[Ascending Colon Cancer with Radical Resection after Stent Reimplantation Due to Colonic Stent Obstruction for Palliation-A Case Report].

Since the insurance coverage of colorectal stents for bowel obstruction due to colorectal cancer in 2012, the use of colorectal stenting for palliation has rapidly spread. We report a case of ascending colon cancer in which a colorectal stent was placed for palliation, but the stent was reimplanted due to obstruction, followed by radical resection. The patient was a 92- year-old woman who was brought to the emergency room at the age of 90 years with repeated vomiting and abdominal pain, and was diagnosed as colorectal cancer ileus caused by ascending colon cancer, and a colorectal stent was inserted. She received palliative care and had been asymptomatic for 1 year and 3 months, but due to in-stent stenosis, she had bowel obstruction and sent to emergency room, and another stent was installed. The patient had a good course, but 4 months after the second stenting, she was concerned about restenosis and referred to the department of surgery, then performed a radical resection. The indication for colorectal stents for palliative purposes should be considered on a case-by- case basis, including ADL, stage of the disease, and prognosis.

[A Case of Two-Stage Operation for Esophageal Cancer with Sarcoidosis].

A 69-year-old man with dysphagia was diagnosed with advanced esophageal cancer by upper gastrointestinal endoscopy. He had undergone pancreatic tail and partial transverse colon resection for pancreatic cancer, and right hilar lymph node biopsy and partial lower lobe resection for the diagnosis of pulmonary sarcoidosis. Contrast-enhanced computed tomography(CT)scan showed no change over time in lymph node enlargement in the mediastinum, so metastasis of esophageal cancer was considered to be negative. Therefore, the diagnosis of advanced esophageal cancer, Mt, type 2, T2N0M0, cStage Ⅱ, was made, and surgery was performed after 2 courses of DCF therapy. Because of the adhesions in the thoracic cavity and possible problems with elevation of the gastric tube and blood flow due to resection of the pancreatic tail, it was decided to perform two-stage operation. Although imaging studies over time, as in the present case, can help in the diagnosis, it is difficult to distinguish whether enlarged lymph nodes are reactive changes or metastases. In this study, we experienced a case of thoracic esophageal cancer complicated by sarcoidosis with enlarged mediastinal lymph nodes.

[A Case of Refractory Lymphorrhea after Laparoscopic Distal Gastrectomy].

An 84-year-old man with gastric cancer, cT2N0M0, cStage Ⅰ underwent laparoscopic distal gastrectomy, D1+dissection, and Roux-en-Y reconstruction. We started enteral nutrition on the second postoperative day, but milky drainage appeared from the drain on the fifth postoperative day. The triglyceride in the ascites was markedly elevated, and it was diagnosed as a lymphorrhea. Neither conservative treatment nor lymphangiography were successful. We decided to perform surgical intervention because the lymphorrhea did not improve for about 1 month after gastrectomy. At laparotomy, we detected the lymphatic ducts using enteral nutrition of fat formulas during surgery and successfully closed the lymphatic ducts by suturing and ligation on the 38th postoperative day. Prolonged lymphorrhea causes extreme deterioration of the patient's general condition. Prolonged total parenteral nutrition also increases the risk of infection. It is important to perform surgical treatment for intractable lymphorrhea that does not improve with conservative treatment without hesitation.

[A Case of Conversion Surgery after Chemotherapy for Advanced Gastric Cancer with Peritoneal Disseminations].

BACKGROUND: Advanced gastric cancer with peritoneal dissemination is difficult to treat, although prognosis has improved with chemotherapy and the introduction of molecular targeted drugs. CASE: A 65-year-old male was diagnosed as type 3 advanced gastric cancer on the posterior wall of antrum by esophagogastroduodenoscopy for anemia screening. When the patient underwent radical surgery, multiple disseminated nodules(P1c)were detected. After chemotherapy(SOX, PTX plus RAM)was administered, the tumor shrank, and staging laparoscopy was performed. Since disseminated nodules have disappeared, distal gastrectomy(R0)was performed as conversion surgery. As postoperative adjuvant chemotherapy, S-1 was administered for about 1 year and 6 months. During repair of incisional hernia at 1 year postoperatively, the patient was confirmed to have no disseminated recurrence. The patient is currently alive with no sign of recurrence for 4 years.

