Intratumoral Budding in Pretreatment Biopsies, among Tumor Microenvironmental Components, Can Predict Prognosis and Neoadjuvant Therapy Response in Colorectal Adenocarcinoma.

Background and Objectives: The prediction of the prognosis and effect of neoadjuvant therapy is vital for patients with advanced or unresectable colorectal carcinoma (CRC). Materials and Methods: We investigated several tumor microenvironment factors, such as intratumoral budding (ITB), desmoplastic reaction (DR), and Klintrup-Mäkinen (KM) inflammation grade, and the tumor-stroma ratio (TSR) in pretreatment biopsy samples (PBSs) collected from patients with advanced or unresectable CRC. A total of 85 patients with 74 rectal carcinomas and 11 colon cancers treated at our hospital were enrolled; 66 patients had curative surgery and 19 patients received palliative treatment. Results: High-grade ITB was associated with recurrence (p = 0.002), death (p = 0.034), and cancer-specific death (p = 0.034). Immature DR was associated with a higher grade of clinical tumor-node-metastasis stage (cTNM) (p = 0.045), cN category (p = 0.045), and cM category (p = 0.046). The KM grade and TSR were not related to any clinicopathological factors. High-grade ITB had a significant relationship with tumor regression in patients who received curative surgery (p = 0.049). Conclusions: High-grade ITB in PBSs is a potential unfavorable prognostic factor for patients with advanced CRC. Immature DR, TSR, and KM grade could not predict prognosis or therapy response in PBSs.

Prognostic value of noggin protein expression in patients with resected gastric cancer.

BACKGROUND: Noggin and RNA-binding protein for multiple splicing 2 (RBPMS2) are known to regulate the expression of smooth muscle cells, endothelial cells, and osteoblasts. However, the prognostic role of combined Noggin and RBPMS2 expression in resected gastric cancer (GC) is unclear. METHODS: A total of 163 patients with GC who underwent gastrectomy were included in this study. The expression of Noggin and RBPMS2 proteins in tumor cells at the tumor center and invasive front of resected GC was evaluated by immunohistochemistry, and in conjunction with clinicopathological parameters the patient survival was analyzed. RESULTS: RBPMS2 protein expression was high at the tumor center (n = 86, 52.8%) and low at the invasive front (n = 69, 42.3%), while Noggin protein expression was high in both tumor center (n = 91, 55.8%) and the invasive front (n = 90, 55.2%). Noggin expression at the invasive front and tumor center was significantly decreased in advanced T stage, non-intestinal-type (invasive front, P = 0.008 and P <  0.001; tumor center lesion, P = 0.013 and P = 0.001). RBPMS2 expression at the invasive front was significantly decreased in non-intestinal-type and positive lymphatic invasion (P <  0.001 and P = 0.013). Multivariate analysis revealed that high Noggin protein expression of the invasive front was an independent prognostic factor for overall survival (hazard ratio [HR], 0.58; 95% confidence interval [CI]; 0.35-0.97, P <  0.036), but not at the tumor center (HR, 1.35; 95% CI; 0.81-2.26, P = 0.251). CONCLUSIONS: Our study indicates that high Noggin expression is a crucial prognostic factor for favorable outcomes in patients with resected GC.

QKI, a miR-200 target gene, suppresses epithelial-to-mesenchymal transition and tumor growth.

The microRNA-200 (miR-200) family plays a major role in specifying epithelial phenotype by preventing expression of the transcription repressors ZEB1 and ZEB2, which are well-known regulators of the epithelial-to-mesenchymal transition (EMT) in epithelial tumors including oral squamous cell carcinoma (OSCC). Here, we elucidated whether miR-200 family members control RNA-binding protein quaking (QKI), a newly identified tumor suppressor that is regulated during EMT. We predicted that miR-200a and miR-200b could recognize QKI 3'-UTR by analyzing TargetScan and The Cancer Genome Atlas head and neck squamous cell carcinoma (HNSCC) dataset. Forced expression of miR-200b/a/429 inhibited expression of ZEB1/2 and decreased cell migration in OSCC cell lines CAL27 and HSC3. QKI expression was also suppressed by miR-200 overexpression, and the 3'-UTR of QKI mRNA was directly targeted by miR-200 in luciferase reporter assays. Interestingly, shRNA-mediated knockdown of QKI led to pronounced EMT and protumor effects in both in vitro and in vivo studies of OSCC. Furthermore, high expression of QKI protein is associated with favorable prognosis in surgically resected HNSCC and lung adenocarcinoma. In conclusion, QKI increases during EMT and is targeted by miR-200; while, it suppresses EMT and tumorigenesis. We suggest that QKI and miR-200 form a negative feedback loop to maintain homeostatic responses to EMT-inducing signals.

