Expansion of tumor-infiltrating lymphocytes in non-small cell lung cancer: Clinical potential and efficacy in EGFR mutation subsets.

Our study aimed to expand tumor-infiltrating lymphocytes (TILs) from primary non-small cell lung cancers (NSCLCs) and evaluate their reactivity against tumor cells. We expanded TILs from 103 primary NSCLCs using histopathological analysis, flow cytometry, IFN-γ release assays, cell-mediated cytotoxicity assays, and in vivo efficacy tests. TIL expansion was observed in all cases, regardless of EGFR mutation status. There was also an increase in the median CD4+/CD8+ ratio during expansion. In post-rapid expansion protocol (REP) TILs, 13 out of 16 cases, including all three cases with EGFR mutations, exhibited a two-fold or greater increase in IFN-γ secretion. The cytotoxicity assay revealed enhanced tumor cell death in three of the seven cases, two of which had EGFR mutations. In vivo functional testing in a patient-derived xenograft model showed a reduction in tumor volume. The anti-tumor activity of post-REP TILs underscores their potential as a therapeutic option for advanced NSCLC, irrespective of mutation status.

Discordant PD-L1 results between 28-8 and 22C3 assays are associated with outcomes of gastric cancer patients treated with nivolumab plus chemotherapy.

BACKGROUND: We evaluated the concordance/discordance of PD-L1 staining results between the 28-8 and 22C3 assays and its impact on the efficacy outcomes of advanced gastric cancer patients treated with nivolumab plus chemotherapy. METHODS: This retrospective study involved 143 gastric cancer patients treated with first-line nivolumab plus chemotherapy whose PD-L1 results with both 28-8 and 22C3 assays were available. The concordance/discordance between these assays and the inter-observer variability were evaluated for PD-L1 combined positive score (CPS) positivity. Discordant PD-L1 results were analyzed regarding survival outcomes. RESULTS: The agreement rates and Cohen's kappa values between the 28-8 and 22C3 assays were 78.3% and 0.56 (for CPS ≥ 1), 81.8% and 0.60 (for CPS ≥ 5), and 88.8% and 0.66 (for CPS ≥ 10), respectively. Inter-observer variability, as represented by the intra-class correlation coefficient, was 0.89 and 0.88 for the 28-8 and 22C3 assays, respectively. With PD-L1 CPS ≥ 5 defined as positive, 35 (24.5%) and 82 (57.3%) had concordantly positive and negative results, respectively, between the 28-8 and 22C3 assays, whereas 26 (18.2%) had discordant results. Progression-free survival was shorter for those who exhibited negatively concordant PD-L1 results and discordant PD-L1 positivity between the 28-8 and 22C3 assays relative to those with positively concordant PD-L1 results (P = 0.013). CONCLUSION: PD-L1 assays by 28-8 and 22C3 showed suboptimal concordance, while inter-observer variability was not critical in advanced gastric cancer. Discordant PD-L1 results between 28-8 and 22C3 assays may be associated with unfavorable efficacy outcomes in patients treated with nivolumab plus chemotherapy.

Clinical implications of pediatric biliary intraepithelial neoplasia diagnosed from a choledochal cyst specimen.

BACKGROUND: Biliary intraepithelial neoplasia (BilIN), a noninvasive precursor of cholangiocarcinoma, can manifest malignant transformation. Since cholangiocarcinoma (CCA) may progress due to chronic inflammation in the bile ducts and gallbladder, choledochal cysts are considered a precursor to CCA. However, BilIN has rarely been reported in children, to date. METHODS: We reviewed medical records of patients (< 18 years of age, n = 329) who underwent choledochal cyst excision at Asan Medical Center from 2008 to 2022. BilIN was diagnosed in 15 patients. Subsequent analyses were performed of the demographics, surgical procedures, clinical course, and outcomes in these patients. Subgroup analysis and multivariate logistic regression test were performed to identify factors influencing BilIN occurrence. RESULTS: The mean age of the patients included in our study was 40.1 ± 47.6 months. In 15 patients, BilIN of various grades was diagnosed. Todani type I was prevalent in 80% of the patients. The median age at surgery was 17 months. During a mean follow-up of 63.3 ± 94.0 months, no adverse events such as stone formation in the remnant intrapancreatic common bile duct and intrahepatic duct or cholangiocarcinoma were observed, indicating a favorable outcome until now. CONCLUSIONS: The potential progression of choledochal cysts to BilIN in children was demonstrated. These results could underscore the importance of early and comprehensive excision of choledochal cysts, including resection margins for associated lesions and more thorough postoperative surveillance in patients with or at risk of BilIN.