[A Case of Long-Term Survival without Recurrence following Resection of Hepatic and Pulmonary Metastases of Gastric Cancer].

A 78-year-female underwent distal gastrectomy for gastric cancer. The final diagnosis was moderately differentiated tubular adenocarcinoma, T4a, N2, M0, Stage ⅢB. Four years later, S6 hepatic metastasis and S9 pulmonary metastasis were detected. After 10 courses of S-1 plus oxaliplatin therapy, she received partial hepatectomy(S6). One year after hepatectomy, she underwent partial pulmonary resection for lung metastasis in the left lung(S9). Histopathological findings revealed the lung tumor was a pulmonary metastasis from gastric cancer with a small primary lung adenocarcinoma. There has been no recurrence for 30 months since the last operation.

The multigene classifiers 95GC/42GC/155GC for precision medicine in ER-positive HER2-negative early breast cancer.

In clinical decision-making, to decide the indication for adjuvant chemotherapy for estrogen receptor-positive (ER+), human epidermal growth factor receptor-2-negative (HER2-), and node-negative (n0) breast cancer patients, the accurate estimation of recurrence risk is essential. Unfortunately, conventional prognostic factors, such as tumor size, histological grade and ER, progesterone receptor (PR), and HER2 status as well as Ki67 index, are not sufficiently accurate for such estimation. Therefore, several multigene assays (MGAs) based on the mRNA expression analysis of multiple genes in tumor tissue have been developed to better predict patient prognosis. These assays include Oncotype DX, MammaPrint, PAM50, GGI, EndoPredict, and BCI. We developed Curebest™ 95-Gene Classifier Breast (95GC) classifier, which is unique in that mRNA expression data of all 20 000 human genes are secondarily obtainable, as the 95GC assay is performed using Affymetrix microarray. This can capture mRNA expression of not only 95 genes but also every gene at once, and such gene expression data can be utilized by the other MGAs that we have developed, such as the 155GC, which is used for the prognostic prediction of ER+/HER2- breast cancer patients treated with neoadjuvant chemotherapy. We also developed the 42GC for predicting late recurrence in ER+/HER2- breast cancer patients. In this mini-review, our recent attempt at the development of various MGAs, which is expected to facilitate the implementation of precision medicine in ER+/HER2- breast cancer patients, is presented with a special emphasis on 95GC.

Structural Phase Transitions of a Molecular Metal Oxide.

The structural phase of a metal oxide changes with temperature and pressure. During phase transitions, component ions move in multidimensional metal-oxygen networks. Such macroscopic structural events are robust to changes in particle size, even at scales of around 10 nm, and size effects limiting these transitions are particularly important in, for example, high-density memory applications of ferroelectrics. In this study, we examined structural transitions of the molecular metal oxide [Na@(SO3 )2 (n-BuPO3 )4 MoV 4 MoVI 14 O49 ]5- (Molecule 1) at approximately 2 nm by using single-crystal X-ray diffraction analysis. The Na+ encapsulated in the discrete metal-oxide anion exhibited a reversible order-disorder transition with distortion of the Mo-O molecular framework induced by temperature. Similar order-disorder transitions were also triggered by chemical pressure induced by removing crystalline solvent molecules in the single-crystal state or by substituting the countercation to change the molecular packing.

Anisotropic Polyoxometalate Cages Assembled via Layers of Heteroanion Templates.

The synthesis of anisotropic redox-active polyoxometalates (POMs) that can switch between multiple states is critical for understanding the mechanism of assembly of structures with a high aspect ratio, as well as for their application in electronic devices. However, a synthetic methodology for the controlled growth of such clusters is lacking. Here we describe a strategy, using the heteroanion-directed assembly, to produce a family of 10 multi-layered, anisotropic POM cages templated by redox-active pyramidal heteroanions with the composition [W16Mo2O54(XO3)]n-, [W21Mo3O75/76(XO3)2]m-, and [W26Mo4O93(XO3)3]o- for the double, triple, and quadruple layered clusters, respectively. It was found that the introduction of reduced molybdate is essential for self-assembly and results in mixed-metal (W/Mo) and mixed-valence (WVI/MoV) POM cages, as confirmed by an array of analytical techniques. To probe the archetype in detail, a tetrabutyl ammonium (TBA) salt derivative of a fully oxidized two-layered cage is produced as a model structure to confirm that all the cages are a statistical mixture of isostructures with variable ratios of W/Mo. Finally, it was found that multilayered POM cages exhibit dipolar relaxations due to the presence of the mixed valence WVI/MoV metal centers, demonstrating their potential use for electronic materials.

