A prediction model for early systemic recurrence in breast cancer using a molecular diagnostic analysis of sentinel lymph nodes: A large-scale, multicenter cohort study.

BACKGROUND: The one-step nucleic acid amplification (OSNA) assay can quantify the cytokeratin 19 messenger RNA copy number as a proxy for sentinel lymph node (SN) metastasis in breast cancer. A large-scale, multicenter cohort study was performed to determine the prognostic value of the SN tumor burden based on a molecular readout and to establish a model for the prediction of early systemic recurrence in patients using the OSNA assay. METHODS: SN biopsies from 4757 patients with breast cancer were analyzed with the OSNA assay. The patients were randomly assigned to the training or validation cohort at a ratio of 2:1. On the basis of the training cohort, the threshold SN tumor burden value for stratifying distant recurrence was determined with Youden's index; predictors of distant recurrence were investigated via multivariable analyses. Based on the selected predictors, a model for estimating 5-year distant recurrence-free survival was constructed, and predictive performance was measured with the validation cohort. RESULTS: The prognostic cutoff value for the SN tumor burden was 1100 copies/µL. The following variables were significantly associated with distant recurrence and were used to construct the prediction model: SN tumor burden, age, pT classification, grade, progesterone receptor, adjuvant cytotoxic chemotherapy, and adjuvant anti-human epidermal growth factor receptor 2 therapy. The values for the area under the curve, sensitivity, specificity, and accuracy of the prediction model were 0.83, 63.4%, 81.7%, and 81.1%, respectively. CONCLUSIONS: Using the OSNA assay, the molecular readout-based SN tumor burden is an independent prognostic factor for early breast cancer. This model accurately predicts early systemic recurrence and may facilitate decision-making related to treatment.

A case of breast squamous cell carcinoma following breast augmentation with liquid silicone injection after 16 years.

BACKGROUND: Breast augmentation has been linked to various complications, including cancerous tumors. The majority type of breast cancer associated with breast augmentation is adenocarcinoma. Primary squamous cell carcinoma (SCC) of the breast is extremely rare in both augmented and non-augmented women. Due to the low incidence, the possible origin and the mechanism of carcinogenesis of the breast SCC are not well understood. Here, we report a rare case of pure SCC 16 years after breast augmentation with liquid silicone injection. CASE PRESENTATION: A 51-year-old Japanese woman was suffered from prolonged breast fluid retention in her left breast. Multiple unknown foreign bodies caused difficulties to investigate the inflammatory focus with ultrasonography. After unsuccessful surgical drainage and antibiotics treatments, the long-standing fluid retention was surgically removed and pathologically investigated. SCC was found in the removed tissue, and the patient underwent a total left mastectomy followed by postoperative chemotherapy. Pathological analysis revealed multiple cystic structures with a hard shell which enclosed high viscous liquid. A qualitative analysis using a Fourier transform infrared spectroscope defined the liquid as pure silicon, which possibly caused the squamous cell carcinogenesis. CONCLUSIONS: Although liquid silicone injection is not a current option for breast augmentation, the injected silicone could result in cancerous tumor generation after years. This case revealed that unphysiological substances could lead to unexpected biological reactions, which caused difficulties in diagnosis with our routine examination. It will be required that accumulate information from more cases and develop novel diagnostic equipment and biomarkers to address these artificial substance-derived tumors.

MRI Texture Analysis of Background Parenchymal Enhancement of the Breast.

PURPOSE: The purpose of this study was to determine texture parameters reflecting the background parenchymal enhancement (BPE) of the breast, which were acquired using texture analysis (TA). METHODS: We investigated 52 breasts of the 26 subjects who underwent dynamic contrast-enhanced MRI. One experienced reader scored BPE visually (i.e., minimal, mild, moderate, and marked). TA, including 12 texture parameters, was performed to distinguish the BPE scores quantitatively. Relationships between the visual BPE scores and texture parameters were evaluated using analysis of variance and receiver operating characteristic analysis. RESULTS: The variance and skewness of signal intensity were useful for differentiating between moderate and mild or minimal BPE or between mild and minimal BPE, respectively, with the cutoff value of 356.7 for variance and that of 0.21 for skewness. Some TA features could be useful for defining breast lesions from the BPE. CONCLUSION: TA may be useful for quantifying the BPE of the breast.