Effectiveness of a healthy lifestyle program based on a mobile serious game for childhood cancer survivors: A quasi-randomized trial.

PURPOSE: This study aimed to develop and evaluate the effectiveness of a healthy lifestyle program based on a mobile serious game (HLP-MSG) to enhance the lifestyles of childhood cancer survivors (CCSs). METHODS: This program proceeded in two stages: development and evaluation, using a non-synchronized design with a quasi-randomized trial. The participants were CCSs aged 6-13 years whose treatment was terminated at least 12 months prior. Data were collected at baseline, and post-intervention, with a follow-up after four weeks using the Child Healthy Lifestyle Profile (CHLP). The experimental (n = 26) and control groups (n = 25) were compared. Data were analyzed using descriptive statistics, chi-squared tests, t-tests, and repeated-measures ANOVA. RESULTS: The HLP-MSG promoted a healthy lifestyle by solving 26 quests, including seven sub-elements (nutrition, exercise, hygiene, interpersonal relationships, stress management, meaning of life, and health responsibility). This study revealed significant differences in the interaction between measurement time and group assignment in the CHLP (p = .006) and physical activity (p = .013), one of the seven sub-dimensions. CONCLUSIONS: A healthy lifestyle program based on a mobile serious game is a feasible health education modality to enhance the physical, psychological, social, and spiritual health of CCSs. IMPLICATIONS TO PRACTICE: The findings add to scientific evidence on a mobile serious game for health education among CCSs. The HLP-MSG provides an evolutionary educational modality that can be delivered non-face-to-face to promote CCSs' continuous healthy behavior maintenance. Moreover, the HLP-MSG is adolescent-friendly and can be utilized as a healthcare tool for parents and children to cooperate.

Identification of intratumoral fluid-containing area by magnetic resonance imaging to predict prognosis in patients with pancreatic ductal adenocarcinoma after curative resection.

OBJECTIVES: To compare the prognosis of pancreatic ductal adenocarcinoma (PDAC) after curative resection according to the type of intratumoral fluid-containing area identified on MRI. METHODS: This retrospective study included 112 consecutive patients who underwent upfront surgery with margin-negative resection between 2012 and 2019. All patients underwent MRI within 1 month before surgery. Three radiologists independently assessed the MRI findings, determined whether intratumoral fluid-containing areas were present, and classified all intratumoral fluid-containing areas by type (i.e., imaging necrosis or neoplastic mucin cysts). Recurrence-free survival (RFS) and overall survival (OS) were evaluated by the Kaplan-Meier method and the Cox proportional hazards model. Histopathological differences according to the type of intratumoral fluid-containing area were assessed. RESULTS: Of the 112 PDAC patients, intratumoral fluid-containing areas were identified on MRI in 33 (29.5%), among which 18 were classified as imaging necrosis and 15 as neoplastic mucin cysts. PDAC patients with imaging necrosis demonstrated significantly shorter RFS (mean 6.1 months versus 47.3 months; p < .001) and OS (18.4 months versus 55.0 months, p = .001) than those with neoplastic mucin cysts. Multivariable analysis showed that only the type of intratumoral fluid-containing area was significantly associated with RFS (hazard ratio, 2.25 and 0.38; p = .009 and p = .046 for imaging necrosis and neoplastic mucin cysts, respectively). PDAC with imaging necrosis had more frequent histological necrosis, more aggressive tumor differentiation, and higher tumor cellularity than PDAC with neoplastic mucin cysts (p ≤ .02). CONCLUSION: The detection and discrimination of intratumoral fluid-containing areas on preoperative MRI may be useful in predicting the prognosis of PDAC patients after curative resection. KEY POINTS: • Pancreatic ductal adenocarcinoma (PDAC) patients with imaging necrosis demonstrated significantly shorter survival than those with neoplastic mucin cysts after curative resection. • Multivariable analysis showed that only the type of intratumoral fluid-containing area identified on MRI was significantly associated with recurrence-free survival. • PDAC with imaging necrosis had more frequent histological necrosis, more aggressive tumor differentiation, and higher tumor cellularity than PDAC with neoplastic mucin cysts.

