Demonstration of aerosol profile measurement with a dual-wavelength high-spectral-resolution lidar using a scanning interferometer.

Simple dual-wavelength high-spectral-resolution lidar at 355 and 532 nm with a scanning interferometer was developed for continuous observations of aerosol profiles. Scanning the interferometer periodically over a range of one fringe at 532 nm (1.5 fringes at 355 nm) enabled recording of range-resolved interference signals at these two wavelengths. Reference signals taken from the transmitted laser were used to correct the interference phase shift due to laser frequency variation for every scan. Profiles of aerosol backscatter and extinction coefficients were retrieved from range-resolved interference data. One month of continuous measurements demonstrated the robustness of the system.

Cultural Difference in Conflict Management Strategies of Children and Its Development: Comparing 3- and 5-Year-Olds Across China, Japan, and Korea.

Research Findings: The purpose of this study was to examine differences in the development of conflict management strategies, focusing on 3- and 5-year-olds, through a comparison of 3 neighboring Asian cultures, those of China (n = 114), Japan (n = 98), and Korea (n = 90). The dual concern model of conflict management was adopted to probe which strategy children would prefer to use in 2 hypothetical conflict situations. Results indicated that, first, for disagreement, 3-year-olds in the 3 countries equally preferred the dominating strategy. For competition for resources, 3-year-olds differed in their strategy preference across all cultures. Second, the observed strategy preference of 3- to 5-year-old children in this study was more or less different from that of older schoolchildren, regardless of culture. Practice or Policy: These findings suggest the significance of the context, the complexity of the phenomenon of the development of cultural differences, and the significance of cohort sampling.

INK4 Tumor Suppressor Proteins Mediate Resistance to CDK4/6 Kinase Inhibitors.

Cyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identified several genetic alterations (e.g., FAT1, PTEN, or ARID1A loss) converging on upregulation of CDK6. Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g., p18INK4C). In vitro binding and kinase assays together with physical modeling reveal that the p18INK4C-cyclin D-CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects in vivo, demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance. SIGNIFICANCE: CDK4/6 kinase activation represents a common mechanism by which oncogenic signaling induces proliferation and is potentially targetable by ATP competitive inhibitors. We identify a CDK6-INK4 complex that is resilient to current-generation inhibitors and develop a new strategy for more effective inhibition of CDK4/6 kinases.This article is highlighted in the In This Issue feature, p. 275.

Long-term outcomes of oligometastatic breast cancer patients treated with curative intent: an updated report.

BACKGROUND: Oligometastatic breast cancer (OMBC) is characterized by limited metastatic tumor numbers and sites. We have reported a 20-year overall survival (OS) rate and relapse-free rate (RFR) of 34.1% and 27.4%, respectively, in a retrospective analysis of OMBC patients treated with curative intent including a multidisciplinary approach. Metastatic breast cancer (MBC) is generally incurable; however, OMBC might be a potentially curable subset. The previous analysis included isolated locoregional recurrence (ILRR) cases, which differs from distant metastasis in treatment strategies. Therefore, in this study, we excluded ILRR cases and provided an update on clinical outcomes. We also performed a detailed subgroup analysis of OMBC patients by introducing new prognostic variables. METHODS: Data of 73 OMBC patients, including 10 ILRR cases, treated in our institution between 1980 and 2010 were retrospectively analyzed. OMBC was defined as the presence of metastatic lesions in 1-2 organs, < 5 lesions per metastasized organ, and lesion diameter < 5 cm. RESULTS: The median follow-up duration was 151 (range 12-350) months. Twenty-eight (44%) patients received local therapy. Excluding ILRR cases, the OS rates were 28.3% and 18.9% and RFRs were 26.7% at 20 and 25 years, respectively. In multivariate analysis, single-organ involvement and three or fewer metastatic lesions per organ were associated with a longer progression-free and relapse-free interval (RFI). CONCLUSIONS: Relapse-free interval reached a plateau after 20 years at approximately 25% probability. Patients with long-term survival without disease relapse are considered cured. Curative-intent therapy should be considered for OMBC patients, especially those with low tumor volume.

Do Decreased Breast Microcalcifications After Neoadjuvant Chemotherapy Predict Pathologic Complete Response?