Ferroelectric Behavior of a Hexamethylenetetramine-Based Molecular Perovskite Structure.

We report the development of a molecular ferroelectric material inspired by the hexamethylenetetramine (hmta) non-centrosymmetric molecular rotator. The bromide salt of diprotonated hmta (hmtaH2 ) crystalized as (hmtaH2 )(NH4 )Br3 in a metal-free ABX3 perovskite-type structure, in which the A and B sites are occupied by hmtaH2 2+ and ammonium cations, respectively. The compound crystallized in the Pma2 polar space group. A distorted polar perovskite structure formed owing to the distortion of {(NH4 )Br6 } octahedrons that are stabilized through the formation of NH⋅⋅⋅Br hydrogen bonds and the orientational ordering of positive charges on the non-centrosymmetric hmtaH2 molecules. This spontaneous polarization exhibited ferroelectric behavior with a nominally high Curie temperature (>400 K), in which the electrical switching of polarization originates from the rotation of the hmtaH2 unit.

Construction of a novel multi-gene assay (42-gene classifier) for prediction of late recurrence in ER-positive breast cancer patients.

PURPOSE: Prediction models for late (> 5 years) recurrence in ER-positive breast cancer need to be developed for the accurate selection of patients for extended hormonal therapy. We attempted to develop such a prediction model focusing on the differences in gene expression between breast cancers with early and late recurrence. METHODS: For the training set, 779 ER-positive breast cancers treated with tamoxifen alone for 5 years were selected from the databases (GSE6532, GSE12093, GSE17705, and GSE26971). For the validation set, 221 ER-positive breast cancers treated with adjuvant hormonal therapy for 5 years with or without chemotherapy at our hospital were included. Gene expression was assayed by DNA microarray analysis (Affymetrix U133 plus 2.0). RESULTS: With the 42 genes differentially expressed in early and late recurrence breast cancers in the training set, a prediction model (42GC) for late recurrence was constructed. The patients classified by 42GC into the late recurrence-like group showed a significantly (P = 0.006) higher late recurrence rate as expected but a significantly (P = 1.62 × E-13) lower rate for early recurrence than non-late recurrence-like group. These observations were confirmed for the validation set, i.e., P = 0.020 for late recurrence and P = 5.70 × E-5 for early recurrence. CONCLUSION: We developed a unique prediction model (42GC) for late recurrence by focusing on the biological differences between breast cancers with early and late recurrence. Interestingly, patients in the late recurrence-like group by 42GC were at low risk for early recurrence.

Giant Hysteretic Single-Molecule Electric Polarisation Switching above Room Temperature.

Continual progress has been achieved in information technology through unrelenting miniaturisation of the single memory bit in integrated ferromagnetic, ferroelectric, optical, and related circuits. However, as miniaturisation approaches its theoretical limit, new memory materials are being sought. Herein, we report a unique material exhibiting single-molecule electric polarisation switching that can operate above room temperature. The phenomenon occurs in a Preyssler-type polyoxometalate (POM) cluster we call a single-molecule electret (SME). It exhibits all the characteristics of ferroelectricity but without long-range dipole ordering. The SME affords bi-stability as a result of the two potential positions of localisation of a Tb3+ ion trapped in the POM, resulting in extremely slow relaxation of the polarisation and electric hysteresis with high spontaneous polarisation and coercive electric fields. Our findings suggest that SMEs can potentially be applied to ultrahigh-density memory and other molecular-level electronic devices operating above room temperature.

Endocrine sensitivity of estrogen receptor-positive breast cancer is negatively correlated with aspartate-ß-hydroxylase expression.

