device structure, it suffers negligible performance degradation even at a high relative humidity of 80%. The TENGs also demonstrated excellent mechanical durability due to the elasticity and flexibility of the sponge structure. Consequently, the TENGs can reliably harvest energy even under harsh conditions. The approach introduced here is a simple, effective, and reliable way to fabricate compact and packaged TENGs for potential applications in wearable energy-harvesting devices.

Prognostic significance of S100A4-expression and subcellular localization in early-stage breast cancer.

PURPOSE: Prognostic factors are useful in order to identify early-stage breast cancer patients who might benefit from adjuvant treatment. The metastasis-promoting protein S100A4 has previously been associated with poor prognosis in breast cancer patients. The protein is expressed in diverse subcellular compartments, including the cytoplasm, extracellular space, and nucleus. Nuclear expression is an independent predictor of poor outcome in several cancer types, but the significance of subcellular expression has not yet been assessed in breast cancer. METHODS: Nuclear and cytoplasmic expression of S100A4 was assessed by immunohistochemistry in prospectively collected tumor samples from early-stage breast cancer patients using tissue microarrays. RESULTS: In patients not receiving adjuvant systemic therapy, nuclear or cytoplasmic expression was found in 44/291 tumors (15%). Expression of either nuclear or cytoplasmic S100A4 was associated with histological grade III, triple-negative subtype, and Ki-67-expression. Patients with S100A4-positive tumors had inferior metastasis-free and overall survival compared to S100A4-negative. When expression was analyzed separately, nuclear S100A4 was a significant predictor of outcome, while cytoplasmic was not. In patients who received adjuvant treatment 23/300 tumors (8%) were S100A4-positive, but no tumors displayed nuclear staining alone. S100A4-expression was strongly associated with histological grade III and triple-negative subtype. Although not significant, metastasis-free and overall survival was numerically reduced in patients with S100A4-positive tumors. CONCLUSION: S100A4-expression was associated with poor outcome in early-stage breast cancer, but the low percentage of positive tumors and the modest survival differences imply that the clinical utility in selection of patients for adjuvant treatment is limited.

Optimizing photo-mineralization of aqueous methyl orange by nano-ZnO catalyst under simulated natural conditions.

BACKGROUND: Photo-degradation of organic contaminants into non-hazardous mineral compounds is emerging as a strategy to purify water and environment. Tremendous research is being done using direct solar light for these purposes. In this paper we report on optimum conditions for complete mineralization of aqueous methyl orange using lab-prepared ZnO nanopowder catalyst under simulated solar light. RESULTS: Nano-scale ZnO powder was prepared in the lab by standard methods, and then characterized using electronic absorption spectra, photolumenscence emission (PL) spectra, XRD, and SEM. The powder involved a wurtzite structure with ~19 nm particles living in agglomerates. Photo-degradation progressed faster under neutral or slightly acidic conditions which resemble natural waters. Increasing catalyst concentration increased photodegradation rate to a certain limit. Values of catalyst turn over number and degradation percentage increased under higher light intensity, whereas the quantum yield values decreased. The photocatalytic efficiency of nano-ZnO powders in methyl orange photodegradation in water with solar light has been affected by changing the working conditions. More importantly, the process may be used under natural water conditions with pH normally less than 7, with no need to use high concentrations of catalyst or contaminant. The results also highlight the negative impact of possible high concentrations of CO2 on water purification processes. Effects of other added gaseous flows to the reaction mixture are also discussed. CONCLUSION: ZnO nano-particles are useful catalyst for complete mineralization of organic contaminants in water. Photo-degradation of organic contaminants with ZnO nano-particles, methyl orange being an example, should be considered for future large scale water purification processes under natural conditions.

Altered antioxidant system stimulates dielectric barrier discharge plasma-induced cell death for solid tumor cell treatment.

This study reports the experimental findings and plasma delivery approach developed at the Plasma Bioscience Research Center, Korea for the assessment of antitumor activity of dielectric barrier discharge (DBD) for cancer treatment. Detailed investigation of biological effects occurring after atmospheric pressure non-thermal (APNT) plasma application during in vitro experiments revealed the role of reactive oxygen species (ROS) in modulation of the antioxidant defense system, cellular metabolic activity, and apoptosis induction in cancer cells. To understand basic cellular mechanisms, we investigated the effects of APNT DBD plasma on antioxidant defense against oxidative stress in various malignant cells as well as normal cells. T98G glioblastoma, SNU80 thyroid carcinoma, KB oral carcinoma and a non-malignant HEK293 embryonic human cell lines were treated with APNT DBD plasma and cellular effects due to reactive oxygen species were observed. Plasma significantly decreased the metabolic viability and clonogenicity of T98G, SNU80, KB and HEK293 cell lines. Enhanced ROS in the cells led to death via alteration of total antioxidant activity, and NADP+/NADPH and GSH/GSSG ratios 24 hours (h) post plasma treatment. This effect was confirmed by annexin V-FITC and propidium iodide staining. These consequences suggested that the failure of antioxidant defense machinery, with compromised redox status, might have led to sensitization of the malignant cells. These findings suggest a promising approach for solid tumor therapy by delivering a lethal dose of APNT plasma to tumor cells while sparing normal healthy tissues.

