Genomic landscape of extraordinary responses in metastatic breast cancer.

Extreme responders to anticancer therapy are rare among advanced breast cancer patients. Researchers, however, have yet to investigate treatment responses therein on the whole exome level. We performed whole exome analysis to characterize the genomic landscape of extreme responders among metastatic breast cancer patients. Clinical samples were obtained from breast cancer patients who showed exceptional responses to anti-HER2 therapy or hormonal therapy and from those who did not. Matched breast tumor tissue (somatic DNA) and blood samples (germline DNA) were collected from a total of 30 responders and 15 non-responders. Whole exome sequencing using Illumina HiSeq2500 was performed for all 45 patients (90 samples). Somatic single nucleotide variants (SNVs), indels, and copy number variants (CNVs) were identified for the genomes of each patient. Group-specific somatic variants and mutational burden were statistically analyzed. Sequencing of cancer exomes for all patients revealed 1839 somatic SNVs (1661 missense, 120 nonsense, 43 splice-site, 15 start/stop-lost) and 368 insertions/deletions (273 frameshift, 95 in-frame), with a median of 0.7 mutations per megabase (range, 0.08 to 4.2 mutations per megabase). Responders harbored a significantly lower nonsynonymous mutational burden (median, 26 vs. 59, P = 0.02) and fewer CNVs (median 13.6 vs. 97.7, P = 0.05) than non-responders. Multivariate analyses of factors influencing progression-free survival showed that a high mutational burden and visceral metastases were significantly related with disease progression. Extreme responders to treatment for metastatic breast cancer are characterized by fewer nonsynonymous mutations and CNVs.

Improvement of atopic dermatitis-like skin lesions by Platycodon grandiflorum fermented by Lactobacillus plantarum in NC/Nga mice.

Atopic dermatitis (AD) is characterized as a multi-factorial inflammatory skin disease that has been increasing worldwide. Previously, we demonstrated that FPG, which is Platycodon grandiflorum (PG) fermented by Lactobacillus plantarum (LP), increases the level of interferon (IFN)-gamma in mouse splenocytes in vitro. In this study, we investigated the effects of FPG in an animal model of AD, with a particular emphasis on its effects on T helper (Th)1 and Th2 immune responses. To assess the potential use of FPG for the inhibition of AD, we established a model of AD-like skin lesions in NC/Nga mice. Immunoglobulin isotypes (Igs) and Th1/Th2 cytokines in the sera and spleens of AD-like mice were examined. In addition, histological examination was also performed. AD symptoms in skin lesions improved following oral administration of FPG. IgE secretion was significantly down-regulated, and this was accompanied by decreased levels of interleukin (IL)-4 and IgG1 and increased serum levels of IL-12p40 and IgG2a in FPG-treated animals. In splenocytes, the production of the Th1 cytokines IL-12p40 and IFN-gamma was up-regulated, while the levels of the Th2 cytokines IL-4 and 5 were down-regulated by FPG treatment. These results suggest that FPG inhibits the development of AD-like skin lesions in NC/Nga mice by suppressing the Th2 cell response and increasing the Th1 cell responses. Our results indicate that FPG is safe and effective for the prevention of AD-like skin lesions.

Inhibitory effect of Platycodon grandiflorum on T(H)1 and T(H)2 immune responses in a murine model of 2,4-dinitrofluorobenzene-induced atopic dermatitis-like skin lesions.

BACKGROUND: Platycodon grandiflorum is a traditional Asian medicine that is used to treat pulmonary and respiratory allergic disorders. OBJECTIVE: to investigate the effects of P grandiflorum in vivo in an animal model of atopic dermatitis (AD), with particular emphasis on its effects on T(H)1 and T(H)2 immune responses. METHODS: we established a model of AD-like skin lesions in NC/Nga mice. After oral administration of P grandiflorum, we measured cytokine and immunoglobulin profiles along with histologic examination of skin. RESULTS: P grandiflorum was nontoxic in a 2,4-dinitrofluorobenzene-induced model of AD-like skin lesions in NC/Nga mice. AD symptoms in skin lesions improved after oral administration of P grandiflorum. IgE secretion was significantly downregulated in P grandiflorum-treated animals, accompanied by decreased levels of interleukin (IL) 4 and IgG1 and increased serum levels of IL-12p40 and IgG2a. In isolated splenocytes, the production of the T(H)1 cytokines IL-12p40 and interferon-γ was upregulated by P grandiflorum, whereas the levels of the T(H)2 cytokines IL-4 and IL-5 were downregulated in a mouse model of AD-like skin lesions. CONCLUSIONS: these results suggest that P grandiflorum inhibits the development of AD-like skin lesions in NC/Nga mice by suppressing the T(H)2 cell response and increasing the T(H)1 cell responses. Our results indicate that P grandiflorum is safe and effective as a natural herbal medicine for the treatment of AD-like skin lesions.