Prognostic value of Dickkopf-1 and ß-catenin expression in advanced gastric cancer.

BACKGROUND: Dickkopf-1 (DKK1) is a Wnt/ß-catenin pathway antagonist related to gastric cancer (GC) carcinogenesis. However, the prognostic role of combined DKK1 and ß-catenin expression in advanced GC (AGC) is not clear. METHODS: In total, 158 patients with AGC who underwent gastric resection were enrolled in this study. DKK1 and ß-catenin expression was evaluated in whole tumor sections by immunohistochemistry. RESULTS: DKK1 expression was high in 73 (46.2%) patients, while ß-catenin expression was positive in 51 (32.3%) patients. The expression of DKK1 was positively correlated with that of ß-catenin (P < 0.001). The combined expression of DKK1 and ß-catenin was significantly associated with high N stage (N2 and N3) (P = 0.042). In addition, patients with high DKK expression demonstrated poorer overall (OS) (P < 0.001) and disease-free survival (DFS) (P = 0.001). However, there were no differences between high DKK1 expression with ß-catenin positivity and high DKK1 expression with ß-catenin negativity (OS, P = 0.379: DFS, P = 0.255). Multivariate analysis revealed that high DKK1 alone or high DKK1 with ß-catenin positivity were independent prognostic factors for both OS (high DKK1: hazard ratio [HR], 2.130; 95% confidence interval [CI]; 1.370-3.312, P = 0.001; high DKK1 with ß-catenin positivity: HR, 2.140; 95% CI, 1.343-3.409: P = 0.001) and DFS (high DKK1: HR, 2.092; 95% CI, 1.180-3.708; P = 0.012; high DKK1 with ß-catenin positivity: HR, 2.357; 95% CI, 1.291-4.306; P = 0.005). CONCLUSION: Our results indicate that high DKK1 expression regardless of ß-catenin positivity is a crucial prognostic factor for predicting tumor recurrence and survival in patients with resected AGC.

Role of autophagy-related protein expression in patients with rectal cancer treated with neoadjuvant chemoradiotherapy.

BACKGROUND: Autophagy, a cellular degradation process, has complex roles in tumourigenesis and resistance to cancer treatment in humans. The aim of this study was to explore the expression levels of autophagy-related proteins in patients with rectal cancer and evaluate their clinical role in the neoadjuvant chemoradiotherapy setting. METHODS: All specimens evaluated were obtained from 101 patients with colorectal cancer who had undergone neoadjuvant chemoradiotherapy and curative surgery. The primary outcomes measured were the expression levels of two autophagy-related proteins (microtubule-associated protein 1 light chain 3 beta (LC3ß) and beclin-1) by immunohistochemistry and their association with clinicopathological parameters and patient survival. RESULTS: Among the 101 patients, the frequency of high expression of beclin-1 was 31.7% (32/101) and that of LC3ß was 46.5% (47/101). A pathologic complete response was inversely associated with LC3ß expression (P = 0.003) and alterations in the expression of autophagy-related proteins (P = 0.046). In the multivariate analysis, however, autophagy-related protein expression did not show prognostic significance for relapse-free survival or overall survival. CONCLUSIONS: High expression of autophagy-related proteins shows a strong negative association with the efficacy of neoadjuvant chemoradiotherapy in patients with rectal cancer. Autophagy has clear implications as a therapeutic target with which to improve the efficacy of neoadjuvant chemoradiotherapy.

Outcomes in elderly patients treated with a single-agent or combination regimen as first-line chemotherapy for recurrent or metastatic gastric cancer.

