PubMed Health⌕ Search

Biomedical subjects

Tadashi Ikeda

Publications and source records attributed to Tadashi Ikeda.

At least 19 recordsLinked to original sources

Evaluation of novel modified tangential irradiation technique for breast cancer patients using dose-volume histograms.

PURPOSE: We have previously reported that entire axillary lymph node regions could be irradiated by the modified tangential irradiation technique (MTIT). In this study, MTIT was compared with a conventional irradiation technique (CTIT) using dose-volume histograms to verify how adequately MTIT covers the breast and axillary lymph node region and the extent to which it involves the lung and heart. METHODS AND MATERIALS: Forty-four patients with early-stage breast cancer were treated by lumpectomy, axillary dissection, and postoperative radiotherapy. Twenty-two patients were treated with MTIT and 22 with CTIT. In 25 patients, the breast tumor was on the left and in 19 on the right. During axillary dissection, surgical clips were left as markers at the border of the axillary lymph node region. MTIT was planned by setting the dorsal edge of the radiation field on a lateral-view simulator film at the dorsal edge of the humeral head and the cranial edge of the radiation field at the caudal edge of the humeral head. CTIT was planned to ensure radiation of the breast tissue without considering the axillary region. In this study, all patients underwent computed tomography, and the CT data were transmitted on-line to a radiotherapy planning system, in which the dose-distribution computed tomography images and dose-volume histograms were calculated by defining the breast, axillary region (levels I, II, and III), lung, and heart region. RESULTS: Dose-volume histogram analysis demonstrated that breast tissue was radiated with an 86.5-100% volume (median 96.5%) by MTIT and an 83-100% volume (median, 95%) by CTIT at >95% of the isocenter dose. The axillary lymph node regions at Levels I, II, and III were irradiated with 84-100% (median, 94.5%), 59-100% (median, 89%), and 70-100% (median, 89.5%) volumes, respectively, by MTIT and with 2-84% (median, 38%), 0-53% (median, 15%), and 0-31% (median, 0%) volumes, respectively, by CTIT at >70% of the isocenter dose. The ipsilateral lung was irradiated with a 5-22% volume (median, 11.5%) by MTIT and 5-15% volume (median 9%) by CTIT at >90% of the isocenter dose. In all 25 left-sided breast cancer patients, the volumes irradiated with an 80% isocenter dose were <30 cm(3). CONCLUSION: The results of our study demonstrated that the breast tissue was sufficiently irradiated with both CTIT and MTIT planning, the axillary lymph node areas irradiated by MTIT were much wider than those irradiated by CTIT at all levels, and the lung and heart volumes irradiated by MTIT were small.

Adult↗

Therapeutic angiogenesis by the controlled release of basic fibroblast growth factor for ischemic limb and heart injury: toward safety and minimal invasiveness.

We review our studies on therapeutic angiogenesis using basic fibroblast growth factor (bFGF) released in a controlled manner from biodegradable gelatin hydrogel (GH). The bFGF-GH was intramuscularly injected in rabbits with limb ischemia. The group treated with bFGF showed an increase in tissue blood flow under laser Doppler imaging and histology showed a greater vascular density compared with controls. Also, bFGF-GH was subepicardially injected into old heart infarcts in rats. In the group treated with bFGF, improved left ventricular function was shown by echocardiography and cardiac catheterization, increased regional blood flow in the peri-infarct area was detected by pinhole single-photon emission computed tomography using (201)Tl, and increased vascular density was demonstrated by histology. In rabbits with acute myocardial infarction, the heart was wrapped with the omentum (including the gastroepiploic artery) and a bFGF-GH sheet was applied. Postoperative assessment revealed rich communication from the gastroepiploic artery to the coronary artery and improved cardiac function. The controlled release of bFGF was effective for both limb and heart ischemia and is considered to be suitable for clinical use because its application in animals was feasible and safe with minimal invasiveness.

Angiography↗

Pharmacological assessment of composite arterial conduits using angiography early in the postoperative period.