Systematic analysis of challenge-driven improvements in molecular prognostic models for breast cancer.

Although molecular prognostics in breast cancer are among the most successful examples of translating genomic analysis to clinical applications, optimal approaches to breast cancer clinical risk prediction remain controversial. The Sage Bionetworks-DREAM Breast Cancer Prognosis Challenge (BCC) is a crowdsourced research study for breast cancer prognostic modeling using genome-scale data. The BCC provided a community of data analysts with a common platform for data access and blinded evaluation of model accuracy in predicting breast cancer survival on the basis of gene expression data, copy number data, and clinical covariates. This approach offered the opportunity to assess whether a crowdsourced community Challenge would generate models of breast cancer prognosis commensurate with or exceeding current best-in-class approaches. The BCC comprised multiple rounds of blinded evaluations on held-out portions of data on 1981 patients, resulting in more than 1400 models submitted as open source code. Participants then retrained their models on the full data set of 1981 samples and submitted up to five models for validation in a newly generated data set of 184 breast cancer patients. Analysis of the BCC results suggests that the best-performing modeling strategy outperformed previously reported methods in blinded evaluations; model performance was consistent across several independent evaluations; and aggregating community-developed models achieved performance on par with the best-performing individual models.

CdS-sensitized TiO2 in phenazopyridine photo-degradation: catalyst efficiency, stability and feasibility assessment.

Mineralization of phenazopyridine, 1, in water, under solar-simulator radiation was efficiently achieved using nanoparticle CdS-sensitized rutile TiO(2), TiO(2)/CdS, 2, as photo-catalysts. Despite that, 2 showed two main drawbacks. Firstly, the system was difficult to recover by simple filtration, and demanded centrifugation. Secondly, the sensitizer CdS showed relatively high tendency to leach out hazardous Cd(2+) ions under photo-degradation reaction conditions. In an attempt to solve out such difficulties, 2 was supported onto sand surface. The sand/TiO(2)/CdS system, 3, was easier to recover but showed slightly lower catalytic activity compared to 2. On the other hand, the support failed to prevent leaching of Cd(2+). This indicates limited future applicability of CdS-sensitized TiO(2) photo-catalyst systems, in solar-based water purification strategies, unless leaching out tendency is completely prevented.

The prognostic impact of occult nodal metastasis in early breast carcinoma.

The clinical relevance of isolated tumor cell (ITC: 0.2-2.0 mm) in axillary lymph nodes (ALNs) remains unknown. The aim of this study was to determine their prognostic significance. A total of 295 patients considered as pN0 after routine histological assessment, were reevaluated with ten-level cytokeratin immunohistochemistry (IHC) and two-level hematoxylin-eosin sections. Survival rates, i.e. disease-free survival (DFS), distant disease-free survival (DDFS) and breast cancer specific survival (BCSS) were compared with those of reevaluated node-negative patients. A total of 84 patients (28%) had ITC/MM identified on IHC sections. ITC had no impact on survival at a median 8.2 years of follow-up, whereas MM showed a trend toward poorer DFS (P = 0.091, log rank) and DDFS (P = 0.066) and significantly reduced BCSS (P = 0.016). In multivariate analyses, detection of MM was an independent prognostic factor for DDFS (P = 0.025) and BCSS (P = 0.01) in adjuvant un-treated patients. Micrometastases (MMs) in axillary lymph nodes have prognostic impact. This was not found for ITC. This finding supports the use of systemic adjuvant therapy in patients with MM.

Ki-67 expression in primary breast carcinomas and their axillary lymph node metastases: clinical implications.

Proliferative activity of tumour cells assessed by immunohistochemical Ki-67 expression is one of several prognostic indicators in breast cancer. The major objective of this study was to investigate the prognostic impact of Ki-67 proliferative activity in the axillary lymph node metastases and in the matched primary breast carcinoma from 194 patients. There was a statistically significant up-regulation of Ki-67 protein in the metastatic deposit compared to where the primary tumour was found (p = 0.001). A low Ki-67 index in both the primary and the metastatic tumours was a favorable prognostic factor. A high index in both primary and metastatic lesion and an up-regulation from a low index in the primary tumour to a high index in the metastatic deposit represented an unfavorable prognostic factor. Multivariate analysis showed that Ki-67 expression in the metastases was a superior independent prognostic factor of clinical outcomes compared to that in the primary tumours. Ki-67 expression in > or =10% of carcinoma cells in the primary tumours and > or =15% in the nodal metastases seems to be optimal cut-off levels. Ki-67 is of value as an independent prognostic factor in breast cancer.