Sarcomatoid change in combined hepatocellular carcinoma and cholangiocarcinoma as a poor prognostic factor.

Background: Sarcomatoid change is rarely seen in epithelial malignancy that can be observed in diverse organs. Although a sarcomatoid change in combined hepatocellular-cholangiocarcinoma (cHCC-CC) is assumed to be a poor prognostic factor, this issue has not been studied due to its rare incidence. In this study, we aimed to identify the oncological impact of sarcomatoid change in patients with cHCC-CC and verify that sarcomatoid change is a poor prognostic factor for resected cHCC-CC. Methods: Between January 2006 and December 2020, 102 patients who underwent surgical resection for cHCC-CC were retrospectively reviewed. The hazard ratio (HR) according to sarcomatoid change was calculated using other known prognostic factors for cHCC-CC. In addition, the patients were divided into two groups according to the sarcomatoid change, and their survival was compared. Results: The multivariate analysis demonstrated that sarcomatoid change in cHCC-CC is a poor prognostic factor {disease-free survival (DFS), HR =3.84 [95% confidence interval (CI): 1.63-9.10], P=0.002; overall survival (OS), HR =3.94 (95% CI: 1.67-9.31), P=0.002}. In the survival analysis, the sarcomatoid change group displayed a worse prognosis compared to the non-sarcomatoid change group {DFS: 4.0 [interquartile range (IQR): 1.2-6.8] vs. 23.0 (IQR: 9.3-36.7) months, P=0.001; OS: 19.0 (IQR: 7.2-30.8) vs. 85.0 (IQR: 31.8-138.2) months, P=0.004}. Conclusions: Sarcomatoid change is a poor prognostic factor for resected cHCC-CC.

Tumor necrosis in magnetic resonance imaging predicts urothelial carcinoma with squamous differentiation in muscle-invasive bladder carcinoma.

PURPOSE: This study investigated radiologic features on preoperative MRI to differentiate urothelial carcinoma with squamous differentiation (UCSD) from conventional urothelial carcinoma (UC) in muscle-invasive bladder carcinoma. METHODS: Ninety-nine patients who underwent radical cystectomy and a preoperative bladder MRI scan within three months before surgery were retrospectively enrolled. Various MRI features, including tumor length, location, multiplicity, long-to-short axis ratio, morphology, radiologic stage, and degree of severe necrosis, were analyzed. Univariable and multivariable logistic regression analyses were performed to identify MRI features predictive of UCSD. The diagnostic performance of a significant MRI feature was assessed using 5-fold cross-validation. RESULTS: Among the MRI features, significant radiologic findings associated with UCSD in the univariable analysis included heterogeneous tumor signal intensity in T2-weighted images (odds ratio [OR], 3.365; 95% confidence interval [CI], 1.213-9.986; P = 0.022) and contrast-enhanced T1-weighted images (OR, 4.428; 95% CI, 1.519-12.730; P = 0.007), as well as marked (≥ 50%) severe necrosis (OR, 17.100; 95% CI, 4.699-73.563; P < 0.001). In the multivariable analysis, marked (≥ 50%) severe necrosis (odds ratio [OR], 13.755; 95% confidence interval [CI], 2.796-89.118; P = 0.004) was a significant predictor of UCSD. Marked (≥ 50%) severe necrosis showed a high specificity of 95.0% with a precision of 65.0% for diagnosing UCSD based on 5-fold cross-validation. CONCLUSION: Preoperative bladder MRI revealing marked severe necrosis may be indicative of UCSD and can assist in distinguishing it from conventional UC.

Histopathologic image-based deep learning classifier for predicting platinum-based treatment responses in high-grade serous ovarian cancer.

Platinum-based chemotherapy is the cornerstone treatment for female high-grade serous ovarian carcinoma (HGSOC), but choosing an appropriate treatment for patients hinges on their responsiveness to it. Currently, no available biomarkers can promptly predict responses to platinum-based treatment. Therefore, we developed the Pathologic Risk Classifier for HGSOC (PathoRiCH), a histopathologic image-based classifier. PathoRiCH was trained on an in-house cohort (n = 394) and validated on two independent external cohorts (n = 284 and n = 136). The PathoRiCH-predicted favorable and poor response groups show significantly different platinum-free intervals in all three cohorts. Combining PathoRiCH with molecular biomarkers provides an even more powerful tool for the risk stratification of patients. The decisions of PathoRiCH are explained through visualization and a transcriptomic analysis, which bolster the reliability of our model's decisions. PathoRiCH exhibits better predictive performance than current molecular biomarkers. PathoRiCH will provide a solid foundation for developing an innovative tool to transform the current diagnostic pipeline for HGSOC.

