Breast cancer has been the second most common solid tumor that metastasizes to the central nervous system after lung cancer.Triple-negative breast cancer(TNBC)has an earlier occurrence and high incidence of brain metastasis with its associated poor prognosis and limited treatment options due to the presence of the blood-brain barrier and lack of targeted drugs.Local treatment,including surgery and radiation therapy,are still the main therapy for brain metastasis.Surgical resection can not only relieve neurologic impairment of brain metastasis patients,but also can clarify the pathological type.Moreover,surgical resection combined with radiotherapy can improve the prognosis of brain metastasis patients compared to surgery or radiotherapy alone.By now,whole-brain radiation therapy(WBRT)is still considered the gold standard for multiple brain metastases,and meningeal metastases,but it will lead to neurocognitive decline,so hippocampal avoidance is essential.For selected patients with oligometastases,stereotactic radiotherapy has replaced WBRT to reduce cognitive toxicity.However,local treatment of TNBC brain metastasis cannot control the progress of brain metastasis and has significant side effects,so systemic therapy is needed.Chemotherapy drugs such as capecitabine and cisplatin can penetrate the blood-brain barrier,but their efficacy is limited.Therefore,the research and development of new targeted drugs and the exploration of new targets are necessary for TNBC brain metastasis.Research has found that patients carrying germline BRCA1/2 mutations have a higher risk of brain metastasis.Currently,the poly adenosine diphosphate ribose polymerase(PARP)inhibitor demonstrated antitumor activity in patients with advanced breast cancer and a germline BRCA1/2 mutation,and it can penetrate the blood-brain barrier.The phase Ⅲ trial EMBRACA reported that the PARP inhibitor talazoparib can prolong the progression-free survival of TNBC patients with brain metastasis.In addition,antibody drug conjugates(ADCs)trastuzumab deruxtecan(T-DXd)can also penetrate the blood-brain barrier.Studies such as DEBBRAH have shown that T-DXd has significant therapeutic effects in HER2 positive brain metastasis patients,while research on HER2 low expression patients has not yet reached the endpoint,and its role in TNBC brain metastasis is worth looking forward to.Sacituzumab govitecan(SG)is also an ADC composed of an antibody targeting the human trophoblast cell-surface antigen 2.The phase Ⅲ ASCENT study showed that in the full population(including 61 patients with brain metastasis),SG could significantly prolong the progression-free survival of advanced TNBC patients compared to the patients who received chemotherapy.ANG1005,a novel taxane derivative,can cross the blood-brain barrier as well.A multicenter,open-label phase Ⅱ study revealed that ANG1005 could prolong overall survival of patients with brain metastasis.In addition,phosphoinositide3-kinase,(PI3K)/protein kinase(AKT)/mammalian target of rapamycin(mTOR)pathway inhibitors,fatty acid synthase inhibitors,and the drugs with new delivery systems have become potential treatment options for TNBC brain metastasis patients.Although the Impassion 130 reported that no benefit trend for immunotherapy in TNBC brain metastasis,basic research has shown that radiotherapy combined with immunotherapy has a synergistic effect.Currently,multiple clinical trials(NCT03483012,NCT03449238,etc.)are exploring the efficacy of radiotherapy combined with immunotherapy in brain metastasis,and the results are promising.This article reviewed the research progress of TNBC brain metastasis treatment.