Although prognostic markers for early estrogen receptor (ER)-positive breast cancer have been extensively developed, predictive markers for adjuvant endocrine therapy are still lacking. Focusing on the mechanisms underlying endocrine resistance, we investigated whether the endocrine sensitivity of ER-positive breast cancer cells was correlated with the expression of aspartate-ß-hydroxylase (ASPH), which is involved in the development of hepatocellular carcinoma. ASPH expression in ER-positive and tamoxifen-resistant breast cancer cells was upregulated by the MAPK and phosphoinositide-3 kinase (PI3K) pathways, which both play pivotal roles in endocrine resistance. In the clinical setting, ASPH expression was negatively correlated with recurrence-free survival of luminal B breast cancer patients that received adjuvant endocrine therapy, but not in patients that did not receive adjuvant endocrine therapy. Luminal B breast cancer is one of the intrinsic molecular subtypes identified by the Prediction Analysis of Microarray 50 (PAM50) multiple gene classifier, and because of its poor response to endocrine therapy, chemotherapy in addition to endocrine therapy is generally required after surgical resection. Our results suggest that the endocrine sensitivity of luminal B breast cancer can be assessed by examining ASPH expression, which promotes the consideration of a prospective study on the association between ASPH expression at the mRNA and protein levels in luminal B breast cancer and subsequent response to endocrine therapy.

Investigating the formation of "molybdenum blues" with gel electrophoresis and mass spectrometry.

The reduction of solutions of acidified molybdate leads to the formation of a family of nanostructured molybdenum blue (MB) wheels which are linked together in a series of complex reaction networks. These networks are complex because the species which define the nodes are extremely labile, unstable, and common to many different networks. Herein, we combine gel electrophoresis and electrospray ionization mass spectrometry (ESI-MS) to investigate the effect of the pH and the ratio of reactants and reducing agents, R (R = [S2O4(2-)]/[MoO4(2-)]), on the complex underlying set of equilibria that make up MBs. By mapping the reaction parameter space given by experimental variables such as pH, R, solvent medium, and type of counterion, we show that the species present range from nanostructured MB wheels (comprising ca. 154 Mo atoms) to smaller molecular capsules, [(SO3)2Mo(V)2Mo(VI)16O54](6-) ({S2Mo18}), and templated hexameric [(µ6-SO3)Mo(V)6O15(µ2-SO3)3](8-)({S4Mo6}) anions. The parallel effects of templation and reduction on the self-assembly process are discussed, taking into consideration the Lewis basicity of the template, the oxidation state of the Mo centers, and the polarity of the reaction medium. Finally, we report a new type of molecular cage (TBA)5[Na(SO3)2(PhPO3)4Mo(V)4Mo(VI)14O49]·nMeCN (1), templated by SO3(2-) anions and decorated by organic ligands. This discovery results from the exploration of the cooperative effect of two anions possessing comparable Lewis basicity, and we believe this constitutes a new synthetic approach for the design of new nanostructured molecular metal oxides and will lead to a greater understanding of the complex reaction networks underpinning the assembly of this family of nanoclusters.

Electrical network of single-crystalline metal oxide nanoclusters wired by π-molecules.

In a mixed-valence polyoxometalate, electrons are usually delocalized within the cluster anion because of low level of inter-cluster interaction. Herein, we report the structure and electrical properties of a single crystal in which mixed-valence polyoxometalates were electrically wired by cationic π-molecules of tetrathiafulvalene substituted with pyridinium. Electron-transport characteristics are suggested to represent electron hopping through strong interactions between cluster and cationic π-molecules.

Investigation of recurrence prediction ability of EndoPredict® using microarray data from fresh frozen tissues in ER-positive, HER2-negative breast cancer and indication expansion of EndoPredict® from microarray data from fresh-frozen to FFPE tissues.

BACKGROUND: EndoPredict® (EP) is a multigene assay to predict distant recurrence risk in luminal breast cancer. EP measures the expression of 12 genes in primary tumor by qRT-PCR from formalin-fixed paraffin-embedded (FFPE) tissues and calculates EP risk score that indicates the risk of distant recurrence. We evaluated the performance of EP in predicting distant recurrence risk using microarray data from fresh frozen (FF) tissues. We also examined the applicability of EP to microarray data from FFPE tissues. METHODS: We analyzed the publicly available data of 431 node-negative and 270 node-positive patients with luminal breast cancer who received endocrine therapy alone. We evaluated the prognostic value of EP using microarray data from FF tissues. Next, we created an algorithm to calculate EP risk score using microarray data from FFPE tissues. We examined the correlation coefficient of EP risk score and concordance rate of EP risk high/low using microarray data from FFPE/FF tissue pairs in a validation set of 39 patients. RESULTS: In 431 node-negative patients, the distant recurrence-free survival (DRFS) rate was significantly worse in those with high EP risk scores (P = 3.68 × 10-6, log-rank). The 5-year DRFS was 95.2% in those with low EP risk score. In the validation set, the correlation coefficient of EP risk score was 0.93 and the concordance rate of EP risk high/low was 91.7%. CONCLUSIONS: EP using microarray data from FF tissues was useful in predicting distant recurrence risk in luminal breast cancer, and EP might be utilized in microarray data from FFPE tissues.