Concordance of HER2 status between core needle biopsy and surgical resection specimens of breast cancer: an analysis focusing on the HER2-low status.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low status has recently gained attention because of the potential therapeutic benefits of antibody-drug conjugates (ADCs) in breast cancer patients. We aimed to investigate the concordance of HER2 status between core needle biopsy (CNB) and subsequent surgical resection specimens focusing on the HER2-low status. METHODS: This retrospective study was conducted in 1,387 patients with invasive breast cancer whose HER2 status was evaluated in both CNB and surgical resection specimens. The discordance rates between CNB and surgical resection specimens and the clinicopathological features associated with HER2 status discordance were analyzed. RESULTS: The overall concordance rates of HER2 status between CNB and surgical resection specimens were 99.0% (κ = 0.925) for two-group classification (negative vs. positive) and 78.5% (κ = 0.587) for three-group classification (zero vs. low vs. positive). The largest discordance occurred in CNB-HER2-zero cases with 42.8% of them reclassified as HER2-low in surgical resection. HER2 discordance was associated with lower histologic grade, tumor multiplicity, and luminal A subtype. In multivariate analysis, tumor multiplicity and estrogen receptor (ER) positivity were independent predictive factors for HER2-zero to low conversion. CONCLUSIONS: Incorporation of HER2-low category in HER2 status interpretation reduces the concordance rate between CNB and surgical resection specimens. Tumor multiplicity and ER positivity are predictive factors for conversion from HER2-zero to HER2-low status. Therefore, HER2 status should be re-evaluated in resection specimens when considering ADCs in tumors exhibiting multiplicity and ER positivity.

Artificial-Intelligence-Assisted Detection of Metastatic Colorectal Cancer Cells in Ascitic Fluid.

Ascites cytology is a cost-effective test for metastatic colorectal cancer (CRC) in the abdominal cavity. However, metastatic carcinoma of the peritoneum is difficult to diagnose based on biopsy findings, and ascitic aspiration cytology has a low sensitivity and specificity and a high inter-observer variability. The aim of the present study was to apply artificial intelligence (AI) to classify benign and malignant cells in ascites cytology patch images of metastatic CRC using a deep convolutional neural network. Datasets were collected from The OPEN AI Dataset Project, a nationwide cytology dataset for AI research. The numbers of patch images used for training, validation, and testing were 56,560, 7068, and 6534, respectively. We evaluated 1041 patch images of benign and metastatic CRC in the ascitic fluid to compare the performance of pathologists and an AI algorithm, and to examine whether the diagnostic accuracy of pathologists improved with the assistance of AI. This AI method showed an accuracy, a sensitivity, and a specificity of 93.74%, 87.76%, and 99.75%, respectively, for the differential diagnosis of malignant and benign ascites. The diagnostic accuracy and sensitivity of the pathologist with the assistance of the proposed AI method increased from 86.8% to 90.5% and from 73.3% to 79.3%, respectively. The proposed deep learning method may assist pathologists with different levels of experience in diagnosing metastatic CRC cells of ascites.

Application of Small Cell Lung Cancer Molecular Subtyping Markers to Small Cell Neuroendocrine Carcinoma of the Cervix: NEUROD1 as a Poor Prognostic Factor.

Cervical small cell neuroendocrine carcinoma (CSCNEC) is a rare, aggressive type of cervical cancer. The treatment for CSCNEC follows the chemotherapeutic regimens used for small cell lung cancer (SCLC), with which it shares similar clinical and histologic features. For the first time, we applied neuroendocrine (NE) and SCLC molecular subtyping immunohistochemical markers [achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1] in 45 patients with CSCNEC. For the combined NE score, 51.1% of NE-high and 48.9% of NE-low subtypes were identified. The NE-high subtype tended to show worse progression-free survival and overall survival (OS) than the NE-low subtype ( P =0.059 and P =0.07, respectively). Applying the SCLC molecular subtyping, 53.3% of cases were identified as NEUROD1-dominant, 17.8% as ASCL1-dominant, 13.3% as YAP-dominant, and 4.4% as POU2F3-dominant, while 11.1% of cases showed negative expression for all markers; the distribution was different from that of SCLC. The NEUROD1-dominant subtype exhibited the worst OS, while the POU2F3 subtype exhibited the best OS ( P =0.003), similar to SCLC. In addition, the ASCL1-dominant and NEUROD1-dominant subtypes showed high NE scores, while yes-associated protein 1-dominant and POU2F3-dominant subtypes showed low NE scores ( P =0.008). In multivariate analysis, the NEUROD1 expression was further identified as the independent prognostic factor for worse OS, together with the high FIGO stage. CSCNEC was revealed to be a heterogeneous disease with different biological phenotypes and to share some similarities and differences with SCLC. Regarding the ongoing development of tailored treatments based on biomarkers in SCLC, the application of biomarker-driven individualized therapy would improve clinical outcomes in patients with CSCNEC.