PURPOSE: Sentinel lymph node biopsy (SLNB), a critical staging and treatment step, has replaced axillary lymph node (LN) dissection as the standard staging procedure for early stage breast cancer patients with clinically negative axillary LNs. Hence, using a murine sentinel lymph node (SLN) model, we investigated the localization effect of the new receptor-targeted tracer, indocyanine green (ICG)-rituximab, on breast cancer SLNB. METHODS: After establishing the murine SLN model, different doses of ICG-rituximab were subcutaneously injected into the hind insteps of BALB/c mice to determine the optimal dose and imaging time using continuous (> 3 hours) MDM-I fluorescence vasculature imaging. To explore the capacity of ICG-rituximab for sustained SLN localization with the optimal dose, MDM-I imaging was monitored at 6, 12, and 24 hours. RESULTS: The popliteal LN was defined as the SLN for hindlimb lymphatic drainage, the iliac LN as the secondary, and the para-aortic or renal LN as the tertiary LNs. The SLN initial imaging and optimal imaging times were shortened with increased ICG-rituximab doses, and the imaging rates of the secondary and tertiary LNs increased accordingly. The optimal ICG dose was 0.12 μg, and its optimal imaging time was 34 minutes. After 24 hours, the SLN imaging rate remained 100%, while those of the secondary and the tertiary LNs increased from 0% (6 hours) and 0% (6 hours) to 10% (12 hours) and 10% (12 hours) to 20% (24 hours) and 10% (24 hours), respectively. CONCLUSION: ICG-rituximab localized to the SLN without imaging from the secondary or tertiary LNs within 6 hours. The optimal ICG dose was 0.12 μg, and the optimal interval for SLN detection was 34 minutes to 6 hours post-injection. This novel receptor-targeted tracer is of great value to clinical research and application.
Animals ; Breast Neoplasms ; Breast ; Drainage ; Fluorescence ; Hindlimb ; Humans ; Indocyanine Green ; Lymph Nodes ; Mice ; Models, Animal ; Rituximab ; Sentinel Lymph Node Biopsy

Objective:To determine the optimal time to perform sentinel lymph node biopsy(SLNB)in patients with clinically node-negative disease and assess clinically node-positive patients who would acquire greater benefits from axillary downstaging surgery af-ter neoadjuvant chemotherapy(NAC).Methods:From October 2010 to November 2017,206 patients with breast cancer who under-went surgery after NAC were included in this retrospective study in Shandong Cancer Hospital Breast Cancer Center.Their clinicopatho-logic data were collected to discuss the correlation between axillary node pathologic complete response(apCR)and different molecu-lar subtypes.Results:Among 206 patients who received NAC,183 patients had clinically node-positive disease.The frequency of apCR after NAC was 33.3%(61/183),which was significantly higher in patients with human epidermal growth factor receptor 2(HER-2)-posi-tive subtype[with targeted therapy,62.1%(18/29);without targeted therapy,34.5%(10/29)]and triple-negative breast cancer(TNBC) (41.0%)(16/39)than in patients with HER-2-negative luminal subtype breast cancer[19.8%(17/86)](P<0.001). Among 23 patients with Cn0 tumors,the rate of positive sentinel lymph nodes after NAC was 26.1%(6/23);this rate was 36.4%(4/11),25.0%(1/4),and 12.5% (1/8)among patients with HER-2-negative luminal subtype breast cancer,TNBC,and HER-2-positive subtype breast cancer,respective-ly.Conclusions:Molecular subtypes could predict the chance of achieving apCR.For patients with clinically node-negative disease,it would be preferable to perform SLNB prior to NAC for patients with HER-2-negative luminal subtype breast cancer.SLNB after NAC for those with TNBC and HER-2-positive subtype breast cancer could decrease the chances of axillary lymph node dissection.For patients with initial clinically node-positive disease converting to clinically node-negative disease after NAC,especially in TNBC and HER-2-posi-tive subtype breast cancer,these patients might benefit more from axillary downstaging surgery after NAC.

Internal mammary lymph node irradiation (IMLNI) could reduce local recurrence and distant recurrence and improve survival.The NCCN Guidelines have updated the recommends in IMLNI.However, the relative toxicities of IMLNI to the heart and lungs should be carefully considered by clinicians, so individualized indications for IMLNI are needed.Internal mammary sentinel lymph node biopsy (IM-SLNB) could be an accurate technique to guide IMLNI with minimally invasive staging, and provide more survival benefits to patients.This article reviews the benefits of IMLNI, controls of the side effect, and discussion of IMLNI guided by IM-SLNB.

OBJECTIVEThe aim of this study was to determine the impact of routinely performed internal mammary sentinel lymph node biopsy (IM-SLNB) on the staging and treatment, and to analyze the success rate, complications and learning curve.

METHODSAll patients with biopsy-proven breast cancer who underwent sentinel lymph node biopsy between 2012 and 2014 were included in a prospective analysis. Internal mammary sentinel lymph node biopsy (IM-SLNB) was performed in all patients with IM-SLN visualized on preoperative lymphoscintigraphy and/or detected by intraoperative gamma probe detection. The adjuvant treatment plan was adjusted according to the current guidelines.