BACKGROUND: Palliative chemotherapy is used to prolong survival among elderly patients with inoperable gastric cancer (GC). We analyzed differences between single and combination first-line palliative chemotherapy among these patients. METHODS: Included patients were >70 years old and were treated for GC at four clinical centers of the Catholic University of Korea. Baseline characteristics, the first-line chemotherapy regimen, treatment responses, toxicities, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: Between 2005 and 2012, 178 > 70-year-old patients with GC received palliative chemotherapy using single or combination regimens. Median ages were 77 years (range 71-89) in the single regimen group (SG, 70 patients) and 73 years (range 71-81) in the combination group (CG, 108 patients). Patients in the SG received S-1 or capecitabine. The most common regimen in the CG was platinum combined with fluorouracil. The most common response in both groups was stable disease (SG, 45.7 %; CG, 48.1 %). In the SG and CG, median PFS times were 4.4 months (95 % confidence interval [CI] 2.85-5.95) and 4.1 months (95 % CI 2.62-5.57; P = 0.295), respectively; median OS times were 6.6 months (95 % CI 4.17-9.08) and 7.6 months (95 % CI 5.50-9.69; P = 0.782), respectively. Hematologic (P < 0.001) and non-hematologic toxicities (P < 0.001) were more frequent in the CG. The most common causes of chemotherapy cessation were disease progression in the SG and decreased performance status in the CG. CONCLUSIONS: Single-agent treatment should be considered a first-line palliative chemotherapy option for elderly patients with GC.

Human papillomavirus-stratified analysis of the prognostic role of miR-21 in oral cavity and oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV) infection plays a significant role in the development and progression of head and neck squamous cell carcinoma (HNSCC). Expression of miR-21 has a prognostic role in a wide variety of cancers. The upregulation of miR-21 suppresses a number of target genes, including phosphatase tensin homologue (PTEN) and programmed cell death 4 (PDCD4). We investigated the association between the expression of miR-21 and the clinical features of HNSCC using stratified analysis based on HPV infection status. HPV status and miR-21 expression in HNSCC tissues from 167 patients were evaluated using in situ hybridization. The expression of PDCD4 and PTEN was examined by immunohistochemistry. The up-regulation of stromal miR-21 expression occurred in 40.6% of HPV-negative samples and 28.3% of the HPV-positive group. In HPV-stratified multivariate analysis, high miR-21 expression was associated with poor cancer-specific survival in HPV-negative tumors, but not in HPV-positive tumors. There was a significant association between miR-21 and cytoplasmic PDCD4 overexpression in HPV-negative HNSCCs. We suggest that stromal miR-21 expression is an independent prognostic factor in HPV-negative tumors and miR-21 may play different roles depending on HPV infection status.

Impact of PIK3CA and cell cycle pathway genetic alterations on durvalumab efficacy in patients with head and neck squamous cell carcinoma: Post hoc analysis of TRIUMPH study.

OBJECTIVES: This study aimed to investigate whether genetic alterations in PI3KCA and the cell cycle pathways influence the efficacy of durvalumab, an immune checkpoint inhibitor, in patients with head and neck squamous cell carcinoma (HNSCC) who had previously failed platinum-based treatment. MATERIALS AND METHODS: We obtained data from a phase II umbrella trial of patients with HNSCC who failed platinum-based treatment (TRIUMPH, NCT03292250). Patients receiving durvalumab treatment comprised those with PIK3CA alterations (Group A), those with cell cycle pathway alterations such as CDKN2A (Group B), and those with no druggable genetic alterations (Group C). We analyzed the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in each group and evaluated the potential predictive factors for durvalumab. RESULTS: We analyzed the data of 87 patients: 18, 12, and 57 in groups A, B, and C, respectively. The ORRs were 27.8 %, 8.3 %, and 15.8 % in Groups A, B, and C, respectively (P = 0.329), and the median PFS for each group was 2.3, 1.6, and 1.7 months, respectively, with no significant differences between the groups (P = 0.24). Notably, patients with lower neutrophil-lymphocyte ratio (NLR) (≤5.8) had longer PFS (median, 2.8 vs 1.6 months, P < 0.001), while those with lower platelet-lymphocyte ratio (PLR) (≤491.2) exhibited longer PFS (median, 1.8 vs 1.2 months, P < 0.001). CONCLUSION: Durvalumab's efficacy was similar, irrespective of the presence of PIK3CA or cell cycle pathway genetic alterations in patients with platinum-resistant HNSCC. The NLR and PLR may be promising predictive biomarkers.