Validation of late recurrence prediction by gene expression profiles and clinicopathological factors in estrogen receptor-positive breast cancer.

BACKGROUND: The mechanism of late recurrence (LR) of estrogen receptor (ER)-positive breast cancer remains unclear, as previous studies have separately investigated "gene expression profiles" and "clinicopathological factors." Thus, this study aimed to evaluate the predictive capability of LR by combining the two independent factors of gene expression profiles (42-gene classifier: 42GC) and clinicopathological factors (Clinical Treatment Score post-5 years: CTS5) in multiple large cohorts. METHODS: We analyzed microarray CEL file data downloaded from public databases of 28 global cohorts. A total of 2,454 patients with ER-positive breast cancer were analyzed for 42GC, and 1,263 of these, with complete clinicopathological data were analyzed for CTS5. RESULTS: In the analysis of recurrent patients, the 42GC LR and CTS5 low-risk group tended to have LR. Notably, in the analysis of patients with and without recurrence, the highest LR rate beyond 5 years was observed in the CTS5 high-risk group. The combination of the 42GC and CTS5 high-risk groups showed the highest LR rate (16.9%), significantly exceeding that of the 42GC non-LR (NLR) and CTS5 low-risk combination (5.41%) (p = 0.038, odds ratio = 3.53). Furthermore, incorporating a third factor, 95GC, potentially reduced the number of patients prioritized for extended hormonal therapy for approximately one-quarter of patients. CONCLUSIONS: Results confirmed that the two factors, gene expression profiles and clinicopathological factors, affect the time of recurrence. It also showed that the biological predisposition for LR (CTS5 low-risk) differed from the high LR rate (CTS5 high-risk). In clinical practice, patients with the 42GC LR and CTS5 high-risk combination should be prioritized for extended hormonal therapy. The addition of CTS5 and 95GC to 42GC allows for better risk classification of LR.

Comparison of efficacy of 95-gene and 21-gene classifier (Oncotype DX) for prediction of recurrence in ER-positive and node-negative breast cancer patients.

We recently developed a 95-gene classifier (95(GC)) for the prognostic prediction for ER-positive and node-negative breast cancer patients treated with only adjuvant hormonal therapy. The aim of this study was to validate the efficacy of 95(GC) and compare it with that of 21(GC) (Oncotype DX) as well as to evaluate the combination of 95(GC) and 21(GC). DNA microarray data (gene expression) of ER-positive and node-negative breast cancer patients (n = 459) treated with adjuvant hormone therapy alone as well as those of ER-positive breast cancer patients treated with neoadjuvant chemotherapy (n = 359) were classified with 95(GC) and 21(GC) (Recurrence Online at http://www.recurrenceonline.com/ ). 95(GC) classified the 459 patients into low-risk (n = 285; 10 year relapse-free survival: 88.8 %) and high-risk groups (n = 174; 70.6 %) (P = 5.5e-10), and 21(GC) into low-risk group (n = 286; 89.3 %), intermediate-risk (n = 81; 75.7 %), and high-risk (n = 92; 64.7 %) groups (P = 2.9e-10). The combination of 95(GC) and 21(GC) classified them into low-risk (n = 324; 88.9 %) and high-risk (n = 135; 65.0 %) groups (P = 5.9e-14), and also showed that pathological complete response rates were significantly (P = 2.5e-6) higher for the high-risk (17.9 %) than the low-risk group (3.6 %). In addition, we demonstrated that 95(GC) was calculated on a single-sample basis if the reference robust multi-array average workflow was used for normalization. The prognostic prediction capability of 95(GC) appears to be comparable to that of 21(GC). Moreover, their combination seems to result in the identification of more low-risk patients who do not need chemotherapy than either classification alone. The patients in the high-risk group were found to be more chemo-sensitive so that they can benefit more from adjuvant chemotherapy.