RESULTSIn a total of 349 patients, 249 patients (71.1%) showed internal mammary drainage. IM-SLNB was performed in 153 patients with internal mammary drainage, with a success rate of IM-SLNB of 97.4% (149/153). Pleural lesion and internal mammary artery bleeding were found in 7.2% and 5.2% patients, respectively. In 8.1% of patients (12/149) the IM-SLN was tumor positive. In the group of patients who underwent IM-SLNB, lymph node staging was changed in 8.1% of patients, and IMLNs radiotherapy was guided by these results, however, systemic treatment was changed in only 0.7% of the patients.

CONCLUSIONSIM-SLNB has a high successful rate and good safety. Identification of internal mammary metastases through IM-SLNB may provide more accurate staging and guide the tailored internal mammary radiotherapy.

TRIAL REGISTRATIONClinicalTrials. gov, NCT01642511.

Breast ; pathology ; Breast Neoplasms ; pathology ; Female ; Humans ; Learning Curve ; Lymph Nodes ; pathology ; Lymphatic Metastasis ; Mammary Arteries ; Neoplasm Staging ; methods ; Neoplasms, Second Primary ; Prospective Studies ; Sentinel Lymph Node Biopsy ; methods

Background and purpose:Sentinel lymph node biopsy is regarded as the standard of care in pa-tients without clinical axillary lymph node metastases in early-stage breast cancer. Accurate detection of sentinel lymph node is an important step for staging, prognosis, and treatment. In this study, a new sentinel lymph node tracer was produced by the rituximab to combine with the lfuorescence tracer (indocyanine green, ICG), and to identify the most appropriate combination ratio of the two agents. Its biological property and safety limitation were evaluated.Methods:Rituximab was combined directly with ICG. The new tracer was analyzed for labeled rate by instant thin-layer chroma-tography-silica gel, molecular integrity by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and molecular immune activity by ELLAS. The safety limitation was tested according to the Chinese Pharmacopeia. The localization ability of sentinel lymph node was tested in mice.Results:The new tracer was intact and kept the immune activity of rituximab. The ICG labeled rate of rituximab was 100%. The new tracer was bacteria and pyogen free, and was safe to body with location injection. The most appropriate combination ratio of rituximab and ICG was 4∶1 and 6∶1 with the best sentinel lymph node imaging. The location of sentinel lymph node identiifed by the new tracer was accorded with the radiotracer.Conclusion:The preparation method of the new sentinel lymph node tracer is simple and no radioactive injury. The new tracer has no bacteria, no pyogen and no acute toxicity, and can be used in sentinel lymph node visual-ization.

Background and purpose:Sentinel lymph node biopsy has replaced axillary lymph node dissec-tion as the standard staging procedure in early breast cancer patients with clinically negative axillary lymph nodes. It is a critical step for staging and treatment. This study investigated the localization effect of a novel tracer for breast cancer sentinel lymph node biopsy [indocyanine green (ICG)-rituximab (R)], using the hind limb drainage in mice as an animal model.Methods:For exploring the optimal dose and imaging time, different doses of ICG-R were injected subcutane-ously to the dorsum of the foot in the BALB/c mice. Then the lfuorescence vasculature imaging instrument was used continuously to observe the popliteal fossa lymph node (as sentinel lymph node) from the injection to 3 h after injection. For exploring the sustained localization effect, the optimal dose of ICG-R was injected and the imaging instrument was used from imaging to 24 h after injection.Results:The time from injection to imaging and the time from injection to the optimal imaging were shortened with the increased doses, and the imaging rate of the second or third level node increased accordingly. The best dosage of the novel tracer was 0.12 μg (dosage of indocyanine green) and the time from injection to the optimal imaging was about 34 min. After the observation for 24 h, the imaging rate of sentinel lymphnode was maintained at 100%, and the imaging rate of the second and the third level lymph node increased from 0% to 20% and 10%, respectively.Conclusion:ICG-R could clearly locate the sentinel lymph node. There is no imaging of the second level lymph node within 6 h. The novel tracer has high value in the clinical application.

