Impact of oral statin therapy on clinical outcomes in patients with cT1 breast cancer.

PURPOSE: A previous meta-analysis examining the relationship between statin use and breast cancer reported that the inhibitory effect of statins on breast cancer may be more pronounced in early-stage cases. In this study, we aimed to investigate the effects of hyperlipidemia treatment at the time of breast cancer diagnosis and to examine its correlation with metastasis to axillary lymph nodes among patients with so-called cT1 breast cancer whose primary lesion was 2 cm or less and was pathologically evaluated by sentinel lymph node biopsy or axillary lymph node dissection. We also investigated the effects of hyperlipidemic drugs on the prognosis of patients with early-stage breast cancer. METHODS: After excluding cases that did not meet the criteria, we analyzed data from 719 patients who were diagnosed with breast cancer, with a primary lesion of 2 cm or less identified by preoperative imaging, and who underwent surgery without preoperative chemotherapy. RESULTS: Regarding hyperlipidemia drugs, no correlation was found between statin use and lymph node metastasis (p = 0.226), although a correlation was found between lipophilic statin use and lymph node metastasis (p = 0.042). Also, the disease-free survival periods were prolonged following treatment of hyperlipidemia (p = 0.047, hazard ratio: 0.399) and statin administration (p = 0.028, hazard ratio: 0.328). CONCLUSION: In cT1 breast cancer, the results suggest that oral statin therapy may contribute to favorable outcomes.

Clinical verification of the relationship between serum lipid metabolism and immune activity in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Lipid metabolism has been recently reported to affect the prognosis and tumor immune activity in cancer patients. However, the effect of lipid metabolism on chemosensitivity in patients with breast cancer treated with neoadjuvant chemotherapy (NAC) remains unclear. METHODS: We examined 327 patients with breast cancer who were treated with NAC followed by curative surgery. The correlations between the serum levels of total cholesterol (TC) and triglyceride (TG) and the clinicopathological features, including the efficacy of NAC, neutrophil-to-lymphocyte ratio (NLR), and absolute lymphocyte count (ALC), were evaluated retrospectively. RESULTS: Serum TG levels were increased after NAC in all the subtypes, and the rate of change was the highest, especially in triple-negative breast cancer (TNBC) (21.0% → 48.1%). In addition, only TNBC patients with an objective response (OR) had significantly higher TG levels after NAC than those without (P = 0.049). Patients with a high ALC before NAC had significantly higher TG levels after NAC than patients with all breast cancer (P = 0.001), HER2-enriched breast cancer (P = 0.021), and TNBC (P = 0.008). Patients with a low NLR before NAC had significantly higher TG levels after NAC only among patients with TNBC (P = 0.025). In patients with human epidermal growth factor receptor 2-enriched breast cancer, the group with normal TC levels before NAC had significantly better OS than those with high TC levels (P = 0.013, log-rank test), and in patients with TNBC, the group with high TC levels after NAC had significantly better OS than those with normal TC levels (P = 0.014, log-rank test). CONCLUSIONS: Good systemic immune activity and chemosensitivity may be associated with lipid metabolism regulated by NAC in TNBC patients.

Eribulin Treatment Promotes Re-expression of Estrogen Receptor in Endocrine Therapy-resistant Hormone Receptor-positive Breast Cancer Cells.

BACKGROUND/AIM: Hypoxia is significantly associated with the development of drug resistance, and endocrine therapy is ineffective against hormone receptor (HR)-positive breast cancer in hypoxic tumor environments. Eribulin has a unique anticancer effect in breast cancer cells and improves tumor hypoxia by vascular remodeling. Therefore, we investigated the effect of eribulin on HR-positive breast cancer cells that were resistant to endocrine blockade. MATERIALS AND METHODS: We established hypoxia-resistant breast cancer cell lines by continuous culture in a hypoxic environment. Parental and hypoxia-resistant cell lines were treated with eribulin and/or tamoxifen, and estrogen receptor (ER)-, epithelial-mesenchymal transition-, and hypoxia-related gene and protein expression changes in each surviving cell line were assessed. In addition, proliferation was assessed after eribulin treatment in the parental and hypoxia-resistant cell lines. We also assessed the effect of eribulin in vivo using subcutaneous xenograft models. RESULTS: Hypoxia-resistant cell lines showed significantly decreased expression of epithelial and ER-related markers and exhibited a higher level of resistance to tamoxifen. Conversely, eribulin treatment increased epithelial and ER-related gene and protein expression in hypoxia-resistant cell lines and enhanced the anticancer effect of tamoxifen. In in vivo xenograft models, eribulin treatment of hypoxia- and tamoxifen-resistant tumors slightly induced the re-expression of ER. In addition, hypoxia-resistant tumors treated with eribulin tended to respond better to tamoxifen. CONCLUSION: Eribulin ameliorated the aggressive behavior caused by hypoxia and induced the re-expression of ER in hypoxia-resistant breast cancer cells. Eribulin treatment of HR-positive breast cancer may resensitize cells to hormone blockade.

Prognostic Impact of Smoking on Bevacizumab Combination Chemotherapy for Advanced Breast Cancer.