Soluble interleukin-6 receptor is a prognostic marker for relapse-free survival in estrogen receptor-positive breast cancer.

Considering the protumorigenic roles of interleukin-6 (IL-6) transsignaling, we assessed the serum levels of IL-6, soluble interleukin-6 receptor (sIL-6R), and soluble glycoprotein 130 (sgp130) in 143 patients with breast cancer. Serum levels of IL-6 were elevated with advanced T and N stage. Serum levels of sIL-6R were lower in patients with estrogen receptor-positive cancer. The median values of IL-6 and sgp130 did not differ between patients with recurrence and those without recurrence. However, higher serum levels of sIL-6R at diagnosis were associated with significantly shorter relapse-free survival in patients with estrogen receptor-positive breast cancer.

Glucose transporter 1 (GLUT1) of anaerobic glycolysis as predictive and prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer.

PURPOSE: We investigated the relationships between biomarkers related to anaerobic glycolytic metabolism (GLUT1, LDH5, PDK1, and HIF-1α proteins), pathologic response, and prognosis. METHODS: All stage II and stage III rectal cancer patients had 50.4 Gy (1.8 Gy/day in 28 fractions) over 5.5 weeks, plus 5-fluorouracil (425 mg/m(2)/day) and leucovorin (20 mg/m(2)/day) bolus on days 1 to 5 and 29 to 33, and surgery was performed at 7 to 10 weeks after completion of all therapies. Expression of GLUT1, LDH5, PDK1, and HIF-1α proteins was determined by immunohistochemistry and was assessed in 104 patients with rectal cancer treated with neoadjuvant chemoradiotherapy. RESULTS: This study included stage II and III rectal cancer patients, and each stage accounted for each 50 % of the total cases. A high expression of GLUT1 protein was associated with a significantly lower rate of ypCR compared with low expression of GLUT1 protein (4.0 % vs. 27.8 %, respectively; p = 0.012). GLUT1 expression was also significantly higher in the poor response group (Grade 0, 1) than in the good response group (Grade 2, 3) (34.0 % vs. 14.8 %, respectively; p = 0.022). In recurrence analysis, the expression of GLUT1 protein demonstrated a significant correlation with time to recurrence, based on a log-rank method (p = 0.016). When analyzed by multiple Cox regression, the positive expression of GLUT1 was the most significant and independent unfavorable prognostic factor (p = 0.004). CONCLUSIONS: GLUT1 expression is a predictive and prognostic factor for pathologic complete response and recurrence in rectal cancer patients treated with 5-flurouracil and leucovorin neo-adjuvant chemoradiotherapy.

Efficacy of the granisetron transdermal system for the control of nausea and vomiting induced by highly emetogenic chemotherapy: a multicenter, randomized, controlled trial.

BACKGROUND/AIMS: We compared the efficacy of the granisetron transdermal system (GTS) with that of ondansetron for controlling chemotherapy-induced nausea and vomiting (CINV) in patients treated with highly emetogenic chemotherapy (HEC). METHODS: We randomized a total of 389 patients to groups treated by GTS and ondansetron before HEC. The primary endpoint was the percentage of patients achieving complete response (CR; no retching/vomiting/rescue medication) of CINV from the time of chemotherapy initiation to 24 hours after the last administration of chemotherapy (prespecified non-inferiority margin of 15%). Quality of life (QoL) was also assessed using the Functional Living Index-Emesis (FLIE). RESULTS: The per protocol analysis included 152 (47.80%) and 166 patients (52.20%) in the GTS and ondansetron groups, respectively. In the full analysis set, the most common diagnosis, regimen, and period of chemotherapy were lung cancer (149 patients, 40.27%), cisplatin-based regimen (297 patients, 80.27%), and 1 day chemotherapy (221 patients, 59.73%). The CR rates were 86.84% and 90.36% in the GTS and ondansetron groups, respectively; the treatment difference was -3.52% (95% confidence interval, -10.52 to 3.48) and met the primary endpoint, indicating that GTS was not inferior to ondansetron. Patient satisfaction, assessed on the FLIE, showed significantly higher scores in the GTS group compared to the ondansetron group (mean ± standard deviation, 1,547.38 ± 306.00 and 1,494.07 ± 312.05 mm, respectively; p = 0.0449). CONCLUSION: GTS provided effective, safe, and well-tolerated control of CINV and improved the QoL in HEC.