OBJECTIVETo ascertain whether proanthocyanidins inhibit cell growth and migration by increasing let-7a expression in pancreatic cancer AsPC-1 cells.

METHODSThe proliferation rate, cell apoptosis rate and cell migration ability of AsPC-1 cells treated with proanthocyanidins were measured by MTT assay, Annexin V-FITC/PI staining, and Transwell migration assay, respectively. The expression of let-7a AsPC cells was detected by miRNA real-time RT-PCR after proanthocyanidins treatment. The changes in the biological behaviors of AsPC-1 cells were evaluated after transfection with let-7a mimics.

RESULTSCompared with the control group, proanthocyanidins treatment caused dose-dependent decrements of the proliferation rate and migration ability and increased the apoptosis rate in AsPC-1 cells. AsPC-1 cells with proanthocyanidins treatment showed increased expression of let-7a. Transfection with let-7a mimics resulted in obvious decreases in the cell growth rate and migration ability, and proanthocyanidins treatment significantly enhanced the inhibitory effect of let-7a mimics.

CONCLUSIONProanthocyanidins-induced cell growth and migration inhibition are partially mediated by up-regulation of let-7a expression in AsPC-1 cells.

Apoptosis ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Humans ; MicroRNAs ; metabolism ; Pancreatic Neoplasms ; pathology ; Proanthocyanidins ; chemistry ; Transfection ; Up-Regulation

Objective To verify the accuracy of the modified technique for internal mammary sentinel lymph node biopsy ( IM-SLNB) in breast cancer .Methods In the validation study , the radiotracer was injected with the modified technique , and fluorescence tracer was injected into the peritumoral breast tissue .The radioac-tive IM-SLN was identified by preoperative lymphoscintigraphy and γprobe.The radioactive IM-SLN received bi-opsy during operation .The status of the fluorescence tracer was identified by the fluorescence imaging system . Results A total of 162 patients were enrolled from Sep .2013 to Dec.2014.IM-SLNB was performed in 110 pa-tients.The radiotracer and the fluorescence tracer were identified in the same IM-SLN in 94 cases, and the con-cordance rate was 85.5%(Case-base, Spearman coefficient correlation 0.823, P<0.001).Conclusion Dif-ferent tracers injected into the different sites of the intra-parenchyma can reach the same IM-SLN, proving the ac-curacy of the modified technique and the hypothesis of IM-SLN lymphatic drainage pattern ( IM-SLN receives not only the lymphatic drainage from the primary tumor area but the entire breast parenchyma ) .

Objective:This study was conducted to evaluate the roles of internal mammary sentinel lymph node biopsy (IM-SL-NB) in the treatment of breast cancer patients with clinically positive axillary lymph nodes. Methods:This study is a one-armed clini-cal research conducted from June 2013 to October 2014. A total of 64 breast cancer patients from Shandong Cancer Hospital with clini-cally positive axillary lymph nodes were enrolled in the study. All patients underwent axillary lymph node dissection. Meanwhile, IM-SLNB was performed in all patients using the new injection method of radiotracer. Results:Among the 64 enrolled patients, the visual-ization rate of internal mammary lymph node was 59.4%(38/64). For the 38 patients who were subjected to visualization of the internal mammary node, the detection rate was 100%(38/38), and the incidence of complications was 7.9%(3/38). The metastasis rate of inter-nal mammary lymph node was 21.1%(8/38). Patients with upper inner quadrant tumors and metastasis of more axillary lymph nodes had a significantly higher chance of developing sentinel lymph node metastasis (P<0.001 and P=0.017, respectively) than the other pa-tients. The clinical benefit rate of the above mentioned treatment was 59.4%. Among the patients, 12.5%(8/64) received extra internal mammary radiotherapy, whereas 46.9%(30/64) patients avoided the unnecessary internal mammary radiotherapy. Conclusion:IM-SL-NB should be performed in breast cancer patients with clinically positive axillary lymph nodes because IM-SLNB could provide the ac-curate indication of radiation to the internal mammary area, especially for the patients with upper inner quadrant tumors and those with a suspiciously high level of axillary lymph node metastasis.