BACKGROUND: Clinical response evaluation by image examination after neoadjuvant chemotherapy for breast cancer is important for determining drug response and progression. Mammography is less correlated with pathologic response assessment than magnetic resonance imaging or ultrasonography. The present study clarified characteristics of breast cancer patients with decreased microcalcifications after neoadjuvant chemotherapy to increase the accuracy of mammographic assessment. PATIENTS AND METHODS: Consecutive patients who received neoadjuvant chemotherapy for breast cancer at our hospital from January 2013 to June 2017 were retrospectively reviewed. Characteristics of cases of microcalcifications before neoadjuvant chemotherapy and those showing a reduction after were examined. Stromal tumor-infiltrating lymphocytes were evaluated in the biopsy. Pathologic complete response was also explored in patients exhibiting a decrease in microcalcifications by neoadjuvant chemotherapy. RESULTS: Seventy breast cancer cases were included; 37 had no malignant microcalcifications before neoadjuvant chemotherapy and 33 did. Breast cancer with microcalcifications was significantly more positive for human epidermal growth factor receptor 2 than those without microcalcifications (48% vs. 22%, P = .018). Only 6 of 33 patients with microcalcifications before neoadjuvant chemotherapy showed a decrease after treatment. These patients tended to have high stromal tumor-infiltrating lymphocytes (50% vs. 17%), segmental microcalcifications (66% vs. 33%), and pleomorphic/linear microcalcifications (83% vs. 37%). CONCLUSION: These results suggest that neoadjuvant chemotherapy is able to decrease malignant calcifications, particularly segmental and pleomorphic/linear microcalcifications. By clarifying the mechanisms of formation and disappearance of microcalcifications, a consensus can be reached on whether microcalcifications apparent by mammography are useful for evaluating response to neoadjuvant chemotherapy.

Incidental discovery of follicular lymphoma by sentinel lymph node biopsy and skin-sparing mastectomy for Paget's disease associated with invasive breast cancer.

In breast cancer surgery, establishing a diagnosis other than lymph node metastasis of breast cancer, when performing a sentinel node biopsy in individuals with breast cancer, is rare. Here, we report a case of incidental discovery of follicular lymphoma by sentinel lymph node biopsy for Paget's disease associated with invasive breast cancer. A 60-year-old female initially presented with erosion on her left nipple and was clinically diagnosed with stage IA human epidermal growth factor receptor type 2 (HER2)-positive breast cancer and Paget's disease. Accordingly, skin-sparing mastectomy, sentinel lymph node biopsy, and immediate breast reconstruction were performed. Although an intraoperative pathological examination of frozen sections of lymph nodes presented no evidence of metastasis, it revealed large follicles. Based on immunohistochemistry of the additional lymph nodes, she was diagnosed with follicular lymphoma. Therefore, we initiated chemotherapy for follicular lymphoma followed by trastuzumab. At present, 6 years after the operation for breast cancer, the patient is doing well.

Features of Microcalcifications on Screening Mammography in Young Women

Background: There is no decrease in the number of breast cancer deaths if screening mammography is performed in women aged <40 years. However, NCCN guidelines recommend screening mammography in young women at risk of hereditary breast cancer. Therefore, more accurate screening mammography for young women is needed. Objective: To evaluate the features of screening mammographic findings, particularly microcalcifications, in women aged <50 years to increase the positive predictive value of screening mammography in young women. Methods: We retrospectively reviewed the data of consecutive women who underwent opportunistic and organized breast cancer screening at the Sakuragaoka Hospital (Shizuoka, Japan) between April 2013 and March 2015. We compared the mammographic findings and features of microcalcifications between women aged <40 and 40­49 years and those aged 50­74 years. Results: The study included 3645 women. Of these 3645 women, 415 (11.4%) were aged <40 years, 1219 (33.4%) were aged 40­49 years, and 2011 (55.2%) were aged 50­74 years. Women aged <50 years were more likely to be recalled for microcalcifications than those aged 50­74 years (<40 years, 4.8%; 40­49 years, 4.3%; 50­74 years, 3.3%). Young women were more likely to be recalled for small round and segmental microcalcifications [<40 years, odds ratio (OR): 1.799 (95% CI: 0.751­2.846); 40­49 years, OR: 1.394 (95% CI: 0.714­2.074)] and less likely to be recalled for small round and grouped microcalcifications [<40 years, OR: 0.603 (95% CI: 0.181­1.025); 40­49 years, OR: 0.961 (95% CI: 0.496­1.428)] compared with women aged 50­74 years. Conclusions: On screening mammography, women aged <50 years had a higher tendency to be recalled for microcalcifications, particularly small round and segmental microcalcifications. False-positive results may be reduced by reflecting the characteristics of microcalcification findings among young women without breast cancer in the future.