Association between Posttreatment Serum Platelet-to-Lymphocyte Ratio and Distant Metastases in Patients with Hepatocellular Carcinoma Receiving Curative Radiation Therapy.

BACKGROUND: We sought to investigate whether serum immune and inflammatory parameters can help to predict distant metastasis (DM) in patients with unresectable hepatocellular carcinoma (HCC) undergoing curative radiation therapy (RT). METHODS: A total of 76 RT courses were analyzed. The following variables were included in the analysis: systemic inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), absolute lymphocyte count, lymphocyte-to-monocyte ratio, albumin, albumin-to-alkaline phosphatase ratio, RT-related parameters, and levels of total protein, hemoglobin, α-fetoprotein, and PIVKA-II. Distant control (DC) and overall survival (OS) rates were calculated and compared. RESULTS: The mean age was 61.4 years, and most patients were men (n = 62, 81.6%). The median RT fraction number and fractional doses were 12 (range, 4-30) and 5 (range, 2-12) Gy, respectively. With a median follow-up of 12 (range, 3.1-56.7) months, the 1-year DC and OS rates were 64.4% and 55.2%, respectively. The development of DM significantly deteriorated OS (p = 0.013). In the multivariate analysis, significant independent prognostic indicators for DC and OS rates were the highest posttreatment PLR (≤235.7 vs. >235.7, p = 0.006) and the lowest posttreatment PNI (≤25.4 vs. >25.4, p < 0.001), respectively. CONCLUSIONS: Posttreatment serum PLR might be helpfully used as a predictive biomarker of DM in unresectable HCC patients undergoing RT. Future research is necessary to confirm our findings.

A Randomized Phase III Study of Patients With Advanced Gastric Adenocarcinoma Without Progression After Six Cycles of XELOX (Capecitabine Plus Oxaliplatin) Followed by Capecitabine Maintenance or Clinical Observation.

PURPOSE: Oxaliplatin, a component of the capecitabine plus oxaliplatin (XELOX) regimen, has a more favorable toxicity profile than cisplatin in patients with advanced gastric cancer (GC). However, oxaliplatin can induce sensory neuropathy and cumulative, dose-related toxicities. Thus, the capecitabine maintenance regimen may achieve the maximum treatment effect while reducing the cumulative neurotoxicity of oxaliplatin. This study aimed to compare the survival of patients with advanced GC between capecitabine maintenance and observation after 1st line XELOX chemotherapy. MATERIALS AND METHODS: Sixty-three patients treated with six cycles of XELOX for advanced GC in six hospitals of the Catholic University of Korea were randomized 1:1 to receive capecitabine maintenance or observation. The primary endpoint was progression-free survival (PFS), analyzed using a two-sided log-rank test stratified at a 5% significance level. RESULTS: Between 2015 and 2020, 32 and 31 patients were randomized into the maintenance and observation groups, respectively. After randomization, the median number of capecitabine maintenance cycles was 6. The PFS was significantly higher in the maintenance group than the observation group (6.3 vs. 4.1 months, P=0.010). Overall survival was not significantly different between the 2 groups (18.2 vs. 16.5 months, P=0.624). Toxicities, such as hand-foot syndrome, were reported in some maintenance group patients. Maintenance treatment was a significant factor associated with PFS in multivariate analysis (hazard ratio, 0.472; 95% confidence interval, 0.250-0.890; P=0.020). CONCLUSIONS: After 6 cycles of XELOX chemotherapy, capecitabine maintenance significantly prolonged PFS compared with observation, and toxicity was manageable. Maintenance treatment was a significant prognostic factor associated with PFS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02289547.

Analysis of Genomic Alterations Associated with Recurrence in Early Stage HER2-Positive Breast Cancer.