Feasibility of deep learning-based fully automated classification of microsatellite instability in tissue slides of colorectal cancer.

High levels of microsatellite instability (MSI-H) occurs in about 15% of sporadic colorectal cancer (CRC) and is an important predictive marker for response to immune checkpoint inhibitors. To test the feasibility of a deep learning (DL)-based classifier as a screening tool for MSI status, we built a fully automated DL-based MSI classifier using pathology whole-slide images (WSIs) of CRCs. On small image patches of The Cancer Genome Atlas (TCGA) CRC WSI dataset, tissue/non-tissue, normal/tumor and MSS/MSI-H classifiers were applied sequentially for the fully automated prediction of the MSI status. The classifiers were also tested on an independent cohort. Furthermore, to test how the expansion of the training data affects the performance of the DL-based classifier, additional classifier trained on both TCGA and external datasets was tested. The areas under the receiver operating characteristic curves were 0.892 and 0.972 for the TCGA and external datasets, respectively, by a classifier trained on both datasets. The performance of the DL-based classifier was much better than that of previously reported histomorphology-based methods. We speculated that about 40% of CRC slides could be screened for MSI status without molecular testing by the DL-based classifier. These results demonstrated that the DL-based method has potential as a screening tool to discriminate molecular alteration in tissue slides.

Presence of tertiary lymphoid structures determines the level of tumor-infiltrating lymphocytes in primary breast cancer and metastasis.

The level of tumor-infiltrating lymphocytes and presence of tertiary lymphoid structures are significant prognostic and predictive factors in primary breast cancer. However, the understanding about differences in tumor-infiltrating lymphocytes and tertiary lymphoid structures at various metastatic sites or between primary breast tumors and metastatic sites is limited. A total of 335 cases of metastatic breast cancer from four metastatic sites (lung, liver, brain, and ovary) were included. We analyzed the percentages of tumor-infiltrating lymphocytes and presence of tertiary lymphoid structures in the primary and metastatic sites. The mean level of tumor-infiltrating lymphocytes in the lung metastases was higher than in the liver, brain, ovary, and matched primary tumors, while metastatic tumors of the liver and brain showed lower levels of tumor-infiltrating lymphocytes than primary tumors. Tertiary lymphoid structures were only found in the lung and liver, and in cases of brain metastases the change of tertiary lymphoid structures from present to absent significantly affected the level of tumor-infiltrating lymphocytes in metastases compared with that in matched primary tumors. Patients with a lower histological grade, hormone receptor positivity in primary tumors and metastases, a lower level of tumor-infiltrating lymphocytes and absence of tertiary lymphoid structures in primary tumors, a higher level of tumor-infiltrating lymphocytes and presence of tertiary lymphoid structures in metastases, and lung metastases showed significantly better overall survival. Our results showed that metastatic breast tumors in the lung had more tumor-infiltrating lymphocytes than did tumors at other sites and matched primary tumors. In addition, the presence of tertiary lymphoid structures in metastatic sites is a critical factor for the level of tumor-infiltrating lymphocytes.

Clear Cell Hidradenoma: Characteristic Imaging Features on Ultrasonography, Computed Tomography, and Magnetic Resonance Imaging.