Clinical activity of nivolumab in combination with eribulin in HER2-negative metastatic breast cancer: A phase IB/II study (KCSG BR18-16).

AIM: We evaluated the efficacy and safety of nivolumab and eribulin combination therapy for metastatic breast cancer (BC) in Asian populations. METHODS: In this parallel phase II study, adult patients with histologically confirmed recurrent/metastatic hormone receptor-positive/HER2-negative (HR+HER2-) or triple-negative BC (TNBC) were prospectively enroled from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). They received nivolumab (360 mg) on day 1 plus eribulin (1.4 mg/m2) on days 1 and 8 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was the investigator-assessed 6-month progression-free survival (PFS) rate in each subtype. Secondary endpoints included investigator-assessed objective response rate (ORR) as per Response Evaluation Criteria in Advanced Solid Tumors version 1.1, disease control rate, overall survival, and treatment toxicity. The association between PD-L1 expression and efficacy was investigated. RESULTS: Forty-five patients with HR+HER2- BC and 45 with TNBC were enroled. Their median age was 51 (range, 31-71) years, and 74 (82.2%) received one or two prior treatments before enrolment. Six-month PFS was 47.2% and 25.1% in the HR+HER2- and TNBC cohorts, respectively. Median PFS was 5.6 (95% confidence interval [CI]: 5.3-7.4) and 3.0 (95% CI: 2.1-5.2) months in the HR+HER2- and TNBC groups, respectively. ORRs were 53.3% (complete response [CR]: 0, partial response [PR]: 24) and 28.9% (CR: 1, PR: 12). Patients with PD-L1+ tumours (PD-L1 expression ≥1%) and PD-L1- tumours (ORR 50% versus 53.8% in HR+HER2-, 30.8% versus 29.0% in TNBC) had similar ORRs. Neutropenia was the most common grade 3/4 adverse event; the most common immune-related adverse events (AEs) were grades 1/2 hypothyroidism and pruritus. Five patients discontinued therapy because of immune-related AEs. CONCLUSION: Nivolumab plus eribulin showed promising efficacy and tolerable safety in previously treated HER2- metastatic BC. TRIAL REGISTRATION: NCT04061863.

Pathologically confirmed pancreatic hamartoma after surgical resection with an aldosterone-producing adrenal tumor: a case report.

Pancreatic hamartoma is a benign tumor of the pancreas with an extremely low incidence and is commonly diagnosed by pathologic examination after surgery. This report describes the case of a 57-year-old female who was referred for the evaluation of a pancreatic mass and an adrenal incidentaloma. Further imaging studies suggested pancreatic neuroendocrine tumor and aldosterone-producing adrenal tumor. Pylorus-preserving pancreaticoduodenectomy was performed with the initial impression of a pancreatic neuroendocrine tumor. However, pathology results revealed a pancreatic hamartoma. Multiple endocrine neoplasia type 1 syndrome was discussed as a probable explanation for tumor masses in both the pancreas and adrenal gland.

Occupancy-Based Energy Consumption Estimation Improvement through Deep Learning.

The energy consumed in buildings constitutes more than half of the total electricity consumption and is highly correlated with the number of occupants; therefore, it is necessary to use occupancy information in energy consumption analysis. However, the number of occupants may not be accurate owing to measurement errors caused by various factors, such as the locations of sensors or cameras and the communication environment. In this study, occupancy was measured using an object recognition camera, the number of people was additionally collected by manual aggregation, measurement error in occupancy count was analyzed, and the true count was estimated using a deep learning model. The energy consumption based on occupancy was predicted using the measured and estimated values. To this end, deep learning was used to predict energy consumption after analyzing the correlation between occupancy and energy consumption. Results showed that the performance of occupancy estimation was 1.9 based on RMSE, which is a 71.1% improvement compared to the original occupancy sensing. The RMSE of predicted energy consumption based on the estimated occupancy was 56.0, which is a 5.2% improvement compared to the original energy estimation.