Altered intracellular region of MUC1 and disrupted correlation of polarity-related molecules in breast cancer subtypes.

MUC1 glycoprotein is overexpressed and its intracellular localization altered during breast carcinoma tumorigenesis. The present study aimed to clarify the relationship of cytoplasmic localization of MUC1 with the breast cancer subtype and the correlation of 10 molecules associated with cell polarity in breast cancer subtypes. We immunostained 131 formalin-fixed and paraffin-embedded breast cancer specimens with an anti-MUC1 antibody (MUC1/CORE). For 48 of the 131 tumor specimens, laser-assisted microdissection and real-time quantitative RT-PCR were performed to analyze mRNA levels of MUC1 and 10 molecules, ß-catenin, E-cadherin, claudin 3, claudin 4, claudin 7, RhoA, cdc42, Rac1, Par3 and Par6. Localization of MUC1 protein varied among breast cancer subtypes, that is, both the apical domain and cytoplasm in luminal A-like tumors (P < 0.01) and both the cytoplasm and cell membrane in luminal B-like (growth factor receptor 2 [HER2]+) tumors (P < 0.05), and no expression was found in triple negative tumors (P < 0.001). Estrogen receptor (ER)+ breast cancers showed higher MUC1 mRNA levels than ER- breast cancers (P < 0.01). The incidence of mutual correlations of expression levels between two of the 10 molecules (55 combinations) was 54.5% in normal breast tissue and 38.2% in luminal A-like specimens, 16.4% in luminal B-like (HER2+), 3.6% in HER2 and 18.2% in triple negative specimens. In conclusion, each breast cancer subtype has characteristic cytoplasmic localization patterns of MUC1 and different degrees of disrupted correlation of the expression levels between the 10 examined molecules in comparison with normal breast tissue.

[Long-term response to eribulin in patients with metastatic breast cancer-report of 2 cases].

Case 1: Case 1 involved a 42-year-old woman who had been diagnosed as having advanced breast cancer (Stage III B). She had previously received 6 courses of cyclophosphamide, epirubicin, and 5-fluorouracil CEF, 14 courses of weekly paclitaxel, and 2 courses of vinorelbine( VNR). After the courses of chemotherapy, she underwent modified radical mastectomy with axillary lymph node dissection. Two years after surgery, lung metastases were found, and the patient received 6 courses of weekly paclitaxel and 13 courses of nab-paclitaxel. However, the lung metastases progressed after the courses of chemotherapy, and therefore, we decided to administer eribulin as third-line chemotherapy. Eribulin was effective against the lung metastases for more than 1 year. Case 2: Case 2 involved a 52-year-old woman who had been diagnosed as having Stage IIB breast cancer. She had received 4 courses of CEF and 4 courses of docetaxel as neo-adjuvant chemotherapy. After chemotherapy, she underwent breast-conserving surgery with axillary lymph node dissection. Five years postoperatively, multiple liver metastases were found, and the patient received 3 courses. However, the liver metastases progressed after this chemotherapy. Subsequently, we administered nab-paclitaxel; however, it produced severe side effects. We then decided to administer eribulin as second-line chemotherapy. Eribulin was effective against the liver metastases for more than 1 year.

[A case of combined noninvasive ductal and lobular carcinoma].

We report a case of combined noninvasive ductal and lobular carcinoma. The patient was a 54-year-old woman with a breast tumor. The tumor was a palpable movable mass measuring 1 cm in diameter in the AC region of her breast. Mammography, ultrasonography, magnetic resonance imaging, and vacuum-assisted core-needle biopsy were performed. The histopathological diagnosis was intraductal papillary cystic lesion. However, there was also a ductal lesion. We performed lumpectomy, and the diagnosis was combined noninvasive ductal and lobular carcinoma. It was difficult to determine the range of carcinoma, and thus, we performed Bt+Ax. Combined noninvasive ductal and lobular carcinoma is rare. We should study additional cases and develop more adequate treatments.

[Complete response of advanced breast cancer with lymph node metastases to nab-paclitaxel therapy-report of a case].