OBJECTIVES: The purpose of this study was to evaluate the imaging features of clear cell hidradenoma on ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). METHODS: The radiologic and pathologic databases at 2 medical institutions were searched retrospectively from 2004 to 2016 to identify patients with a diagnosis of clear cell hidradenoma. Ultrasonographic, CT, and MRI features were described, and pathologic specimens were reviewed. RESULTS: There were 5 female and 4 male patients. The mean patient age was 48.9 years (range, 28-70 years). Five patients underwent only US; 2 patients underwent only CT; 1 patient underwent both US and CT; and 1 patient underwent US and MRI. Most of the tumors were located primarily in the subcutaneous fat layer. The mean tumor size was 18.4 mm. On US, 6 masses had a heterogeneous echo texture, including an anechoic portion with protruding echogenic portions. Two masses had multiple septa in the anechoic portion. On color Doppler US, blood flow was both central and peripheral in 5 patients. All 3 cases seen on CT presented as a low-attenuation mass with an enhanced solid internal nodule. On MRI, the mass showed heterogeneous signal intensity on T2-weighted images and enhancement of the peripheral wall and internal solid component on contrast-enhanced T1-weighted images. CONCLUSIONS: Clear cell hidradenoma is usually located in the subcutaneous fat layer, has a well-defined margin, appears as a cystic mass with an internal solid nodule, and occasionally has multiple septa on US, CT, and MRI.

Ultrasonographic Features of Eccrine Spiradenoma.

The purpose of this series was to evaluate the features of eccrine spiradenoma on ultrasonography (US). We reviewed the clinical data of 8 patients with eccrine spiradenoma who underwent preoperative US at 4 different medical institutions from 2004 to 2016 and analyzed the US features in terms of the tumor location, size, shape, margin, echo texture, echogenicity, posterior acoustic enhancement, calcification, septum, and color Doppler flow. There were 7 female patients and 1 male patient. The mean patient age was 45.6 years (range, 28-60 years). Most of the tumors were located primarily in the subcutaneous fat layer. The mean size of the tumors was 14.3 mm. The masses had a lobular appearance in 7 patients and had a tractlike structure in 3 patients. In 6 patients, the masses had a heterogeneous echo texture. Six cases showed hypoechogenicity with more hypoechoic foci in the masses, and 2 cases showed hypoechogenicity only. Color Doppler flow was evaluated in 7 patients; the blood flow was central and peripheral in 4 patients and only peripheral in 3 patients. All cases showed posterior acoustic enhancement and had well-defined margins. Calcification and septa were not seen in any cases. Eccrine spiradenoma is usually located in the subcutaneous fat layer, has a well-defined margin, a lobulated appearance, occasionally with a tractlike structure, a heterogeneous echo texture, a hypoechoic appearance with internal hypoechoic foci and posterior acoustic enhancement, and shows blood flow in the peripheral portion, with or without blood flow in the central portion.

Isolated subcutaneous nontuberculous mycobacterial infection: a rare case initially mischaracterized as a soft tissue malignancy.

The occurrence of nontuberculous mycobacterial (NTM) infection is rare, and the involvement of the musculoskeletal system is even less common. However, the incidence of soft tissue and skin NTM infection is increasing, particularly in patients who undergo injections and minor surgical procedures. Given the non-specific clinical manifestations of NTM infection, the lack of knowledge among physicians regarding this rare infection could lead to inaccurate and delayed diagnosis. Herein, we present a case of an isolated subcutaneous NTM infection caused by Mycobacterium abscessus in the upper back of an immunocompetent 68-year-old woman. The clinical presentation, magnetic resonance imaging findings (including diffusion-weighted imaging), and pathologic findings of subcutaneous NTM infection are described and compared with those of tuberculosis and tumor presentations to provide a more accurate clinical picture for a differential diagnosis.

The Value of Preoperative Positron Emission Tomography/Computed Tomography in Node-Negative Endometrial Cancer on Magnetic Resonance Imaging.