OBJECTIVES: Muscular arteries are vulnerable to vasospasm unlike elastic arteries. Having developed experimental models of composite arterial grafts, we assessed and compared the responses of the grafts with different pharmacological agents using angiography early in the postoperative period. SUBJECTS AND METHODS: We harvested the internal thoracic artery (ITA) and brachial-median artery (BMA) from 10 sheep. BMA was used as an alternative to the radial artery. Each vessel was assessed histologically and morphologically. Then, a serial composite graft was constructed so that BMA was interposed. On postoperative day one or two, angiography was performed on the composite graft to measure the diameter of each vessel in response to phenylephrine (alpha-adrenergic receptor agonist), nitroglycerin+phenylephrine, and milrinone+phenylephrine. RESULTS: The BMA had a wide media layer which consisted of abundant smooth muscle cells. The combined intima and media were thicker in BMA than in ITA (p<0.01). After injection of phenylephrine, the BMA diameter decreased (2.5+/-0.4 mm to 1.9+/-0.3 mm, p<0.01), while the ITA diameter remained unchanged (3.7+/-0.2 mm to 3.6+/-0.2 mm). Continuous infusion of nitroglycerin or milrinone prevented phenylephrine-induced vasoconstriction of the BMA (p<0.05). CONCLUSIONS: These results suggest that muscular arteries have a more pronounced vasoconstrictive response to alpha-adrenergic receptor agonists than the elastic arteries. To avoid potential decrease in graft flow of muscular artery, it is advisable to use a vasodilator nitroglycerin or milrinone early in the postoperative period.

Animals↗

Visualization of intramuscular left anterior descending coronary arteries during off-pump bypass surgery.

In off-pump coronary artery bypass surgery, an appropriate method for intraoperative evaluation of grafts and vessels has been awaited. We report the usefulness of a 15-MHz linear transducer for this purpose. A 15-MHz linear transducer with a SONOS 5500 (Philips Medical Systems, Best, Netherlands) was applied epicardially in off-pump coronary artery bypass surgery patients. Vascular anatomy was easily discerned when the transducer was applied in an appropriate way. In 6 patients, intramuscular coronary arteries were easily detected, and in all of these patients, anastomoses were successful. The shapes of the anastomoses were very clearly shown, and the flow and its phase in the bypass graft or coronary artery were measured with synchronization of electrocardiograms in all patients. The total left internal thoracic artery (LITA) flow (28.4 +/- 6.8 mL/s) and the pattern of the flow was dominantly diastolic in all patients. The 15-MHz linear transducer system (Philips) is very useful for detecting intramuscular left anterior descending coronary arteries and may become one of the standard tools for intraoperative evaluation in off-pump coronary artery bypass surgery.

Coronary Artery Bypass↗

Attenuation of adhesion formation after cardiac surgery with a chymase inhibitor in a hamster model.

OBJECTIVE: Chymase is one of the inflammatory mediators and is released from mast cells, which are closely associated with adhesion formation. Chymase also activates transforming growth factor beta1, which promotes tissue fibrosis. However, the role of chymase in cardiac adhesion formation has not yet been elucidated. We have assessed whether a specific chymase inhibitor, Suc-Val-Pro-Phe(p) (OPh)(2), prevents postoperative cardiac adhesions in hamsters. METHODS: In 66 hamsters the epicardium was abraded, and then either chymase inhibitor or placebo was injected into the left thoracic cavity, leaving the pericardium open. Cardiac chymase activity, the level of transforming growth factor beta1 in the pleural fluid, and the density of epicardial mast cells were measured 3 days postoperatively. The degree of adhesion formation was evaluated macroscopically and histologically 2 weeks postoperatively by using a grading score ranging from 0 (no adhesions) to 4 (severe adhesions). RESULTS: The cardiac chymase activity and level of transforming growth factor beta1 were lower in the chymase inhibitor-treated group compared with in the placebo-treated group (45.8 +/- 18.7 vs 79.7 +/- 13.7 microU/mg protein [P <.025] and 15.6 +/- 6.5 vs 33.2 +/- 9.8 microg/mL [P <.01], respectively). The density of mast cells was higher in the placebo-treated group, and there was suppression to 60% of this value in the chymase inhibitor-treated group. The adhesion scores were lower in the chymase inhibitor-treated group compared with in the placebo-treated group (1.3 +/- 1.3 vs 3.0 +/- 1.1, P <.01). CONCLUSION: Use of a chymase inhibitor suppresses not only cardiac chymase activity but also the level of transforming growth factor beta1, and this results in a reduction in postoperative cardiac adhesion.

