Dietary Habits of Newly Diagnosed Patients with Breast Cancer in Korea.

BACKGROUND: In patients with breast cancer, a healthy diet can help reduce breast cancer-specific recurrence, mortality, and comorbid chronic disease rates. There have been few studies on dietary habits immediately after breast cancer diagnosis, especially those involving the Asian population. Therefore, this study aimed to compare the nutritional habits of newly diagnosed patients with breast cancer and the general population without cancer in Korea using propensity score (PS) matching. METHODS: We conducted a case-controlled study of 157 patients with breast cancer and 2,363 cancer-free control participants from the Korea National Health and Nutrition Examination Survey. The PS values for the predicted probability of patients with breast cancer and the general population were estimated using logistic regression analysis, including age and body mass index. The dietary patterns were assessed using a 24-hour recall of 1 day and the Food Frequency Questionnaire. RESULTS: PS matching showed that patients with breast cancer consumed fewer calories and carbohydrates; however, they consumed more protein and fat compared to the general population. Compared to the general population, patients with breast cancer consumed more healthy foods such as fish, seaweed, vegetables, fruit, mixed-grain rice, and nuts; however, they also consumed more soup, stew, and red meat. CONCLUSION: Newly diagnosed patients with breast cancer have some healthy dietary habits compared to the general population. However, there is considerable room for improvement in their diet quality. Our results support the need to develop tailored dietary recommendations for patients with breast cancer during the diagnostic and posttreatment periods to improve their diet quality.

Frequent Intraluminal Growth of Large Muscular Veins in Surgically Resected Colorectal Cancer Tissues: A 3-Dimensional Pathologic Reconstruction Study.

Although venous invasion (VI) is common in colorectal cancers (CRCs) and is associated with distant metastasis, the 3-dimensional (3D) microscopic features and associated mechanisms of VI are not well elucidated. To characterize the patterns of VI, 103 tissue slabs were harvested from surgically resected CRCs with ≥pT2. They were cleared using the modified immunolabeling-enabled 3D imaging of solvent-cleared organs method, labeled with multicolor fluorescent antibodies, including antibodies against cytokeratin 19, desmin, CD31, and E-cadherin, and visualized by confocal laser scanning microscopy. VI was classified as intravasation, intraluminal growth, and/or extravasation, and 2-dimensional and 3D microscopic features were compared. VI was detected more frequently in 3D (56/103 [54.4%]) than in conventional 2-dimensional hematoxylin and eosin-stained slides (33/103 [32%]; P < .001). When VI was present, it was most commonly in the form of intraluminal growth (51/56), followed by extravasation (13/56) and intravasation (5/56). The mean length of intraluminal growth was 334.0 ± 212.4 µm. Neoplastic cell projections extended from cancer cell clusters in the connective tissue surrounding veins, penetrated the smooth muscle layer, and then grew into and filled the venous lumen. E-cadherin expression changed at each invasion phase; intact E-cadherin expression was observed in the cancer cells in the venous walls, but its expression was lost in small clusters of intraluminal neoplastic cells. In addition, reexpression of E-cadherin was observed when cancer cells formed well-oriented tubular structures and accumulated and grew along the luminal side of the venous wall. In contrast, singly scattered cancer cells and cancer cells with poorly defined tubular structures showed loss of E-cadherin expression. E-cadherin expression was intact in the large cohesive clusters of extravasated cancer cells. However, singly scattered cells and smaller projections of neoplastic cells in the stroma outward of venous wall showed a loss of E-cadherin expression. In conclusion, VI was observed in more than half of the CRCs analyzed by 3D histopathologic image reconstruction. Once inside a vein, neoplastic cells can grow intraluminally. The epithelial-mesenchymal transition is not maintained during VI of CRCs.

Antigen-Dependent Inducible T-Cell Reporter System for PET Imaging of Breast Cancer and Glioblastoma.

For the past several decades, chimeric antigen receptor T-cell therapies have shown promise in the treatment of cancers. These treatments would greatly benefit from companion imaging biomarkers to follow the trafficking of T cells in vivo. Methods: Using synthetic biology, we engineered T cells with a chimeric receptor synthetic intramembrane proteolysis receptor (SNIPR) that induces overexpression of an exogenous reporter gene cassette on recognition of specific tumor markers. We then applied a SNIPR-based PET reporter system to 2 cancer-relevant antigens, human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor variant III (EGFRvIII), commonly expressed in breast and glial tumors, respectively. Results: Antigen-specific reporter induction of the SNIPR PET T cells was confirmed in vitro using green fluorescent protein fluorescence, luciferase luminescence, and the HSV-TK PET reporter with 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine ([18F]FHBG). T cells associated with their target antigens were successfully imaged using PET in dual-xenograft HER2+/HER2- and EGFRvIII+/EGFRvIII- animal models, with more than 10-fold higher [18F]FHBG signals seen in antigen-expressing tumors versus the corresponding controls. Conclusion: The main innovation found in this work was PET detection of T cells via specific antigen-induced signals, in contrast to reporter systems relying on constitutive gene expression.