We aimed to compare gene expression in primary tumors of patients with recurrence and nonrecurrence to gain insight into the biology of high-risk HER2-positive early breast cancer. Patients who underwent curative resection and received adjuvant trastuzumab for HER2-positive early breast cancer were evaluated. Gene expression analyses were performed using NanoString Technologies' nCounter Breast Cancer 360 Panel. PAM50 intrinsic subtypes and Breast Cancer Signatures including tumor inflammation signature (TIS) were evaluated. Of 247 patients, 28 (11.3%) had recurrence at a median follow-up of 54.2 months. Patients with pathological stage III, tumor size > 5 cm, axillary lymph node metastases, and hormone receptor-negativity were more frequently observed in the recurrent group compared with the nonrecurrent group. In patients with recurrence, seven genes were upregulated significantly, including WNT11, HAPLN1, FGF10, BBOX1, CXADR, NDP, and EREG, and two genes were downregulated, including CXCL9 and GNLY. TIS score was significantly lower in patients with recurrence compared with controls without recurrence. These findings suggest that activation of oncogenic signaling pathways related to cell proliferation, adhesion, cancer stemness, and noninflamed tumor microenvironment are associated with the risk of recurrence in early stage, HER2-positive breast cancer.

Prognostic value of Dickkopf-1 and ß-catenin expression according to the antitumor immunity of CD8-positive tumor-infiltrating lymphocytes in biliary tract cancer.

The role of ß-catenin and Dickkopf-1 (DKK1) is dependent on the specific immunobiology of T cell inflammation in biliary tract cancer (BTC). We aimed to analyze the role of DKK1 or ß-catenin as a prognostic factor in BTC, and determine the clinical associations of ß-catenin and DKK1 with CD8+ tumor-infiltrating lymphocytes (TIL). We used data from The Cancer Genome Atlas Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. CD8+ TIL expression was a significant predictor of favorable overall survival (OS) and relapse-free survival (RFS) (median OS, 34.9 months in high-TIL, 16.7 months in low-TIL, P < 0.0001 respectively; median RFS, 27.1 months in high-TIL, 10.0 months in low-TIL, P < 0.0001 respectively). In the high-CD8+ TIL BTC group, the tumor expression of ß-catenin and DKK1 had a significant negative impact on either OS or RFS. In the low-TIL BTC group, there were no differences according to ß-catenin and DKK1 expression. Cox regression multivariate analysis demonstrated that CD8+ TIL and ß-catenin retained significant association with OS. Among patients with resected BTC, the ß-catenin and DKK1 protein and high CD8+ TIL levels were associated with poor and good clinical outcomes, respectively.

Elevated serum substance P level as a predictive marker for moderately emetogenic chemotherapy-induced nausea and vomiting: A prospective cohort study.

Chemotherapy-induced nausea and vomiting (CINV) is an unbearable side effect. Identifying high emetic risk patients and providing more active antiemetics strategies are mandatory to improve the tolerability of chemotherapy. In this prospective cohort study, leptin, ghrelin, and substance P were measured at baseline, day 3, and day 14 during the first cycle of chemotherapy. Nausea and vomiting were measured each day for the first 4 days of the first cycle of chemotherapy. Eighty-two patients were enrolled. Colorectal cancer (61%) and gastric cancer (35.4%) were common cancer types. All patients received moderate emetic risk chemotherapy. Forty-five (54.9%) patients had nausea, and 15 (18.3%) patients experienced vomiting. In univariate analysis, a higher level of baseline substance P, which is a target of NK1-RA (Neurokinin 1 receptor antagonist), was a significant predictive marker for chemotherapy-induced nausea [odds ratio (OR): 2.6, 95% confidence interval (CI): 1.02-6.62, p = 0.046]. Regarding chemotherapy-induced vomiting, patients with higher levels of substance P had a greater chance of vomiting [OR: 1.72, 95% CI: 0.49-5.99, p = 0.395] than those with lower levels of substance P. In patients receiving moderate emetic risk chemotherapy, active antiemetics, including NK1-RA, could be considered for those with high levels of substance P.

Clinical implications of APOBEC3A and 3B expression in patients with breast cancer.