Diagnostic Assessment of Deep Learning Algorithms for Frozen Tissue Section Analysis in Women with Breast Cancer.

PURPOSE: Assessing the metastasis status of the sentinel lymph nodes (SLNs) for hematoxylin and eosin-stained frozen tissue sections by pathologists is an essential but tedious and time-consuming task that contributes to accurate breast cancer staging. This study aimed to review a challenge competition (HeLP 2019) for the development of automated solutions for classifying the metastasis status of breast cancer patients. Materials and Methods: A total of 524 digital slides were obtained from frozen SLN sections: 297 (56.7%) from Asan Medical Center (AMC) and 227 (43.4%) from Seoul National University Bundang Hospital (SNUBH), South Korea. The slides were divided into training, development, and validation sets, where the development set comprised slides from both institutions and training and validation set included slides from only AMC and SNUBH, respectively. The algorithms were assessed for area under the receiver operating characteristic curve (AUC) and measurement of the longest metastatic tumor diameter. The final total scores were calculated as the mean of the two metrics, and the three teams with AUC values greater than 0.500 were selected for review and analysis in this study. RESULTS: The top three teams showed AUC values of 0.891, 0.809, and 0.736 and major axis prediction scores of 0.525, 0.459, and 0.387 for the validation set. The major factor that lowered the diagnostic accuracy was micro-metastasis. CONCLUSION: In this challenge competition, accurate deep learning algorithms were developed that can be helpful for making a diagnosis on intraoperative SLN biopsy. The clinical utility of this approach was evaluated by including an external validation set from SNUBH.

Expression of HLA class I is associated with immune cell infiltration and patient outcome in breast cancer.

Downregulation of human leukocyte antigen (HLA) class I is one mechanism of escaping anti-tumor immunity by tumor cells. This study was conducted to compare HLA class I expression in ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC) and to evaluate its association with immune cell infiltration of the tumors and clinical outcome of the patients. A total of 830 cases comprising 288 DCIS and 542 IBC were included in this study. Immunohistochemistry for HLA class I expression was performed using HLA-ABC in tissue microarrays and was analyzed in relation to clinicopathologic characteristics of tumors and infiltration of CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocyte (TIL) subsets and PD-L1+ immune cells. As a whole, there was no difference in HLA class I expression between DCIS and IBC when dichotomized into high or low expression. However, in the HR-negative group, a high level of HLA class I expression was more frequent in IBC than DCIS. On the contrary, in the HR-positive group, a complete loss of HLA class I expression was more frequently observed in IBC than DCIS. High HLA class I expression level was generally associated with aggressive clinicopathologic features of IBC and was associated with high CD4+, CD8+, and FOXP3+ TIL and PD-L1+ immune cell infiltration in both DCIS and IBC. In survival analyses, HLA class I expression was not associated with clinical outcome in DCIS and IBC as a whole; however, low HLA class I expression was associated with poor clinical outcome in HR-negative IBC, especially in triple-negative subtype. In conclusion, this study showed that HLA class I expression increased in association with increased immune cell infiltration during in situ to invasive transition of HR-negative breast cancer, and HLA class I down-regulation had a prognostic value in HR-negative breast cancer.

miR-145, miR-205 and miR-451: potential tumor suppressors involved in the progression of in situ to invasive carcinoma of the breast.