We report a case of breast cancer with lymph node metastases. A complete response was recognized in response to nab-paclitaxel as a first-line therapy after recurrence. The patient was a 50-year-old woman who had a tumor in her right breast. We palpated a mass with clear boundaries in her right breast. The tumor was 2 cm in diameter. Core-needle biopsy of the breast tumor led to a diagnosis of invasive ductal carcinoma (estrogen receptor-, progesterone receptor-, and human epidermal growth factor receptor 2-negative). She received 4 cycles of EC (E: 90 mg/m2/tri-weekly; C: 600 mg/m2 /tri-weekly) plus 4 cycles of TC(T: 75 mg/m2/tri-weekly; C: 600 mg/m2/tri-weekly)as preoperative adjuvant chemotherapy. After chemotherapy, she underwent quadrantectomy plus axillary lymph node dissection. Six months after the operation, lymph node metastases were observed in her right supraclavicular lymph nodes. She received 8 cycles of nab-paclitaxel(260 mg/m2/tri-weekly) therapy. After 8 cycles of treatment, ultrasonography and computed tomography revealed the disappearance of the metastatic lymph nodes. Therefore, a clinical complete response was observed.

[A case of advanced breast cancer with skin ulceration successfully treated with paclitaxel and toremifene therapy].

We report a case of advanced breast cancer with skin ulceration and bleeding (T4bN3bM0, Stage IIIC) achieving a significant improvement of QOL by paclitaxel (PTX) and toremifene (TOR) therapy. The patient was a 31-year-old woman who had ulcerative breast lump with skin ulcer. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesterone receptor, and negative for HER2/neu protein expression. She received 4 courses of tri-weekly CEF (C: 500 mg, E: 60 mg, F: 500 mg/m2/tri-weekly) and 4 courses of weekly PTX (80 mg/m2) with TOR (120 mg/day). The bleeding from the tumor disappeared after CEF chemotherapy. The response for breast tumor after PTX and TOR therapy was evaluated as partial response, and the infraclavicular, subpectoral, and interpectoral lymph nodes metastasis disappeared. Muscle-preserving radical mastectomy (Bt+Ax: Auchincloss) without skin transplantation were performed. She had no recurrence during one year after operation. PTX and TOR therapy were effective for advanced breast tumor, and can improve patient QOL and the clinical outcomes in Stage IIIC advanced breast cancer.

[Indoleamine 2,3-dioxygenase activity during chemotherapy in patients with breast cancer].

We evaluated the significance of indoleamine 2, 3-dioxygenase (IDO) in recurrent breast cancer during chemotherapy. IDO activity can be measured by tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured by high performance liquid chromatography (HPLC). The correlations among age and Trp/Kyn ratio or immunosuppressive acidic protein (IAP) value in pre-chemotherapies or post-chemotherapies were studied. In under 35-year-old patients, there were no correlations between pre-chemotherapy and post-chemotherapy in IAP values and Trp/Kyn ratio. But in over 36-year-old patients, both Trp/Kyn ratio and IAP value in post-chemotherapy were higher than in pre-chemotherapy. These results suggest that the immunological damages for the patients during chemotherapy may depend on the age of patients.

[Treatment strategy of breast carcinoma in the elderly patient-surgery, hormone therapy, and chemotherapy].

We report an elderly breast carcinoma patient with complication. The patient was a 91-year-old woman who had breast lump. The tumor was 3 cm in diameter. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesterone receptor, and positive for HER2/neu protein expression. She received tumorectomy. After operation, she was administered aromatase inhibitor. After six months from operation, metastases of lymph nodes and lung were observed. Although she had administered another aromatase inhibitor, the metastases were rapidly growing. Eight months after operation, she died from carcinomatous lymphangitis. Even the less invasive operation by local anesthesia can progress metastases rapidly in elderly breast cancer patients. This case suggested that a treatment strategy for elderly breast cancer patients should have been determined carefully.

[A case of advanced breast cancer successfully treated with paclitaxel and toremifene therapy].