Animals↗

Hypoxic pulmonary vasoconstriction disappears in a rabbit model of cavopulmonary shunt.

BACKGROUND: Cavopulmonary shunt is widely known as an interim staging procedure in patients with single-ventricle physiology. However, the physiologic characteristics of the pulmonary arterial system after cavopulmonary shunt are not clearly understood. In this article, we developed a rabbit cavopulmonary shunt model and studied the morphologic changes and physiologic characteristics (namely, hypoxic pulmonary vasoconstriction) of pulmonary arteries after cavopulmonary shunt. METHODS: Male Japanese white rabbits aged 12 to 16 weeks were used for the study. In 5 rabbits, the superior vena cava was anastomosed to the right pulmonary artery in an end-to-side fashion, followed by a proximal side ligation of the right pulmonary artery (cavopulmonary shunt group). In 4 rabbits, the superior vena cava and the right pulmonary artery were dissected and clamped for 10 minutes without making a cavopulmonary shunt (sham group). Two weeks after the operation, we then measured the internal diameter of the acinar (internal diameter, 164 +/- 7 microm), the lobular (305 +/- 13 microm), and the segmental (669 +/- 16 microm) pulmonary arteries in both controlled and hypoxic conditions by using a specially designed x-ray television system. Also, morphometric measurements were made in the pulmonary arteries around the terminal bronchioles. RESULTS: Two weeks after the operation, the arterial oxygen tension under room air conditions was significantly lower in the cavopulmonary shunt group than in the sham group (68.2 +/- 2.2 mm Hg vs 91.1 +/- 1.9 mm Hg; P =.01). The baseline internal diameters in the acinar and the lobular (resistance), but not the segmental (conduit), pulmonary arteries on the anastomosed side of the cavopulmonary shunt group were significantly larger than those of pulmonary arteries on the nonanastomosed side of the cavopulmonary shunt group and the sham group. Moreover, the pulmonary arteries on the anastomosed side of the cavopulmonary shunt group did not respond to hypoxia, whereas those on the nonanastomosed side of the cavopulmonary shunt and sham groups did have local internal diameter reductions in the acinar and lobular arteries (-1.1% +/- 1.0% in the anastomosed side vs -17.7% +/- 3.5% in the nonanastomosed side vs -20.9% +/- 6.1% in the sham group; P =.03). In the morphometric studies, the internal diameter of the pulmonary artery accompanying the terminal bronchiole in the anastomosed side of the cavopulmonary shunt group was significantly larger, and the ratio of medial thickness relative to the outer diameter was smaller compared with ratios in the nonanastomosed side of the cavopulmonary shunt group and the sham group. CONCLUSIONS: We developed a rabbit cavopulmonary shunt model. In the anastomosed side of the cavopulmonary shunt group, the peripheral pulmonary arteries, which contributed greatly in regulating the pulmonary vascular resistance, had a local reduction in the basal vascular tone and no hypoxic vasoconstriction 2 weeks after the operation.

Animals↗

[Adjuvant chemotherapy for breast cancer--a current controversy].