Impact of preoperative ultrasonography and fine-needle aspiration of axillary lymph nodes on surgical management of primary breast cancer.

PURPOSE: To evaluate the accuracy of preoperative ultrasonography (US) and US-guided fine-needle aspiration (US-FNA) for detecting axillary lymph node (ALN) metastasis. PATIENTS AND METHODS: We retrospectively reviewed 382 breast cancer patients with clinically negative ALN who underwent US and/or US-FNA for ALN. US-FNA of ALN was performed in 121 patients with suspicious findings on US. The diagnostic performance of US alone or with the addition of US-FNA for detecting ALN metastasis was calculated on the basis of final pathologic reports of ALN surgery. RESULTS: Among a total of 382 patients, 129 had metastatic ALNs while 253 exhibited no signs of axillary metastasis on final pathology. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of axillary US alone were 56.6% (73/129), 81.0% (205/253), 60.3% (73/121), and 78.5% (205/261), respectively. Addition of US-FNA resulted in sensitivity, specificity, PPV, and NPV of 39.5% (51/129), 95.7% (242/253), 82.3% (51/62), and 75.6% (242/320), respectively. Excluding complete responders to neoadjuvant chemotherapy, specificity and PPV after adding US-FNA were increased to 99.6% (242/243) and 98.1% (51/52), respectively. The sensitivity and specificity of ALN metastasis were similar between the palpable and nonpalpable breast cancer groups; however, after adding US-FNA, NPV was increased in the nonpalpable breast cancer group compared with the palpable breast cancer group (p = 0.0398). By including preoperative axillary US and US-FNA, 16.2% (62/382) of all breast cancer patients were able to avoid unnecessary sentinel lymph node biopsy (SLNB). CONCLUSIONS: The combination of axillary US and US-FNA is useful in preoperative work-up of breast cancer patients and provides valuable information for planning proper breast cancer management.

Clinical application of the BI-RADS final assessment to breast sonography in conjunction with mammography.

OBJECTIVE: The objective of our study was to report the results of classification of sonographic findings according to BI-RADS and to calculate the positive predictive value (PPV) for each BI-RADS assessment category. SUBJECTS AND METHODS: We prospectively classified 4,668 breast sonograms according to BI-RADS final assessment category. Suspicious sonographic findings were divided into major and minor suspicious findings. Category 1 was normal and category 2 was a benign finding such as cyst or nodule with uniform and intense hyperechogenicity. A nodule neither category 2 nor category 4 or 5 was defined as category 3. A nodule with one or more suspicious findings, not category 5, was defined as category 4. A nodule with two or more major suspicious findings was defined as category 5. RESULTS: Of the 4,668 cases, 321 cases failed to undergo follow-up of at least 1 year. The PPV was 0.1% in category 1 (3/2,191), 0% in category 2 (0/773), 0.8% in category 3 (6/737), 31.1% in category 4 (161/519), and 96.9% in category 5 (123/127). In palpable lesions (n = 751), the PPV was 2.2% in category 1 (2/93), 0.9% in category 3 (2/217), 54% in category 4 (107/198), and 98% in category 5 (98/100). In nonpalpable lesions (n = 3,596), the PPV was 0.05% in category 1 (1/2,098), 0.8% in category 3 (4/520), 16.8% in category 4 (54/321), and 92.6% in category 5 (25/27). CONCLUSION: As with mammography, placing sonographic lesions into BI-RADS categories is useful for predicting the presence of malignancy.

Unconscious operant conditioning in the paradigm of brain-computer interface based on color perception.

This study investigate the mutual fine-tuning of ongoing EEG rhythmic features with RGB values controlling color shades of computer screen during neuro-feedback training. Fifteen participants had not been informed about the existence of neurofeedback loop (NF), but were guided only to look at the computer screen. It was found that during such unconscious NF training, a variety of color shades on the screen gradually changed from rather various types to the main one within the framework of color palette specified for each individual. This phenomenon was not observed in control experiments with simulated neuro-feedback. Individual color patterns induced on the screen during NF did not depend on the schema of connection between of EEG rhythms and RGB controller. It is suggested that the basic neurophysiological mechanism of described NF training consists of the directed selection of EEG patterns reinforced by comfortable color shades without conscious control.