We report a case of advanced breast cancer with skin ulceration and bleeding (T4bN3bM0: Stage IIIC) achieving a significant improvement of QOL by toremifene and paclitaxel therapy. The patient was a 38-year-old woman with slight anemia who had ulcerative breast lump with skin ulcer. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesteron receptor, and negative for HER2/neu protein expression. She received 6 cycles of tri-weekly FEC (C: 500 mg, E: 60 mg, F: 500 mg/m2) and 16 cycles of weekly paclitaxel (80 mg/m2) with toremifene (120 mg/day). The anemia and the bleeding from the tumor disappeared after FEC chemotherapy. The response for breast tumor after paclitaxel and toremifene therapy was evaluated as partial response, and the infraclavicular, subpectoral, and interpectoral lymph nodes metastasis disappeared. Muscle-preserving radical mastectomy (Bt + Ax: Auchincloss) with skin transplantation was performed. She had no recurrence during one year after the operation. Paclitaxel and Toremifene therapy was effective for advanced breast tumor, and can improve a patient QOL and the clinical outcomes in Stage IIIC advanced breast cancer.

[Recurrence of skin and lymph nodes from asynchronous breast cancer successfully treated with paclitaxel and toremifene therapy--a case report].

We report a case of recurrence of skin and lymph nodes from asynchronous breast cancer achieving a significant improvement of QOL by toremifene and paclitaxel therapy. The patient was a 49-year-old woman who received both sides of muscle-preserving radical mastectomy (Bt+Ax: Auchincloss) had a skin redness of her left breast. Aspiration biopsy cytology for the skin led to a diagnosis of Class V. Skin biopsy for the part of the redness was performed. The pathological diagnosis was an invasive ductal carcinoma, negative for estrogen receptor and positive for progesteron receptor, and negative for HER2/neu protein expression. Ultrasonography showed the subpectral and the inflaclavicular lymph nodes swelling and the skin metastasis. Enhancement CT showed no metastasis of brain, lung, liver, and other organs. Although she had already received 6 cycles of tri-weekly FEC (C: 500 mg, E 60 mg, F: 500 mg/m2) after previous operation, we performed 7 cycles of weekly paclitaxel (80 mg/m2) with toremifene (120 mg/day). The response for the lesion of lymph nodes metastasis after paclitaxel and toremifene therapy was evaluated as a complete response. The subpectoral and the inflaclavicular lymph nodes metastasis disappeared. However, the skin redness of her left breast was still remained. She had received a radiation therapy (30 Gy) for skin metastasis. After radiation therapy, we performed a skin biopsy for the part of the redness. The pathological diagnosis was no carcinoma of skin. She had no recurrence during the two years after the treatment. Paclitaxel and toremifene therapy was effective for a recurrent breast tumor and could improve patient's QOL and the clinical outcomes.

[Indoleamine 2,3-dioxygenase expression in breast cancer patients during chemotherapy].

We evaluated the significance of indoleamine 2,3-dioxygenase (IDO) in recurrent breast cancer patients during chemotherapy. IDO activity can be measured by tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured by High Performance Liquid Chromatography (HPLC). The correlations among Trp/Kyn ratio and immunosuppressive acidic protein (IAP) value in pre-chemotherapies or post-chemotherapies were studied. There were no correlations between pre-chemotherapy and post-chemotherapy in IAP values and Trp/Kyn ratio with weekly paclitaxel therapy. And there were no correlations between pre-chemotherapy and post-chemotherapy in IAP values, but Trp/Kyn ratio in post-chemotherapy was higher than re-chemotherapy with tri-weekly docetaxel therapy. These results suggest that the weekly paclitaxel therapy may be less invasive for recurrent breast cancer patients than the tri-weekly docetaxel therapy.

Identification of a new mutagen, 4,4'-diamino-3,3'-dichloro-5-nitrobiphenyl, in river water flowing through an industrial area in Wakayama, Japan.