EBCTCG meta-analysis revealed a significant reduction in mortality in patients receiving chemotherapy irrespective of nodal status and ER status. Compared with CMF, 5-year RFS and OS favored the anthracycline-containing regimens, 57% vs 54% (p = 0.006) and 72% vs 69% (p = 0.02), respectively. No survival benefit was obtained for CMF durations greater than 6 months. Delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy appears safe and may be preferable for patients at high risk of distant metastasis. No difference in disease-free survival for the 3 dose levels of doxorubicin (60, 75, and 90 mg/m2) was found. Higher doses (100 mg/m2) of epirubicin led to a high survival rate in women with poor-prognosis disease. Dose-dense therapy seems promising but still needs further investigation. Incorporation of taxanes into adjuvant chemotherapy for early breast cancer is also controversial.

Anthracyclines↗

1-hexylcarbamoyl-5-fluorouracil + cyclophosphamide + tamoxifen versus CMF + tamoxifen in women with lymph node-positive breast cancer after primary surgery: a randomized controlled trial.

We studied the usefulness of the oral 5-FU anti-cancer drug 1-hexylcarbamoyl-5-fluorouracil (HCFU) + cyclophosphamide (CPM) + tamoxifen (TAM) (HCT group) in comparison with CMF + TAM (CMFT group) in adjuvant therapy for breast cancer by a non-inferiority study based on a multi-institutional joint study. Clinical stage I, II primary breast cancers with histologically positive axillary lymph node metastasis were randomly assigned to the HCT group or the CMFT group after primary surgery. We registered 136 cases (HCT group 68 cases, CMFT group 68 cases). No significant difference in the 5-year overall survival rate (OS) and the 5-year disease-free survival rate (DFS) was found between the two groups. In the stratified analysis, DFS in cases in which the number of metastatic lymph nodes was 1-3 was significantly better in the HCT group (HCT group 84.3%, CMFT group 69.4%, log-rank test p=0.0496). No significant difference in the total incidence of adverse effects was found between the two groups, but there were significantly less adverse effects of grade 2 or over in the HCT group (p=0.034). The QOL survey at 3 months after surgery showed a significant decline of the QOL regarding lassitude, degree of difficulty in daily life, satisfaction with treatment and present mood in the CMFT group. Study results suggest that 2-year HCT therapy including the oral 5-FU anti-cancer drug HCFU is a useful adjuvant therapy which can replace CMFT therapy in early breast cancer cases with 3 or lower metastatic lymph nodes.

Adult↗

[Current status of sentinel node adenectomy and future perspectives].

Sentinel node adenectomy has rapidly been accepted in recent years. A survey performed under the auspices of the Japanese Breast Cancer Society revealed that about 40% of institutions in Japan have already introduced sentinel lymph adenectomy. Analysis of questionnaire responses from 40 institutions in Japan revealed an identification rate using the dye method alone of 87% compared with 96% using the combined method. The identification rate and the false-negative rate are about the same among various methods used such as colloidal radiotracers, injection site, use of lymphoscintigraphy, etc., provided that the surgeon has adequate experience. It is recommended that the surgeon should start to perform sentinel node adenectomy after experiencing more than 60 cases, because there is a learning curve. Some investigators are devising other methods to replace the RI method, for example, using magnetic particles instead of RI colloid and detecting them using magnetic probes. and a trial to detect lymphatic flow with CT after local injection of contrast medium is also being conducted. Sentinel node adenectomy may become a standard technique for early breast cancer patients in the near future.

Breast Neoplasms↗

Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.

Administration, Oral↗

Phase I study of docetaxel and cyclophosphamide in patients with advanced or recurrent breast cancer.