OBJECTIVE: The aim of this study was to investigate the value of [18F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in predicting lymph node status in node-negative endometrial cancer on preoperative magnetic resonance imaging (MRI). METHODS: Patients with endometrial cancer who underwent both preoperative MRI and FDG-PET/CT followed by hysterectomy and lymphadenectomy were initially included. We then enrolled patients with MRI-defined node-negative disease (lymph nodes <1 cm in the short-axis diameter, or no visible lymph node). Histologic examination was the gold standard for lymph node metastasis diagnosis. The diagnostic performance of FDG-PET/CT in predicting lymph node metastasis was calculated in patient-by-patient and lymph node station-by-station analyses. RESULTS: On preoperative MRI, 362 patients had no lymph node metastasis. All patients underwent pelvic lymph node dissection and 118 patients underwent further para-aortic lymph node dissection. From 2099 lymph node stations, 10,238 lymph nodes were retrieved. Twenty-seven patients (7.5%) had lymph node metastasis in 49 lymph node stations (2.3%) on pathologic examination. FDG-PET/CT identified lymph node metastasis in five patients (18.5%) and eight lymph node stations (16.3%). The median diameter of false-negative metastatic lymph nodes was 6 mm (range 1-22) in the long axis and 3 mm (range 1-11) in the short axis. For para-aortic lymph nodes, FDG-PET/CT diagnosed 2 of 11 patients (18.1%) with para-aortic lymph node metastasis, and 3 of 12 para-aortic lymph node stations (25%) with metastasis. CONCLUSION: Preoperative FDG-PET/CT has low value in predicting lymph node metastasis in node-negative endometrial cancer on preoperative MRI.

ADAR1 expression is associated with tumour-infiltrating lymphocytes in triple-negative breast cancer.

Tumours with a high mutation burden exhibit considerable neoantigens and tumour-infiltrating lymphocytes. RNA editing by ADAR1 is a source of changes in epitope. However, ADAR1 expression in cancer cells and tumour-infiltrating lymphocyte levels in triple-negative breast cancer have not been well evaluated. We immunohistochemically examined ADAR1 expression in 681 triple-negative breast cancer patients and analysed their clinicopathological characteristics. We also analysed basal-like tumours using The Cancer Genome Atlas data. Among the 681 triple-negative breast cancer patients, 45.8% demonstrated high ADAR1 expression. Tumours with high ADAR1 expression exhibited high tumour-infiltrating lymphocyte levels, considerable CD8 + T lymphocyte infiltration, high histological grade and high expression of interferon-related proteins, including HLA-ABC, MxA and PKR. Among patients with lymph node metastasis, those with high tumour-infiltrating lymphocyte levels and low ADAR1 expression demonstrated the best disease-free survival. The Cancer Genome Atlas data analysis of basal-like tumours revealed significant positive correlation between ADAR1 and CD8B expression and positive association of high ADAR1 expression with immune responses and apoptosis pathways. We detected high ADAR1 expression in half of the triple-negative breast cancer patients. In addition to DNA mutations, RNA editing can be related to neoantigens; hence, we need to explore non-synonymous mutations exclusively found using RNA sequencing data to identify clinically relevant neoantigens.

MxA expression is associated with tumor-infiltrating lymphocytes and is a prognostic factor in triple-negative breast cancer.

Interferons (IFNs) play an important role in tumor-immune system interactions. As one of the main mediators of IFNs, myxovirus resistance A (MxA) is upregulated in various cancers. However, the exact role of MxA in breast cancer is not fully understood. As part of the immune response to tumors, tumor-infiltrating lymphocytes (TILs) have prognostic significance in breast cancer. The aim of our present study was to examine the relationship between MxA and immune system components, including the amount of TILs and human leukocyte antigen (HLA) expression, in breast cancer. TILs, MxA expression, HLA intensity, and clinicopathological factors were retrospectively analyzed in 688 patients with primary breast cancer between 1993 and 1998 and in 705 patients with triple-negative breast cancer (TNBC) between 2004 and 2011. MxA expression was higher in TNBC tumors than in other subtypes. High MxA levels were associated with a higher histologic grade, abundant TILs, and stronger HLA-ABC expression in both the TNBC subtype within the consecutive breast cancer cohort and the validation TNBC cohort. MxA expression showed a significant positive correlation with TILs, the number of CD8(+) cells, and the number of CD69(+) cells in the validation TNBC cohort. High MxA levels and abundant TILs were found to be independent prognostic factors for disease-free survival in patients with TNBC. These results indicate that MxA expression is closely related to TILs in TNBC and, along with TILs, provides prognostic information after chemotherapy in patients with TNBC.