3,3'-Dichlorobenzidine (DCB), which has been assigned as a possible carcinogen to humans (Group 2B) by IARC, is produced as a raw material in the manufacture of polymers and dye intermediates. In our previous paper, we identified DCB as an indirect-acting mutagenic constituent in the water concentrates from the Waka River, which flows through an industrial area in Wakayama, Japan. In this study, we have identified a novel mutagen in the water samples from the Waka River. Organic chemicals in the river water were adsorbed to blue rayon at the site where effluents from chemical plants and a sewage plant were discharged into the river. The adsorbate was highly mutagenic in Salmonella YG1024 in the presence and absence of S9 mix, inducing 440,000 and 170,000 revertants/g blue rayon equivalent, respectively. Two mutagenic fractions, which accounted for 18% and 12% of the total mutagenicity of the water concentrate in YG1024 with S9 mix, were separated by HPLC with a reversed-phase column following Sephadex LH20 column chromatography. Both fractions were further separated by HPLC using reversed-phase columns. On the basis of spectral analysis and co-chromatography using an authentic chemical standard, one mutagen in the former fraction was identified as DCB and one mutagen in the latter fraction was deduced to be a novel chemical, a 5-nitro derivative of DCB (5-nitro-DCB; 4,4'-diamino-3,3'-dichloro-5-nitrobiphenyl). 5-Nitro-DCB showed strong mutagenicity in YG1024 especially with S9 mix, inducing 24,200 revertants/microg. 5-Nitro-DCB was detected in water concentrates in the range from less than detection limit to 6.9 microg/g of blue rayon. DCB was also detected in the range from 13.2 to 104 micro/g of blue rayon. These results demonstrate that Waka River water might be continually contaminated with the indirect-acting mutagens DCB and 5-nitro-DCB as major mutagenic constituents of the river water.

Repeated exposures to hyperbaric air suppress neurite outgrowth in PC12 cells.

Hyperbaric exposure induces lesions of the CNS in scuba divers. Repeated exposures to hyperbaric air at 0.5 MPa for 30 min with short intervals suppressed NGF-stimulated neurite outgrowth, concomitant with a decrease in the protein expression of ERK in PC12 cells. Hyperbaric exposure most likely causes direct lesions of neural cells.

[Efficacy of trastuzumab alone therapy was compared to trastuzumab plus taxane therapy in patients of advanced and metastatic breast cancers].

We compared trastuzumab alone therapy (A-group) (n=6) to trastuzumab plus taxane therapy (B-group) (n=12) in patients of advanced and metastatic breast cancers. The response rate of A-group was 33.3%. Six months after, A-group was switched to trastuzumab plus taxane therapy. The response rate of A-group after addition of taxane was improved to 83.3%. The mean duration of response was 6.8 months in A-group after addition of taxane. The response rate of B-group was 83.3%. The mean duration of response was 7.5 months in B-group. The combination therapy of trastuzumab and taxane therapy showed a high response rate. We think that it is possible to start trastuzumab alone therapy because A-group after addition of taxane showed a high response rate. There were no significant differences of immunosuppressive acidic protein (IAP) from the course of chemotherapy in all cases.

[A case of advanced breast cancer successfully treated with multi-disciplinary therapy and S-1 administration].

We report a case of advanced breast cancer (T4b, N3c, M1) achieving a significant improvement on QOL by multi-disciplinary therapy and S-1 administration. The patient was a 59-year-old woman who had ulcerative breast lump with bleeding. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma negative for estrogen receptor, progesterone receptor, and HER2/neu protein expression. The aspiration biopsy cytology was performed from skin lesion, the diagnosis was class V. She received 6 cycles of tri-weekly CEF (C: 500 mg, E: 60 mg, F: 500 mg/m2) therapy. The effect of the breast tumor was partial response, and the bleeding from the breast lump was improved. But the response from metastatic skin tumor was less satisfactory. We performed a radiation therapy (20 Gy) to metastatic skin tumor, and the lesion disappeared after the radiation therapy. Then, we tried docetaxel, but the side effect appeared. So, we started administering S-1 after docetaxel. One year later, she was estimated to be in the long stable disease. Multi-disciplinary therapy can improve a patient QOL and the clinical outcomes in Stage IV advanced breast cancer.

[A case of advanced breast cancer with multiple lung and liver metastases successfully treated with multi-disciplinary therapy].

We report a case of advanced breast cancer with multiple lung and liver metastases (T4bN1M1) achieving a significant improvement of QOL by multi-disciplinary therapy. The patient was a 63-year-old woman with slight jaundice who had ascites and an ulcerative breast lump with multiple lung and liver metastases. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for HER2/neu protein expression. She received 6 cycles of tri-weekly docetaxel (60 mg/m2) and weekly trastuzumab. Although the ascites and the jaundice disappeared after chemotherapy, the response for breast tumor, metastatic sites in the lung and the liver were less satisfactory. Fifteen-months later, she received radiation therapy so that metastasis in the brain was recognized. But she had no neurological symptoms. Multi-disciplinary therapy can improve patient's QOL and the clinical outcomes in Stage IV advanced breast cancer.