BACKGROUND: MicroRNAs (miRNAs) control diverse biologic processes during tumor progression. This study was conducted to identify miRNAs that are implicated in progression of in situ to invasive breast cancer (IBC) and to evaluate their association with clinicopathological features of ductal carcinoma in situ (DCIS). METHODS: We performed miRNA microarray analyses to find differentially expressed miRNAs between DCIS and IBC in a test set, and validated expression levels of selected miRNAs using a different set of tumors. Finally, we evaluated the relationship between clinicopathological features and the expression of selected miRNAs in DCIS samples. RESULTS: We found that miR-145-5p, miR-205-5p and miR-451a are significantly down-regulated in IBC compared to DCIS in the whole group, and in the estrogen receptor (ER)-positive and ER-negative subgroups. In a validation set, miR-145, miR-205, and miR-451 also showed lower expression levels in IBC than in DCIS, irrespective of ER status. Moreover, their expression levels were significantly lower in the invasive component compared to the in situ component within same tumors. MiR-145, miR-205 and miR-451 commonly showed lower expression levels in DCIS with positive HER2 status and high Ki-67 proliferation index. Especially, miR-145 and miR-205 showed lower expression levels in DCIS with microinvasion, compared to pure DCIS. In addition, lower miR-205 expression level was associated with high nuclear grade, comedo type necrosis, and hormone receptor negativity. CONCLUSIONS: Our study showed that miR-145, miR-205 and miR-451 expression decreased in IBC compared to DCIS, and their expression levels were low in DCIS with high-risk features for progression, implying their contributions in the progression of DCIS to invasive carcinoma as tumor suppressors.

Role of CXCL10 in the progression of in situ to invasive carcinoma of the breast.

Tumor immune microenvironment plays a crucial role in tumor progression. We performed immune profiling to compare immune-related gene expression between ductal carcinoma in situ (DCIS) and invasive carcinoma of the breast using nCounter PanCancer immune Profiling Panel and found that CXCL10 was the most significant gene that had the highest difference in expression between them. Effect of CXCL10 on breast cancer cell proliferation and invasion was examined in vitro, and expression of CXCL10 and its relationship with immune cell infiltration was assessed in breast cancer samples. CXCL10 induced cell proliferation, migration and epithelial-mesenchymal transition in MCF-7 and MDA-MB-231 breast cancer cell lines. We confirmed that CXCL10 mRNA expression was significantly higher in invasive carcinoma than in DCIS, especially in hormone receptor (HR)-negative tumors using a validation set. CXCL10 mRNA expression showed a positive correlation with tumor infiltrating lymphocyte (TIL) density in both DCIS and invasive carcinoma; CXCL10-positive tumors generally showed higher infiltration of CD8+ and FOXP3+TILs as well as PD-L1+ immune cells compared to CXCL10-negative tumors, albeit with different patterns according to HR status. In conclusion, our study showed that CXCL10 promotes tumor cell proliferation, invasion, and immune cell infiltration, implying its contribution in the progression of DCIS to invasive carcinoma of the breast.

Prognostic significance of S100A8-positive immune cells in relation to other immune cell infiltration in pre-invasive and invasive breast cancers.

Myeloid-derived suppressor cells (MDSCs) play an important role in tumor progression through both immunologic and non-immunologic mechanisms. This study was conducted to evaluate the expression of S100A8, a well-known MDSC marker, and the significance of its expression in pre-invasive and invasive breast cancers. S100A8 expression in tumor cells (TCs) and immune cells (ICs) was assessed by immunohistochemistry, and its association with clinicopathologic features and infiltration of other IC subsets including CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocytes (TILs) and PD-L1+ ICs was evaluated. S100A8 expression in TCs and ICs showed a positive correlation in pre-invasive carcinoma and invasive carcinoma. S100A8+ ICs, but not S100A8+ TCs, were significantly higher in number in invasive carcinoma than in pre-invasive carcinoma. Infiltration of S100A8+ ICs was revealed as a poor prognostic indicator in pre-invasive and invasive carcinomas, especially in hormone receptor-positive subgroup. Infiltration of CD4+, CD8+, and FOXP3+ TIL subsets and PD-L1+ ICs was significantly higher in S100A8+ IC (+) group than in S100A8+ IC (-) group. Combined analyses of IC subset infiltration revealed that infiltration of S100A8+ ICs was associated with poor clinical outcome in the PD-L1+ IC (-), CD8+ TIL-low, and FOXP3+ TIL-low subgroups. In conclusion, S100A8+ ICs seem to undergo a dynamic change during breast cancer progression in association with other IC subset infiltration. The prognostic impact of S100A8+ IC infiltration was greater in less immunogenic tumors.

Changes and prognostic values of tumor-infiltrating lymphocyte subsets after primary systemic therapy in breast cancer.