Dosimetry in radionuclide therapy: the clinical role of measuring radiation dose.

Radionuclide therapy is a rapidly expanding oncological treatment method. Overwhelmingly, the application of radionuclide therapy in clinical practice relies on fixed or empirical dosing strategies. In principle, the application of dosimetry promises to improve patient outcomes by tailoring administered radionuclide therapy activities to each patient's unique tumour burden and tumour uptake. However, robust prospective data are scarce due to few prospective randomised clinical trials investigating the use of dosimetry in radionuclide therapy. In this Review, we describe the role of dosimetry as it has been applied historically and in modern clinical practice and its potential future applications. We further emphasise areas of future growth and a potential pathway to optimised personalised activity modulation of radionuclide therapy.

Controversial benefit of 5-fluorouracil/leucovorin-based adjuvant chemotherapy for ampullary cancer: a propensity score-matched analysis.

BACKGROUND: Although surgery is the primary treatment for ampullary cancer (AC), the benefit of adjuvant chemotherapy (CTx) has not yet been confirmed. METHODS: AC patients who were administered 5-fluorouracil(FU)/leucovorin(LV)-based CTx after curative intent surgery between 2011 and 2019 were included. Prognosis was compared between the observation (OB) and CTx groups after propensity score matching (PSM) using perioperative variables to control differences in patient characteristics. RESULTS: Before PSM, of 475 patients, those in the CTx group (n = 281) had worse 5-year overall survival (OS) (82.1% vs. 78.5%, p = 0.017) and worse 5-year recurrence-free survival (RFS) (54.9% vs. 75.7%, p < 0.001) than those in the OB group (n = 194). In addition, the CTx group had a higher rate of poor prognostic factors such as a high T stage (p < 0.001), node metastasis (p < 0.001), and poor differentiation (p < 0.001). After PSM, perioperative outcomes were comparable. In addition, there were no significant differences in OS (hazard ratio [HR], 1.085; 95% confidence interval [CI], 0.688-1.710; p = 0.726) or RFS (HR, 0.883; 95% CI, 0.613 1.272; p = 0.505) between the CTx (n = 123) and OB (n = 123) groups even after stratification by TNM stage. Intestinal subtype showed better 5-year OS (83.7% vs 33.2%, p = 0.015) and RFS (46.5% vs 24.9%, p = 0.035) rate compared with pancreatobiliary/mixed subtype. CONCLUSION: Patients who received adjuvant chemotherapy based on 5-FU/LV showed comparable oncologic outcomes to patients in the OB group even after stratification by tumor stage. The patients with intestinal subtype showed oncologic benefit for adjuvant 5-FU/LV CTx compared with pancreatobiliary or mixed subtypes.

A sinonasal yolk sac tumor in an adult.

Yolk sac tumors (YSTs), which are also called endodermal sinus tumors, are malignant tumors of germ cell origin. These tumors usually occur in the gonads, but 20% of cases have been reported at extragonadal sites. The head and neck is a rarely affected region that accounts for just 1% of all malignant tumors of germ cell origin. In addition, YSTs arise mostly in childhood. We present a rare pathologically pure case of primary adult YST in the sinonasal area. A 45-year-old male patient presented with a rapidly growing mass in the nasal cavity, which caused nasal obstruction and bloody post-nasal drip. The histopathologic features indicated pure YST, and immunohistochemical analysis revealed positive reactivity for Sal-like protein 4 and alpha-fetoprotein. Herein, we discuss the clinical, radiologic, and histologic features of this YST and review other cases of sinonasal YST in adults.

Implication of CD69+ CD103+ tissue-resident-like CD8+ T cells as a potential immunotherapeutic target for cholangiocarcinoma.