BACKGROUND: A phase I clinical study of combination chemotherapy with docetaxel and cyclophosphamide (CPA) was performed to determine the maximum tolerated dose (MTD), the incidence and severity of toxicities and the pharmacokinetics in patients with advanced or recurrent breast cancer. METHODS: Docetaxel was administered by intravenous drip infusion over 60 minutes, followed by intravenous bolus injection of CPA every 3-4 weeks. The dosage of docetaxel/CPA was 40/200, 40/400, 50/400, or 60/400 mg/m(2)/day. RESULTS: Fifteen patients were enrolled and received a total of 33 cycles of the combined therapy. The dose limiting toxicities (DLTs) were leukopenia, neutropenia and thrombocytopenia. The MTD was estimated to be docetaxel 60 mg/m(2) in combination with CPA 400 mg/m(2) per day. Plasma clearance of both drugs was similar regardless of dose. The recommended doses of docetaxel/CPA for a phase Utrial are 50/400 mg/m(2)/day every 3-4 weeks. CONCLUSION: The MTD of this combined therapy was docetaxel 60 mg/m(2) and CPA 400 mg/m(2). Neutropenia and leukopeina were common and severe. It is important to stress the need for modification of the dosing scheme.

Adult↗

Long-term results of breast-conserving treatment for early-stage breast cancer in Japanese women from multicenter investigation.

BACKGROUND: Although many clinical data regarding breast-conserving treatment have already been reported from European and North American countries, few clinical data with long-term follow-up have been reported from Japan. METHOD: We collected information on therapeutic and possible or developed prognostic factors and follow-up data for Japanese women who had received breast-conserving treatment consisting of wide excision of the primary tumor, axillary dissection and radiotherapy for unilateral breast cancer considered suitable for breast-conserving treatment from 18 Japanese major breast cancer treating hospitals; 1561 patients were registered. RESULTS: The median follow-up period was 77 months. Five-year disease-free and overall survival rates were 89.4 and 95.9%, respectively. The 5-year local recurrence-free rate was 96.3%. The patients with histologically positive margins (P < 0.0001) or estrogen receptor negative tumor (P = 0.0340) or younger than 40 years old (P < 0.0001) developed statistically significantly more local recurrences. Adjuvant endocrine therapy was essential for the estrogen receptor positive patients to have a lower local recurrence rate. Endocrine therapy did not change the local recurrence rate among estrogen receptor negative patients at all. Multivariate analysis showed histological margin status and the combination of estrogen receptor status and endocrine therapy were independent prognostic factors for local recurrence. CONCLUSION: The 5-year local recurrence rate of Japanese breast cancer patients who were treated with breast-conserving treatment using radiotherapy was 3.7%. Independent prognostic factors for local recurrence were histological margin status and the combination of estrogen receptor status and adjuvant endocrine therapy.

Adult↗

[Globalization of clinical trials].

Based on reviews of the Japanese clinical trial situation in lung cancer, gastric cancer, prostate cancer and breast cancer, it was clear that much progress has been made in short time. There are considerable differences between Japan and the West and also differences between clinical areas in Japan. For regulatory purposes bridging studies have become increasingly important. Use of identical protocols are required for effective bridging. Participations in global phase III trials is the best way of achieving registration in Japan. For successful global trials in Japan it is important to include Japanese investigators in the preparation of the protocol and to recognise the challenges facing such a project. Clinical practice in diagnosis and treatment have many differences, thus it is recommended to have clear and detailed information in the protocol. Hard end points like survival are important since they are not biased by cultural differences. There are clear difficulties with HE or QOL outcomes. The emergence of focus on evidence based medicine is also happening in Japan and will help to harmonize documentation across the world. For large adjuvant or prevention cancer global trials are essential. To facilitate global studies further development of infrastructure is necessary in Japan. Use of electronic data capture web based communication etc. will help overcome communication difficulties. Other improvements that will make Japanese participation in global trials easier and better include establishment of clinical trial centre at each hospital, introduction of trial coordinators or study nurses and an improved collaboration with company staff. A critical issue that also need addressing is agreement of centre target recruitment. We need to introduce a new flexible system in Japan if participation in global trial is to be optimised. If we can address these issues Japanese investigators and collaborative groups should be able to initiate and lead global trials in the future.

Antineoplastic Agents↗

The role of neoadjuvant chemotherapy for breast cancer treatment.

