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Histopathological diagnosis is the ultimate method of attaining the final diagnosis; however, the observation range is limited to the two-dimensional plane, and it requires thin slicing of the tissue, which limits diagnostic information. To seek solutions for these problems, we proposed a novel imaging-based histopathological examination. We used the multiphoton excitation microscopy (MPM) technique to establish a method for visualizing unfixed/unstained human breast tissues. Under near-infrared ray excitation, fresh human breast tissues emitted fluorescent signals with three major peaks, which enabled visualizing the breast tissue morphology without any fixation or dye staining. Our study using human breast tissue samples from 32 patients indicated that experienced pathologists can estimate normal or cancerous lesions using only these MPM images with a kappa coefficient of 1.0. Moreover, we developed an image classification algorithm with artificial intelligence that enabled us to automatically define cancer cells in small areas with a high sensitivity of ≥0.942. Taken together, label-free MPM imaging is a promising method for the real-time automatic diagnosis of breast cancer., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Pancreatic ductal adenocarcinoma (PDAC) is the most life-threating disease among all digestive system malignancies. We developed a blood mRNA PDAC screening system using real-time detection PCR to detect the expression of 56 genes, to discriminate PDAC from noncancer subjects. We undertook a clinical study to assess the performance of the developed system. We collected whole blood RNA from 53 PDAC patients, 102 noncancer subjects, 22 patients with chronic pancreatitis, and 23 patients with intraductal papillary mucinous neoplasms in a per protocol analysis. The sensitivity of the system for PDAC diagnosis was 73.6% (95% confidence interval, 59.7%-84.7%). The specificity for noncancer volunteers, chronic pancreatitis, and patients with intraductal papillary mucinous neoplasms was 64.7% (54.6%-73.9%), 63.6% (40.7%-82.8%), and 47.8% (26.8%-69.4%), respectively. Importantly, the sensitivity of this system for both stage I and stage II PDAC was 78.6% (57.1%-100%), suggesting that detection of PDAC by the system is not dependent on the stage of PDAC. These results indicated that the screening system, relying on assessment of changes in mRNA expression in blood cells, is a viable alternative screening strategy for PDAC., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

For breast cancer patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS), sentinel lymph node (SN) biopsy has been proposed as an axillary staging procedure in selected patients with a higher likelihood of having occult invasive lesions. With detailed histological examination of primary tumors and molecular whole-node analysis of SNs, we aimed to validate whether this selective application accurately identifies patients with SN metastasis. The subjects were 336 patients with a preoperative needle-biopsy diagnosis of DCIS who underwent SN biopsy using the one-step nucleic acid amplification assay in the period 2009-2011. The incidence and preoperative predictors of upstaging to invasive disease on final pathology and SN metastasis, and their correlation, were investigated. Of the 336 patients, 113 (33.6%) had invasive disease, and 6 (1.8%) and 17 (5.0%) had macro- and micrometastasis in axillary nodes respectively. Of the 113 patients with invasive disease, 4 (3.5%) and 9 (8.0%) had macro- and micrometastasis. Predictors of invasive disease included palpability, mammographic mass, and calcifications (spread >20 mm), and intraductal solid structure, but no predictor was found for SN metastasis. Therefore, even though occult invasive disease was found at final pathology, most of the patients had no metastasis or only micrometastasis in axillary nodes. Predictors of invasive disease and SN metastasis were not completely consistent, so the selective SN biopsy for patients with a higher risk of invasive disease may not accurately identify those with SN metastasis. More accurate application of SN biopsy is required for patients with a preoperative diagnosis of DCIS., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