BACKGROUND: The heterogeneous immune landscapes of intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Here we aimed to investigate the implications of tissue-resident memory (TRM)-related features of tumour-infiltrating CD8+ T cells (CD8+ TILs) from ICC patients. METHODS: From ICC patients, we obtained blood samples and ICC surgical specimens (n = 33). We performed multicolour flow cytometry, multiplexed immunohistochemistry and RNA sequencing. RESULTS: When compared to peripheral CD8+ T cells, the CD8+ TILs included significantly higher proportions of the CD69+ CD103- and CD69+ CD103+ TRM-like subsets (P < .001 for both). Relative to CD69- and CD69+ CD103- cells, the CD69+ CD103+ CD8+ TILs harboured higher levels of T-cell markers representing tumour specificity (ie CD39), proliferation (ie Ki-67) and T-cell activation (ie HLA-DR and CD38) (all P < .001). Moreover, compared to the stroma, the tumour margin and core density each had a significantly higher density of CD103+ CD8+ TILs (P < .001 for both). ICCs with high proportions of CD69+ CD103+ cells displayed higher levels of parameters associated with response to immune checkpoint inhibitors (ICIs)-including number of CD8+ TIL infiltrates (P = .019), PD-L1 expression in the tumour (P = .046) and expression of the T cell-inflamed gene signature (P < .001). ICCs with lower proportions of CD69+ CD103+ CD8+ TILs exhibited significant enrichment of genes related to the Wnt/ß-catenin (P < .001) and TGF-ß pathways (P = .002). CONCLUSION: CD69+ CD103+ TRM-like CD8+ TILs represent prominent tumour-specific immune responses and hold promise as a potential therapeutic target in ICC patients. Differential TRM-related features of ICCs may help develop future immunotherapeutic strategies such as maximizing TRM responses or inhibiting pathways contributing to immune evasion.

Spatial Distribution and Prognostic Implications of Tumor-Infiltrating FoxP3- CD4+ T Cells in Biliary Tract Cancer.

PURPOSE: The clinical implications of tumor-infiltrating T cell subsets and their spatial distribution in biliary tract cancer (BTC) patients treated with gemcitabine plus cisplatin were investigated. MATERIALS AND METHODS: A total of 52 BTC patients treated with palliative gemcitabine plus cisplatin were included. Multiplexed immunohistochemistry was performed on tumor tissues, and immune infiltrates were separately analyzed for the stroma, tumor margin, and tumor core. RESULTS: The density of CD8+ T cells, FoxP3- CD4+ helper T cells, and FoxP3+ CD4+ regulatory T cells was significantly higher in the tumor margin than in the stroma and tumor core. The density of LAG3- or TIM3-expressing CD8+ T cell and FoxP3- CD4+ helper T cell infiltrates was also higher in the tumor margin. In extrahepatic cholangiocarcinoma, there was a higher density of T cell subsets in the tumor core and regulatory T cells in all regions. A high density of FoxP3- CD4+ helper T cells in the tumor margin showed a trend toward better progression-free survival (PFS) (p=0.092) and significantly better overall survival (OS) (p=0.012). In multivariate analyses, a high density of FoxP3- CD4+ helper T cells in the tumor margin was independently associated with favorable PFS and OS. CONCLUSION: The tumor margin is the major site for the active infiltration of T cell subsets with higher levels of LAG3 and TIM3 expression in BTC. The density of tumor margin-infiltrating FoxP3- CD4+ helper T cells may be associated with clinical outcomes in BTC patients treated with gemcitabine plus cisplatin.

Lymph node size and its association with nodal metastasis in ductal adenocarcinoma of the pancreas.

BACKGROUND: Although lymph node metastasis is a poor prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC), our understanding of lymph node size in association with PDAC is limited. Increased nodal size in preoperative imaging has been used to detect node metastasis. We evaluated whether lymph node size can be used as a surrogate preoperative marker of lymph node metastasis. METHODS: We assessed nodal size and compared it to the nodal metastatic status of 200 patients with surgically resected PDAC. The size of all lymph nodes and metastatic nodal foci were measured along the long and short axis, and the relationships between nodal size and metastatic status were compared at six cutoff points. RESULTS: A total of 4,525 lymph nodes were examined, 9.1% of which were metastatic. The mean size of the metastatic nodes (long axis, 6.9±5.0 mm; short axis, 4.3±3.1 mm) was significantly larger than that of the non-metastatic nodes (long axis, 5.0±4.0 mm; short axis, 3.0±2.0 mm; all p<.001). Using a 10 mm cutoff, the sensitivity, specificity, positive predictive value, overall accuracy, and area under curve was 24.8%, 88.0%, 17.1%, 82.3%, and 0.60 for the long axis and 7.0%, 99.0%, 40.3%, 90.6%, and 0.61 for the short axis, respectively. CONCLUSIONS: The metastatic nodes are larger than the non-metastatic nodes in PDAC patients. However, the difference in nodal size was too small to be identified with preoperative imaging. The performance of preoperative radiologic imaging to predict lymph nodal metastasis was not good. Therefore, nodal size cannot be used a surrogate preoperative marker of lymph node metastasis.

Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression.

Lin28, a well-known RNA-binding protein, regulates diverse cellular properties. All physiological functions of Lin28A characterized so far have been attributed to its repression of let-7 miRNA biogenesis or modulation of mRNA translational efficiency. Here we show that Lin28A directly binds to a consensus DNA sequence in vitro and in mouse embryonic stem cells in vivo. ChIP-seq and RNA-seq reveal enrichment of Lin28A binding around transcription start sites and a positive correlation between its genomic occupancy and expression of many associated genes. Mechanistically, Lin28A recruits 5-methylcytosine-dioxygenase Tet1 to genomic binding sites to orchestrate 5-methylcytosine and 5-hydroxymethylcytosine dynamics. Either Lin28A or Tet1 knockdown leads to dysregulated DNA methylation and expression of common target genes. These results reveal a surprising role for Lin28A in transcriptional regulation via epigenetic DNA modifications and have implications for understanding mechanisms underlying versatile functions of Lin28A in mammalian systems.

Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair.

Contrary to the long-held belief that DNA methylation of terminally differentiated cells is permanent and essentially immutable, post-mitotic neurons exhibit extensive DNA demethylation. The cellular function of active DNA demethylation in neurons, however, remains largely unknown. Tet family proteins oxidize 5-methylcytosine to initiate active DNA demethylation through the base-excision repair (BER) pathway. We found that synaptic activity bi-directionally regulates neuronal Tet3 expression. Functionally, knockdown of Tet or inhibition of BER in hippocampal neurons elevated excitatory glutamatergic synaptic transmission, whereas overexpressing Tet3 or Tet1 catalytic domain decreased it. Furthermore, dysregulation of Tet3 signaling prevented homeostatic synaptic plasticity. Mechanistically, Tet3 dictated neuronal surface GluR1 levels. RNA-seq analyses further revealed a pivotal role of Tet3 in regulating gene expression in response to global synaptic activity changes. Thus, Tet3 serves as a synaptic activity sensor to epigenetically regulate fundamental properties and meta-plasticity of neurons via active DNA demethylation.

Platelet-rich plasma enhances the dermal regeneration efficacy of human adipose-derived stromal cells administered to skin wounds.

The administration of human adipose-derived stromal cells (hASCs) enhances skin wound healing. However, poor survival of hASCs that are administered to avascular wound regions may limit the therapeutic efficacy of the hASCs. The aim of this study was to determine whether the coadministration of platelet-rich plasma (PRP) and hASCs enhanced the skin wound-healing efficacy of hASCs. Skin regeneration was examined in skin wounds of athymic mice that were either untreated or treated with hASCs, PRP, or both hASCs and PRP. Coadministration of PRP and hASCs resulted in better skin regeneration than hASC administration alone in part by significantly improving the proliferation of administered hASCs by the angiogenic growth factor secretion of the hASCs and surrounding mouse host cells in the wound areas and by promoting neovascularization in the wound beds.

Enhanced cartilage formation via three-dimensional cell engineering of human adipose-derived stem cells.

Autologous chondrocyte implantation is an effective treatment for damaged articular cartilage. However, this method involves surgical procedures that may cause further cartilage degeneration, and in vitro expansion of chondrocytes can result in dedifferentiation. Adipose-derived stem cells (ADSCs) may be an alternative autologous cell source for cartilage regeneration. In this study, we developed an effective method for large-scale in vitro chondrogenic differentiation, which is the procedure that would be required for clinical applications, and the subsequent in vivo cartilage formation of human ADSCs (hADSCs). The spheroid formation and chondrogenic differentiation of hADSCs were induced on a large scale by culturing hADSCs in three-dimensional suspension bioreactors (spinner flasks). In vitro chondrogenic differentiation of hADSCs was enhanced by a spheroid culture compared with a monolayer culture. The enhanced chondrogenesis was probably attributable to hypoxia-related cascades and enhanced cell-cell interactions in hADSC spheroids. On hADSCs loading in fibrin gel and transplantation into subcutaneous space of athymic mice for 4 weeks, the in vivo cartilage formation was enhanced by the transplantation of spheroid-cultured hADSCs compared with that of monolayer-cultured hADSCs. This study shows that the spheroid culture may be an effective method for large-scale in vitro chondrogenic differentiation of hADSCs and subsequent in vivo cartilage formation.