Cytoplasmic expression of high mobility group B1 (HMGB1) is associated with tumor-infiltrating lymphocytes (TILs) in breast cancer.

High mobility group box 1 (HMGB1) is a prototypic alarmin or damage-associated molecule inducing inflammatory mediator release and immune response. Several studies have revealed the prognostic and predictive importance of tumor-infiltrating lymphocytes (TILs) in breast cancer. The present study analyzed the expression of HMGB1 in each breast cancer subtype and the relationship between the expression level of HMGB1 and pathologic parameters including TILs. Two cohorts were studied: 575 consecutive breast cancer patients who underwent surgery between 1995 and 1998; and 767 triple negative breast cancer (TNBC) patients who underwent surgery between 2004 and 2010. The immunohistochemical expression level of HMGB1 in cytoplasm and nucleus was evaluated using tissue microarrays. High HMGB1 expression in cytoplasm was associated with high histologic grade, pT stage, and abundant TILs in the consecutive breast cancer cohort. Cytoplasmic HMGB1 expression was higher in TNBCs and HER2-positive tumors than in hormone receptor-positive tumors. In the TNBC cohort, high cytoplasmic HMGB1 expression was significantly associated with high histologic grade, abundant TILs, and high numbers of CD8+ cells. However, nuclear HMGB1 expression was not associated with histologic grade or TIL levels. Neither cytoplasmic nor nuclear expression of HMGB1 showed prognostic significance in TNBC. Cytoplasmic HMGB1 expression is associated with TIL levels in breast cancer.

Prognostic and predictive value of NanoString-based immune-related gene signatures in a neoadjuvant setting of triple-negative breast cancer: relationship to tumor-infiltrating lymphocytes.

The prognostic significance of tumor-infiltrating lymphocytes and immune signals has been described previously in triple-negative breast cancer (TNBC). Furthermore, recent studies have shown that immunologic parameters are relevant for the response to neoadjuvant chemotherapy (NAC) in breast cancer as well as for outcomes after adjuvant chemotherapy. However, immune signals are variable, and which signals are important is largely unknown. We, therefore, evaluated the expression of immune-related genes in TNBC treated with NAC. We retrospectively evaluated biopsy tissue from 55 patients with primary TNBC treated with NAC (anthracycline, cyclophosphamide, and docetaxel) against the NanoString nCounter GX Human Immunology Panel (579 immune-related genes). Higher expression of cytotoxic molecules, T cell receptor signaling pathway components, cytokines related to T helper cell type 1 (Th1), and B cell markers was associated with a pathologic complete response (pCR). Higher expression of NFKB1, MAPK1, TRAF1, CXCL13, GZMK, and IL7R was significantly associated with pCR, higher Miller-Payne grade, and lower residual cancer burden class. Expression of NFKB1, TRAF1, and CXCL13genes, in particular, was significantly correlated with a longer disease-free survival rate. Conversely, patients those who failed to achieve a pCR showed increased expression of genes related to neutrophils. Higher expression of cytotoxic molecules, T cell receptor signaling pathway components, Th1-related cytokines, and B cell markers is correlated with pCR and survival in TNBC patients treated with NAC. Our results suggest that the activation status of neutrophils may provide additional predictive information for TNBC patients treated with NAC.

Correlations between molecular subtypes and pathologic response patterns of breast cancers after neoadjuvant chemotherapy.