BACKGROUND: We aimed to evaluate the expression of APOBEC3A (A3A), 3B (A3B) mRNA, and germline APOBEC3A/B deletion polymorphism in patients with breast cancers and to investigate the correlation between their expressions and clinicopathological characteristics. METHODS: RNA and DNA samples were extracted from 138 breast cancer tissues and adjacent normal breast tissues. The levels of A3A and A3B mRNA transcripts were determined using quantitative real-time polymerase chain reaction. Insertion and deletion PCR assays were performed to detect the A3B deletion allele. The serum concentrations of soluble programmed death-ligand 1 (sPD-L1) and interferon gamma were determined using enzyme-linked immunosorbent assays. RESULTS: A3B mRNA expression levels were significantly higher in triple-negative breast cancers compared to hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancers. Older age of the patient and high ki-67 expression were associated with increased expression levels of A3A and A3B mRNA. Advanced tumor stage, presence of lymph node involvement, and high histological grade were associated with increased expression levels of A3A mRNA. The APOBEC3A/B deletion allele was found in 77 (55.8%) patients. TP53 and PIK3CA mutations were detected in 62 (44.9%) and 31 (22.5%) patients, respectively. The presence of a PIK3CA mutation was associated with lower A3A mRNA expression levels. There was a weak positive relationship between A3A mRNA expression levels and serum sPD-L1 levels. CONCLUSIONS: There was a difference in A3B mRNA expression levels according to breast cancer subtypes, and high levels of A3A and A3B mRNA expressions were associated with an aggressive phenotype. There was a high incidence of APOBEC3A/B deletion allele. Further studies are needed to identify the clinical significance of APOBEC in Asian patients with breast cancer.

Prognostic implications of stromal hyaluronic acid protein expression in resected oropharyngeal and oral cavity cancers.

BACKGROUND/AIMS: Hyaluronic acid (HA) regulates cell adhesion, migration and proliferation in various cancers. The clinical implications of HA in resected head and neck squamous cell carcinoma have not been elucidated. We investigated the clinical significance and prognostic value of the expression of tumoral and stromal HA and its related proteins in oropharyngeal and oral cavity cancer. METHODS: Resected tissues from oropharyngeal or oral cavity cancer patients undergoing surgery were analysed in tissue microarrays divided into stroma and cancer panels. The expression levels of HA, HA synthases and hyaluronidases were also assessed by immunohistochemistry. RESULTS: A total of 160 resected oropharyngeal or oral cavity cancer tissues were analysed. Stromal HA expression was observed more frequently in human papilloma virus (HPV)-negative tumors, but other clinicopathological characteristics did not differ. In patients with HPV-negative oral cavity cancers, high stromal HA expression was associated with significantly shorter recurrence-free survival and overall survival compared with low stromal HA expression. The expression of HA in both tumors and stroma was significantly correlated with poorer outcomes than other combinations in patients with HPV-negative oral cavity cancers. However, these prognostic roles of HA were not observed in patients with HPV-negative oropharyngeal cancers. In the HPV-stratified multivariate analysis, high stromal HA expression remained an independent indicator of poor prognosis in terms of recurrence-free survival. CONCLUSION: High stromal HA and expression of HA in both tumors and stroma were correlated with poor prognosis in HPV-negative oral cavity cancer, but not in HPV-negative oropharyngeal cancers.

High Endothelial Venule with Concomitant High CD8+ Tumor-Infiltrating Lymphocytes Is Associated with a Favorable Prognosis in Resected Gastric Cancer.

CD8+ tumor-infiltrating lymphocytes (TILs) play a major role in antitumor immunity. High endothelial venules (HEVs) are related to diverse immune cells in solid tumors. We analyzed CD8+ and Foxp3+ TILs in combination with HEVs to determine their prognostic role in advanced gastric cancer (AGC). We enrolled 157 patients with AGC in this study. The densities of CD8+ TILs and Foxp3+ TILs were calculated using immunohistochemical staining. HEVs were evaluated by MECA-79 expression. HEVs were identified in 60 (38.2%) cases and was significantly associated with an increased number of CD8+ TILs (p = 0.027) but not of Foxp3+ TILs (p = 0.455) and CD20+ TILs (p = 0.163). A high CD8+/HEV+ level was significantly associated with nodal metastasis (p = 0.048). In survival analysis, patients with high CD8+/HEV+ levels demonstrated the longest overall survival (OS) (p = 0.015). Furthermore, a high CD8+/HEV+ level was an independent prognostic factor in AGC (p = 0.011; hazard ratio (HR) = 0.435; 95% confidence interval (CI) = 0.245-0.837). HEVs were found to play an important role in antitumor immunity associated with CD8+ TILs in AGC. This analysis of HEVs and CD8+ TILs helps stratify patients with AGC and sheds light on tumor immunity.