Tumor-infiltrating lymphocyte (TIL) levels have prognostic and predictive values in treatment-naïve breast cancers. However, there have been controversies regarding TIL subset changes and their clinical implications in post-treatment breast cancers. This study aimed to explore change and prognostic significance of TIL subset infiltration after primary systemic therapy (PST) in breast cancer. One-hundred-fifty-five patients who had residual disease after anthracycline- or anthracycline plus taxane-based PST were included. The quantities of intratumoral and stromal TIL subsets (CD8+, CD4+, and FOXP3+ TILs) in pre- and post-PST breast cancer samples, as well as changes between them, were analyzed along with their correlations with clinicopathologic features and outcome of patients. As a whole, intratumoral CD8+ and CD4+ TILs increased after PST while stromal TILs decreased. Both intratumoral and stromal FOXP3+ TILs decreased after PST. The chemo-sensitive group [residual cancer burden (RCB) class I and II] showed the same pattern of change in intratumoral CD8+ TILs as the whole group, whereas the chemo-resistant group (RCB class III) showed no significant change in intratumoral CD8+ TIL infiltration after PST. Survival analyses for each TIL subset as well as their ratios revealed that high levels of intratumoral, stromal, and total CD8+ TIL infiltration after PST were independent predictors of longer patient survival. In subgroup analyses, CD8+ TIL infiltration after PST revealed prognostic significance in the chemo-resistant group but not in the chemo-sensitive group. In conclusion, infiltration of CD8+, CD4+, and FOXP3+ TIL changed after PST in the intratumoral and stromal compartments. Especially, increase of intratumoral CD8+ TILs was associated with chemo-responsiveness. Moreover, CD8+ TIL status in residual tumors after PST may be used as a potential prognostic marker in breast cancer patients who receive PST and provide additional prognostic information to chemo-resistant group.

Immune microenvironment in ductal carcinoma in situ: a comparison with invasive carcinoma of the breast.

BACKGROUND: The immune microenvironment in ductal carcinoma in situ (DCIS) and its significance are not well established. This study was conducted to evaluate the immune microenvironment of DCIS including the composition of tumor-infiltrating lymphocyte (TIL) subsets and PD-L1+ immune cells and to compare it with that of invasive breast cancer. MATERIALS AND METHODS: A total of 671 cases including three different disease groups of pure DCIS, DCIS with microinvasion (DCIS-M), and invasive carcinoma were included in this study. CD4+, CD8+, and FOXP3+ TIL subsets and PD-L1+ immune cells were detected with immunohistochemistry using tissue microarrays and were analyzed in relation to clinicopathologic characteristics and different disease groups. RESULTS: In pure DCIS, high infiltrations of CD4+, CD8+, and FOXP3+ T cells and the presence of PD-L1+ immune cells were associated with high nuclear grade, comedo-type necrosis, hormone receptor (HR) negativity, and high Ki-67 proliferation index. All immune cell infiltrations were higher in invasive carcinoma than in pure DCIS regardless of the HR status. While CD4+ T cells were more abundant than CD8+ T cells in pure DCIS, CD8+ T cells were dominant in invasive carcinoma, especially in HR-negative tumors. Within individual cases of invasive carcinoma with DCIS component, all immune cell subset infiltration was higher in the invasive component than in the DCIS component; however, CD4+ TIL infiltration did not differ between the two components in HR-negative tumors. Comparing pure DCIS, DCIS-M, and DCIS associated with invasive carcinoma (DCIS-INV), CD4+ TIL infiltration revealed a gradual increase from pure DCIS to DCIS-M and DCIS-INV in the HR-negative group, whereas FOXP3+ TIL infiltration was significantly increased in DCIS-INV than in pure DCIS in the HR-positive group. The high infiltration of FOXP3+ TIL and the presence of PD-L1+ immune cells were associated with tumor recurrence in patients with pure DCIS. CONCLUSIONS: Our study showed that the immune microenvironment differs significantly not only between DCIS and invasive carcinoma but also between pure DCIS, DCIS-M, and DCIS-INV depending on the HR status.

Prognostic implication of ABC transporters and cancer stem cell markers in patients with stage III colon cancer receiving adjuvant FOLFOX-4 chemotherapy.