Recent advances on polyoxometalate-based molecular and composite materials.

Polyoxometalates (POMs) are a subset of metal oxides with unique physical and chemical properties, which can be reliably modified through various techniques and methods to develop sophisticated materials and devices. In parallel with the large number of new crystal structures reported in the literature, the application of these POMs towards multifunctional materials has attracted considerable attention. This critical review summarizes recent progress on POM-based molecular and composite materials, and particularly highlights the emerging areas that are closely related to surface, electronic, energy, environment, life science, etc. (171 references).

Multi-gene assay 95- and 155-gene classifiers for prognosis prediction and chemotherapy omission in lymphnode positive luminal-type breast cancer.

BACKGROUND: The prognosis of lymphnode positive breast cancer is worse than that of lymph node negative breast cancer but some cases may not require chemotherapy. We investigated the ability of the new multi-gene assays, 95GC and 155GC, to identify patients with lymphnode positive Luminal-type breast cancer whose chemotherapy can be omitted relatively safely. PATIENTS AND METHODS: We extracted 1721 cases of lymphnode positive Luminal-type breast cancer from 22 public database Caucasoid cohorts and 3 Asian cohorts, and performed recurrence prognosis analysis with 95GC and 155GC. RESULTS: Using 95GC, the cases were stratified as the high (n = 917) and low (n = 202) groups according to the prognosis of lymphnode positive Luminal-type endocrine only breast cancer. The 5 years DRFS in the low risk group was relatively good at 90%, and no additional effect of chemotherapy was observed, suggesting omission of chemotherapy. The recurrence prognosis was also significantly dichotomized into the high and low risks by 95GC in 21GC RS 0-25 cases. Here, we found a group with poor prognosis even in post-menopause RS 0-25 and requiring chemotherapy. Additionally, a group in which the prognosis was good in pre-menopause RS 0-25, and the omission of chemotherapy could be considered. Patients in the high-risk group at 155GC had poor prognosis after chemotherapy. 155GC also showed a group that chemotherapy alone was not sufficient. CONCLUSION: In this study, we demonstrated the possibility of accurately selecting patient groups for which chemotherapy can be omitted from lymphnode positive Luminal-type breast cancer.

Validation of the prognosis of patients with ER­positive, HER2­negative and node­negative invasive breast cancer classified as low risk by Curebest™ 95GC Breast in a multi­institutional registry study.

Curebest™ 95GC breast (95GC) is a multigene classifier we developed for the prognostic prediction of patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative and node-negative (ER+/HER2-/n0) invasive breast cancer treated with adjuvant endocrine therapy alone. The aim of the preset study was to evaluate the clinical utility of 95GC in a multiinstitutional registry study. Patients (n=215) with ER+/HER2-/n0 invasive breast cancer who had undergone the 95GC assay in seven hospitals were consecutively recruited in the registry study at various postoperative times. At recruitment, no patients had disease recurrences and were prospectively followed up for a median of 62 (range, 6-91) postoperative months. Of the 124 patients classified as 95GC low risk, 118 received adjuvant endocrine therapy alone and six received adjuvant chemo-endocrine therapy. Only two patients developed distant recurrences, and the 5-year distant recurrence-free survival (DRFS) was as high as 98.0%. Of the 91 patients classified as 95GC high risk, 81 received adjuvant chemo-endocrine therapy and 10 received adjuvant endocrine therapy alone. A total of four of these patients developed distant recurrences (5-year DRFS=95.5%). Among the 95GC high-risk patients, prognosis was significantly improved for the 81 treated with adjuvant chemo-endocrine therapy compared with for the 77 (historical controls) treated with adjuvant endocrine therapy alone (P=0.0002; hazard ratio, 0.24). Compared with the St. Gallen 2013 guideline, a significant de-escalation from 73.1% (155/212) to 40.6% (86/212) in adjuvant chemotherapy was achieved. The excellent prognosis of patients with ER+/HER2-/n0 invasive breast cancer classified as 95GC low risk could be validated in the present registry study, indicating that 95GC is useful for safe de-escalation of adjuvant chemotherapy in patients with ER+/HER2-/n0 invasive breast cancer.