BACKGROUND: The relationship between the pathologic response patterns after neoadjuvant chemotherapy (NAC) and specific subtypes of breast cancer is unclear. METHODS: This study retrospectively analyzed 351 tumors from 348 women with breast cancer who received anthracycline and taxane-based NAC and subsequent surgery. Various histopathologic factors were assessed in the pretreatment biopsy and surgery specimens based on molecular subtypes defined by immunohistochemistry. RESULTS: The tumors without a pathologic complete response in each subtype retained their morphologic features after NAC. Lymphocytic infiltration was higher in the hormone receptor-negative (HR-) tumors than in the HR+ tumors. The HR- tumors showed more necrosis and histiocytic infiltration in the tumor bed than the HR+ tumors. The overall (including in situ carcinoma) and invasive pathologic cancer sizes were similar for the triple-negative tumors only. Although all the subtypes showed significantly reduced tumor size after NAC, the difference between the pre-NAC magnetic resonance imaging (MRI) tumor size and the overall pathologic cancer size was significantly smaller for the HR+/human epidermal growth factor receptor 2-negative (HER2-) subgroup than for the triple-negative subgroup. The triple-negative tumors showed the highest correlation between post-NAC tumor size measured by MRI and overall or invasive pathologic tumor size. CONCLUSION: The molecular subtypes of breast cancer have characteristic pathologic patterns of response to NAC.

Expression of NY-ESO-1 in Triple-Negative Breast Cancer Is Associated with Tumor-Infiltrating Lymphocytes and a Good Prognosis.

OBJECTIVES: Accumulating evidence suggests that immunotherapy has great potential for treating triple-negative breast cancer (TNBC). We analyzed the expression of NY-ESO-1, which is a potent immunogenic cancer testis antigen, and its association with clinicopathological factors in large cohorts of breast cancer patients. METHODS: A total of 623 consecutive breast cancer patients who underwent surgery between 1993 and 1998 and 612 TNBC patients who underwent surgery between 2004 and 2010 at Asan Medical Center were included. Immunohistochemical staining for NY-ESO-1 was performed using tissue microarrays. RESULTS: NY-ESO-1 was expressed in 2.6% of consecutive breast cancers, all of which were TNBC (p < 0.001). NY-ESO-1 expression was identified in 9.7% of the TNBC cohort and was significantly correlated with a higher level of tumor-infiltrating lymphocytes (TIL; p = 0.026). In survival analyses, a lower level of TIL (all, p < 0.001) and the absence of NY-ESO-1 expression (p = 0.024) were significantly associated with poor disease-free survival. Additionally, positive NY-ESO-1 expression was an independent favorable prognostic factor in TNBC patients (p = 0.046). CONCLUSIONS: NY-ESO-1 is specifically expressed in TNBC, and NY-ESO-1 expression is an independent good prognostic factor in TNBC. Evaluation of NY-ESO-1 expression in TNBC might be useful for selecting patients who may benefit from vaccination therapy and also has a prognostic significance in TNBC.

Two histopathologically different diseases: hormone receptor-positive and hormone receptor-negative tumors in HER2-positive breast cancer.

The clinical behavior of human epidermal growth factor 2 (HER2)-positive breast cancer, including pathologic complete response rate and pattern of relapse and metastasis, differs substantially according to hormone receptor (HR) status. We investigated various histopathologic features of HER2-positive breast cancer and their correlation with HR status. We retrospectively analyzed tumors of 450 HER2-positive breast cancer patients treated with chemotherapy and 1 year of trastuzumab. HR-/HER2+ tumors showed higher nuclear grade, less tubule formation, higher histologic grade, frequent apocrine features, diffuse and abundant lymphocytic infiltration, strong HER2 immunohistochemical staining (3+), higher average HER2 copy number and HER2/CEP17 ratio, the absence of HER2 genetic heterogeneity, and greater p53 expression than HR+/HER2+ tumors. An inverse correlation was observed between estrogen receptor or progesterone receptor Allred score and average HER2 copy number or HER2/CEP17 ratio. The percentage of ductal carcinoma in situ (DCIS) within the tumor was negatively correlated with ER Allred score, but positively correlated with average HER2 copy number and HER2/CEP17 ratio. Pathologic tumor size and DCIS percentage also showed a significant inverse correlation. Ratio of metastatic to total examined lymph node number was significantly correlated with average HER2 copy number and HER2/CEP17 ratio. High pT stage (hazard ratio, 2.370; p = 0.027), the presence of lymphovascular invasion (hazard ratio, 2.806; p = 0.005), and HR negativity (hazard ratio, 2.202; 1.074-4.513; p = 0.031) were found to be independent prognostic indicators of poor disease-free survival. In conclusion, HR+/HER2+ and HR-/HER2+ breast cancer showed distinct histopathologic features that may be relevant to their distinct clinical behavior.