Enhanced skin wound healing by a sustained release of growth factors contained in platelet-rich plasma.

Platelet-rich plasma (PRP) contains growth factors that promote tissue regeneration. Previously, we showed that heparin-conjugated fibrin (HCF) exerts the sustained release of growth factors with affinity for heparin. Here, we hypothesize that treatment of skin wound with a mixture of PRP and HCF exerts sustained release of several growth factors contained in PRP and promotes skin wound healing. The release of fibroblast growth factor 2, platelet-derived growth factor-BB, and vascular endothelial growth factor contained in PRP from HCF was sustained for a longer period than those from PRP, calcium-activated PRP (C-PRP), or a mixture of fibrin and PRP (F-PRP). Treatment of full-thickness skin wounds in mice with HCF-PRP resulted in much faster wound closure as well as dermal and epidermal regeneration at day 12 compared to treatment with either C-PRP or F-PRP. Enhanced skin regeneration observed in HCF-PRP group may have been at least partially due to enhanced angiogenesis in the wound beds. Therefore, this method could be useful for skin wound treatment.

Intercellular adhesion molecule-1 is upregulated in ischemic muscle, which mediates trafficking of endothelial progenitor cells.

BACKGROUND: Trafficking of transplanted endothelial progenitor cells (EPCs) to an ischemic organ is a critical step in neovascularization. This study was performed to elucidate the molecular mechanism of EPC trafficking in terms of adhesion molecules. METHODS AND RESULTS: Using murine hindlimb ischemia model, we examined expressions of E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and platelet-endothelial cell adhesion molecule-1 (PECAM-1) in ischemic muscle by immunofluorescence. ICAM-1 was overexpressed in ischemic muscle compared with nonischemic muscle, whereas expressions of E-selectin, VCAM-1, and PECAM-1 did not show that much difference. ICAM-1 was also upregulated by hypoxia in murine endothelial cells (ECs) as assessed by immunoblot and flow cytometry. EPCs were attached to ECs specifically through ICAM-1/beta-2 integrin interaction in vitro. When EPCs were labeled with fluorescent dye or radioisotope (Tc-99m-HMPAO) and systemically administrated in vivo, EPCs preferentially homed to ischemic muscle. By blocking ICAM-1, EPCs entrapment to ischemic limb in vivo was significantly reduced and neovascularization induced by EPC transplantation was attenuated. CONCLUSIONS: ICAM-1 is upregulated by ischemia, and this is closely associated with EPCs entrapment to ischemic limb. Our findings suggest that ICAM-1 expression might be important in regulating the process of neovascularization through its ability to recruit EPCs.

Altered gene expression profiles by sodium/iodide symporter gene transfection in a human anaplastic thyroid carcinoma cell line using a radioactive complementary DNA microarray.

BACKGROUND: The sodium/iodide symporter (NIS) is a membrane glycoprotein that mediates active 131I uptake during the treatment of cancer of the thyroid gland and extrathyroidal tissues. NIS gene transfection, a gene-therapy modality, has been introduced in many types of cancer, such as prostate cancer and breast cancer, and has demonstrated a high potential for the treatment of non-thyroidal cancers. AIM: To investigate the pattern of NIS gene expression and provide evidence of its beneficial effects in human anaplastic cancer ARO cells by using a radioactive complementary DNA (cDNA) microarray. METHODS: For cDNA microarray data analysis, superimposed images and clustergrams were prepared from basic radioactivity data obtained using a phosphoimager system. Gene expression profiles were constructed using the Z-transformed values of genes related to cancer biology. RESULTS: Radioactive cDNA microarray studies showed that 11 genes were upregulated (Z ratio > 1.5) and 31 genes were downregulated (Z ratio < -1.5) in response to NIS gene transfection. Of these differentially expressed genes, 33% were related to cell proliferation and apoptosis. Moreover, NIS gene transfection into an anaplastic thyroid cancer cell line affected the expression of the protein tyrosine phosphatase (PTP) family and Ras oncogene family, including Ras, Rac and Rab. CONCLUSION: The identification of changes in the patterns of gene expression may provide a better understanding of the response of molecular mechanisms to NIS gene transfection.