Cancer stem cell (CSC) and ATP-binding cassette (ABC) transporters are associated with treatment resistance and outcomes of patients with cancer. The present study investigated the prognostic implications of pre-therapeutic expression of ABC transporters and CSC markers in patients with colon cancer (CC) who received adjuvant 5-fluorouracil, leucovorin and oxaliplatin combination therapy (FOLFOX-4). The immunohistochemical expression of 3 ABC transporters, including ABC subfamily C member 2 (ABCC2), ABCC3 and ABC subfamily G member 2 (ABCG2), and 3 CSC markers, including sex determining region Y-box 2 (SOX2), leucine-rich repeat-containing G protein-coupled receptor 5 and aldehyde dehydrogenase 1, were determined in 164 CC tissues from patients with stage III CC, who underwent postoperative FOLFOX-4 chemotherapy. The association between the protein expression and patients' prognoses was statistically analyzed. ABCG2 was associated with favorable overall survival rate (OS; P=0.001), and ABCC2, ABCG2 and SOX2 were associated with increased disease-free survival rate (DFS; P=0.001, 0.002 and 0.013, respectively). In multivariate analyses, ABCG2 was an independent prognostic factor for OS [hazard ratio (HR)=2.877; P=0.046], and ABCC2 and SOX2 were independent prognostic factors for DFS (HR=2.831; P=0.014; HR=2.558, P=0.020, respectively). ABCC2, ABCG2 and SOX2 may be promising prognostic markers for patients with CC receiving FOLFOX-4 therapy.

Clinical implications of changes in the diversity of c-MYC copy number variation after neoadjuvant chemotherapy in breast cancer.

Chemotherapy can alter the makeup of a tumor cell population by exerting selection pressure. We examined the change in Shannon index, a mathematical diversity measure used in ecology, for c-MYC copy number variation (CNV) after neoadjuvant chemotherapy and evaluated its clinical significance in breast cancer. Associations between Shannon indices for c-MYC CNV in pre- and post-neoadjuvant chemotherapy breast cancer samples and clinicopathologic features of tumors as well as patient survival were analyzed in 144 patients. A change in c-MYC amplification and copy number gain status was found in 14.3% and 33.6% with most cases showing positive to negative conversion. The chemo-sensitive group showed a significant decrease in Shannon index after neoadjuvant chemotherapy. However, there was no difference in diversity indices between pre- and post-neoadjuvant chemotherapy specimens in the chemo-resistant group. In survival analyses, high Shannon indices for c-MYC CNV in post-neoadjuvant chemotherapy samples as well as those in pre-neoadjuvant chemotherapy samples were revealed as independent prognostic factors for poor disease-free survival not only in the whole group but also in the chemo-resistant subgroup. These findings suggest that a change in Shannon index for c-MYC CNV after neoadjuvant chemotherapy reflects chemo-responsiveness and that Shannon indices after neoadjuvant chemotherapy have a prognostic value in breast cancer patients who receive neoadjuvant chemotherapy.

Microinvasive Carcinoma versus Ductal Carcinoma In Situ: A Comparison of Clinicopathological Features and Clinical Outcomes.

PURPOSE: Although microinvasive carcinoma is distinct from ductal carcinoma in situ (DCIS), the clinical significance of microinvasion in DCIS remains elusive. The purpose of this study is to evaluate the clinicopathological features and clinical outcomes of microinvasive carcinoma compared with pure DCIS. METHODS: We assessed 613 cases of DCIS and microinvasive carcinoma that were consecutively resected from 2003 to 2014 and analyzed clinicopathological variables, expression of standard biomarkers such as the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), p53, and Ki-67, and tumor recurrence. RESULTS: Among the 613 cases, 136 (22.2%) were classified as microinvasive carcinoma. Microinvasive carcinoma was significantly associated with DCIS with a large extent, high nuclear grade, necrosis, and comedotype architectural pattern. ER and PR expressions were dominantly observed in pure DCIS, whereas positive HER2 status, p53 overexpression, and high Ki-67 proliferation indices were more frequently observed in microinvasive carcinoma. Lymph node metastasis was found in only four cases of microinvasive carcinoma with multifocal microinvasion. In the multivariate analysis, DCIS with a large extent, comedo-type architectural pattern, and negative ER status were found to be independent predictors of microinvasion. During follow-up, 12 patients had ipsilateral breast recurrence, and no differences in recurrence rates were observed between patients with DCIS and those with microinvasive carcinoma. The triple-negative subtype was the only factor that was associated with tumor recurrence. CONCLUSION: Microinvasive carcinomas are distinct from DCIS in terms of clinicopathological features and biomarker expressions but are similar to DCIS in terms of clinical outcomes. Our results suggest that microinvasive carcinoma can be treated and followed up as pure DCIS.