Diagnostic performance of breast-specific gamma imaging in the assessment of residual tumor after neoadjuvant chemotherapy in breast cancer patients.

To evaluate the diagnostic performance of breast-specific gamma imaging (BSGI) in the assessment of residual tumor after neoadjuvant chemotherapy (NAC) in breast cancer patients, female breast cancer patients who underwent NAC, preoperative (99m)Tc-sestamibi BSGI, and subsequent definitive breast surgery were enrolled retrospectively. The accuracy of BSGI in the assessment of residual tumor presence and residual tumor size was evaluated and compared to that of magnetic resonance imaging (MRI) using pathology results as the gold standard. The sensitivity and specificity of BSGI for residual tumor detection in 122 enrolled patients were 74.0 and 72.2 %, respectively, and were comparable to those of MRI (81.7 and 72.2 %; P > 0.100). The residual tumor size was significantly underestimated by BSGI in the luminal subtype (P = 0.008) and by MRI in the luminal (P < 0.001) and HER2 subtypes (P = 0.032), with a significantly lesser degree of underestimation by BSGI than MRI in both subtypes. In the triple-negative subtype, both BSGI and MRI generated accurate tumor size measurements. The residual cellularity of triple-negative tumors was significantly higher than that of the non-triple-negative tumors (P = 0.017). The diagnostic performance of BSGI in the assessment of residual tumor is comparable to that of MRI in breast cancer patients. The assessment of residual tumor extent by BSGI depends on the molecular subtype, but BSGI may be more accurate than MRI. Underestimation of tumor size in the luminal and/or HER2 subtypes by BSGI and MRI may be due to low-residual cellularity.

A distinctive ovarian cancer molecular subgroup characterized by poor prognosis and somatic focal copy number amplifications at chromosome 19.

OBJECTIVE: High-grade serous ovarian cancer (HGS-OvCa), the most common epithelial ovarian cancer, is very complex and heterogeneous at the molecular level. The identification of intrinsic HGS-OvCa subgroups characterized by specific molecular alterations and aggressive behavior could improve patient treatment. METHODS: High-resolution copy number data for 560 HGS-OvCa patients and gene expression data obtained from the TCGA database were analyzed to identify distinct molecular subgroups based on significant focal somatic copy number alterations (SCNAs). RESULTS: Using unsupervised consensus clustering, a subgroup accounting for 26.8% of the patients (150/560 patients) characterized by focal somatic copy number amplification at chromosome 19 was identified. The subgroup was independently associated by multivariate Cox regression analysis with poor overall (HR, 1.61; P = 0.001) and progression-free survival (HR, 1.36; P = 0.036). The specific focal SCNA locations were 19p13.2, 19p13.12, 19p13.11, 19q12, 19q13.12, and 19q13.2. The differential gene expression signature of the subgroup compared with that of the remaining patients also suggested that chromosome 19 was the mainly amplified region. The clinical significances of subgroup 2 were validated in independent data sets using the gene expression signature characteristics. In addition, the subgroup had a tendency toward mutual exclusivity with patients with BRCA1/2 mutations. The most significantly altered pathway of the subgroup was the cyclin and cell cycle regulation pathway. CONCLUSION: A unique molecular subgroup associated with poor survival was identified based on focal SCNAs and could aid the further molecular classification of ovarian cancers.