The standardized assessment of Ki67 labeling index (LI) is of clinical importance to identify patients with primary breast cancer who could benefit from chemotherapy. In this study, we evaluated the interobserver concordance of Ki67 LI assessment. Six surgical pathologists participated and all the slides were prepared from archival breast cancer tissues fixed in 10% buffered formalin for 24 h and stained with MIB-1. Three independent studies were conducted. In the first study, 30 stained slides were assessed using two different methods: the scoring system, with a positive rate scored from 1 (0-9%) to 10 (90-100%) by visual estimate; and the counting method, with approximately 1000 cells counted in hot spots. In the second study, 20 tumors with Ki67 LI 5-25% were assessed, and in the third study, 15 printed photographs of stained slides were assessed to avoid variations by selecting different fields. In study 1, the counting system (intraclass correlation coefficient [ICC], 0.66 [95% confidence interval 0.52-0.78]) demonstrated a better correlation than the scoring system (ICC, 0.57 [0.42-0.72]). In study 2, the assessment for Ki67 LI of 5-25% demonstrated a correlation (ICC, 0.68 [0.50-0.81]) similar to that of study 1 (unrestricted range of Ki67 LI). In study 3, the assessment of Ki67 LI by counting yielded a good concordance (ICC, 0.94 [0.88-0.97]). In conclusion, there was better concordance with the counting system, and concordance was high when the assessed field was predetermined, indicating that the selection of the evaluation area is critical for obtaining reproducible Ki67 LI in breast cancer., (© 2013 Japanese Cancer Association.)

By definition, ductal carcinoma in situ (DCIS) - pre-invasive breast cancer - does not metastasize to the lymph nodes. However, since the introduction of molecular whole-node analysis using the one-step nucleic acid amplification assay for sentinel node (SN) biopsies, the number of patients with DCIS and SN metastasis has increased. The pathogenesis and clinical management of DCIS with SN metastasis remain controversial. In this case-control study, in order to elucidate the pathogenesis of SN metastasis in DCIS, we compared occult invasions between the SN-positive and SN-negative DCIS and investigated predictive factors of occult invasion. The subjects were 24 patients selected from 285 patients with a routine postoperative diagnosis of DCIS who had undergone SN biopsy using the one-step nucleic acid amplification whole-node assay between 2009 and 2011. Of these 24 patients, 12 were SN-positive, and 12 were SN-negative. The 12 SN-negative patients make up the control group and were selected from the 273 SN-negative patients based on patient characteristics. All paraffin blocks of the primary tumor from each patient were step-sectioned with 500-μm intervals until the block was exhausted and histopathologically examined. We analyzed 1830 step-sectioned slides and found occult invasions were more frequent in the SN-positive group (7/12, 58.3%) than in the SN-negative group (3/12, 25.0%). All occult invasions were <5 mm. There was no correlation between occult invasion and SN tumor burden, non-SN metastasis, or patient characteristics. Our results suggest true metastasis from occult invasion may be a potent pathogenesis indicating nodal metastasis in postoperatively diagnosed DCIS. Patient follow-up is required to elucidate the prognostic impact of nodal metastasis and occult invasion., (© 2013 Japanese Cancer Association.)

In patients with breast cancer, taxane as well as anthracycline play central roles in systemic chemotherapy. By evaluating the pathological response, we can gauge sensitivity to primary chemotherapy. However, biomarkers that would predict a response to taxane have not yet been established. We conducted a prospective randomized trial to evaluate whether selecting patients using sensitivity testing based on the gene expression of the tumor might enhance the probability of the pathological response. Five genes were identified as biomarkers derived from a microarray of DNA gene profiles from microdisected breast tumors. In the experimental arm (B1), 12 cycles of weekly paclitaxel, 80 mg/m(2) , were preoperatively given when the sensitivity test was positive and therefore judged to be sensitive to paclitaxel. When the test was negative, meaning insensitive to paclitaxel, four cycles of FEC100 were given (arm B2). In the control arm (A), paclitaxel was administered weekly without the use of the sensitivity test. A total of 92 patients were enrolled and 86 patients were analyzed. The pathological response rate (pRR) of each arm was 36.4% in B1 (expected sensitive to paclitaxel), 21.1% in A (control) and 12.5% in B2, respectively. Weekly paclitaxel-treated patients selected by the sensitivity test did not enhance the pRR. The study failed to validate sensitivity testing using five gene expressions for primary chemotherapy with paclitaxel in patients with breast cancer. However, this study suggests that a randomized phase II study is a robust tool for obtaining a rapid conclusion on the usefulness of biomarkers and could be the foundation for further large clinical trials., (© 2010 Japanese Cancer Association.)