Neoadjuvant chemotherapy has become popular, especially for patients with advanced breast cancer. The pros and cons of neoadjuvant chemotherapy for treating breast cancer patients are reviewed. The advantages of neoadjuvant chemotherapy are 1) overall survival and recurrence-free survival rate are the same as post-operative chemotherapy, 2) serves as an in vivo sensitivity test, 3) increases the rate of breast conserving therapy, 4) facilitates the study of cancer biology. On the other hand, the disadvantages of neoadjuvant chemotherapy are 1) it modifies the stage, 2) treatment delay of PD cases, 3) residual intraductal component may be left behind after breast conserving surgery, 4) there are some cases of over-treatment. Combination chemotherapy is one possible way to increase the pathological CR rate, although the optimal order and cycles have not been determined. To avoid residual cancer cells after breast conserving surgery, the shrinkage pattern should be evaluated by MRI. Core needle biopsy should be performed before neoadjuvant chemotherapy to avoid over-treatment. It is essential to develop more effective regimens and stratify patients based on predictive factors.

Antineoplastic Agents↗

Sentinel lymph node biopsy in breast cancer using technetium-99m tin colloids of different sizes.

Axillary lymph node dissection (ALND) in the treatment of breast cancer is essential for predicting the prognosis and regional control of the tumor. At the same time ALND is associated with pain, numbness and sometimes lymphedema. Sentinel lymph node biopsy (SLNB) is a potential alternative procedure to conventional ALND in clinically node-negative breast cancer. In this study, we prepared the technetium-99m-labeled tin colloids with different sizes and compared their efficacy in SLNB. From September 1998 to February 2002, 184 clinically node-negative breast cancer patients were enrolled in the study at Keio University Hospital. Sentinel lymph nodes (SLNs) were identified by both blue dye and radioisotope. We prepared small-sized technetium-99m-labeled tin colloid (particle size: 200-400 nm in diameter). Regular-sized technetium-99m-labeled tin colloid is 400-1000 nm in diameter. In 74 patients, a SLNB was performed using regular-sized tin colloid; small-sized tin colloid was used in 110 patients. Subsequently, all of the patients were immediately followed by ALND. All dissected lymph nodes were evaluated by routine histopathological examination. The clinicopathological characteristics of the two groups were comparable. The lymphoscintigram detected SLN more frequently in the small-sized colloid group than in the regular-sized colloid group (P < 0.01). Small-sized tin colloid was also superior to regular-sized tin colloid in the SLN identification rate (97.3% versus 86.5%; P = 0.01). The mean value for ex vivo counts of the hottest sentinel lymph nodes of the small-sized colloid group was significantly higher than the counts of the regular-sized colloid group (P < 0.01). There was no significant difference in the accuracy between the two groups. It was concluded that SLNB using the small-sized tin colloid was technically feasible and provided higher detection and identification rates than the regular-sized tin colloid.

Adult↗

Overview: current status of breast conserving therapy in Japan.

Breast conserving operations have become the standard operation for early breast cancer. They were performed in about 40% of all breast cancer patients in Japan in 2000, and the percentage is still increasing. Ductal carcinoma in situ (DCIS) accounts for about 7% of all breast cancers and breast conserving operations for DCIS have been followed by a low in-breast recurrence rate, leading to wider indications for breast conserving operations as screening mammography has come to be used in Japan. In-breast recurrence is correlated to surgical margin status. It is important to evaluate the surgical margin for volume of cancer cell nests as well as for positivity. Neoadjuvant chemotherapy has become popular as an in vivo sensitivity test and as a means of down-staging to increase the possibility of performing a breast conserving operation. There are two patterns of shrinkage when neoadjuvant chemotherapy is effective: cocentric and honeycomb, and the pattern of residual cancer cell nests must be determined before surgery. MRI is an effective method of evaluating residual cancer cell nests. The in-breast recurrence rate after down-staging to perform breast conserving operations is reported to be higher than among candidates for breast conserving operation at the start. Sentinel node biopsy techniques and endoscopic operations are now being assessed in conjunction with breast conserving operations. The current status of breast conserving operations in Japan is reviewed in comparison with their status in Western countries.

Breast Neoplasms↗