BACKGROUND/AIM: Smoking has been a proven carcinogenic risk factor for various cancers, including breast cancer. Furthermore, smoking has been recognized as a prognostic factor of breast cancer. Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) used in combination with chemotherapy to treat breast cancer. We, herein, investigated the effect of smoking on the prognosis of unresectable breast cancer patients who received bevacizumab plus weekly paclitaxel. PATIENTS AND METHODS: From April 2011 to June 2022, 131 patients received bevacizumab plus weekly paclitaxel for unresectable breast cancer. At their first visit to our hospital, smoking status (i.e., period of smoking and amount of smoking per day) was evaluated by interview, and packs-years were calculated. RESULTS: Time to treatment failure (TTF) was significantly longer in the high packs-years group than the low packs-years group (p=0.010, log-rank). The log-rank test showed that the high packs-years group had a significantly longer overall survival than the low packs-years group (p=0.049, log-rank). Multivariate analysis of TTF revealed that progesterone receptor (p=0.005, HR=0.408) and packs-years (p=0.007, HR=0.391) were independent factors. CONCLUSION: A history of smoking may impact prognosis of combination chemotherapy with bevacizumab for advanced breast cancer treatment.

Factor Analysis of Intraoperative Bleeding Loss and its Impact on Prognosis in Breast Cancer.

BACKGROUND/AIM: Intraoperative blood loss (IBL) during the surgical treatment of various cancers affects complication rates and prognosis. However, few studies have examined the importance of minimal IBL in breast cancer surgery. We used factor analysis to examine the prognostic importance of IBL in breast cancer. PATIENTS AND METHODS: One hundred ninety-seven patients who underwent mastectomy plus axillary lymph node dissection (level II) after preoperative chemotherapy between June 2007 and June 2021 were included. Pearson's Chi-square test was used to confirm the relationships between different factors. Kaplan-Meier survival curves and the log-rank test were used to examine prognosis. Logistic regression was performed using a Cox proportional hazards model. RESULTS: The median IBL was 55.0 g (range=5.0-420.0 g). IBL was <100 g in 143 patients (72.5%), 100-200 g in 39 patients (19.8%), and >200 g in 15 patients (7.6%). Logistic regression analysis showed that patients with IBL ≥200 g had a significantly worse prognosis (disease-free survival: p=0.003, log-rank test; overall survival: p<0.001, log-rank test). Factor analysis revealed that HER2-negative status (p=0.015), non-pathological complete response (p=0.031), obesity (p=0.001), heavy smoking (p=0.047), and diabetes mellitus (p=0.004) were significantly associated with increased IBL. CONCLUSION: IBL in breast cancer was correlated with various clinicopathological factors associated with a poor prognosis, suggesting that increased IBL may be associated with poor prognosis in breast cancer as well.

Clinical Verification on the Predictors for Febrile Neutropenia in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy.

BACKGROUND/AIM: Febrile neutropenia (FN) is a potentially life-threatening complication of chemotherapy. In this study, we evaluated the predictors for FN according to neoadjuvant chemotherapy (NAC) in all breast cancer subtypes. PATIENTS AND METHODS: We examined 327 patients with breast cancer treated with NAC. The correlation between the development of FN and clinicopathological features, including systemic inflammatory markers, and prognosis was evaluated retrospectively. RESULTS: There were no significant differences between patients with and without FN in terms of disease-free survival or overall survival (p=0.562, p=0.149, log-rank, respectively). Low body mass index (BMI) (p<0.001), white blood cells (WBC) at baseline (p=0.008), and NAC regimen (p=0.026) significantly related with FN in all patients with breast cancer. Moreover, among patients with hormone receptor-positive/human epidermal growth factor receptor 2-positive breast cancer, low WBC (p=0.007) and low absolute lymphocyte counts (ALC) at baseline (p=0.039) were significantly associated with FN, and overall survival was significantly worse in patients with FN development (p=0.039, log-rank). CONCLUSION: Poor immune activity-related factors, low ALC or BMI, may be useful to predict the development of FN in patients with breast cancer.

Two families with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): case reports and literature review.

Background: Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), a hereditary gastric polyposis syndrome that presents with fundic gastric polyposis, is associated with an increased risk of gastric adenocarcinoma. The four patterns of point mutation in the adenomatous polyposis coli (APC) promoter 1B region have been identified as the cause of GAPPS. GAPPS was first reported in 2012, and only 33 families with GAPPS have been reported worldwide to date. Therefore, the clinical management for GAPPS are still controversial. We herein report two unrelated GAPPS families with the same point mutation site. Case Description: Total seven patients of two families had >100 carpeting polyps in the gastric body and fundus, and one of them (69-year-old female) had gastric adenocarcinoma. As a result of germline analysis, both families harbored a point mutation (c.-192A>G) in APC promoter 1B region, previously reported in only one family. Three of seven patients underwent total gastrectomy, and others were followed-up with regular esophagogastroduodenoscopy (EGD) and biopsy every 6 months. To summarize the reported cases, total 42 patients of 35 families have developed gastric adenocarcinoma. Conclusions: This report may contribute to determining the appropriate guidelines for the clinical practice of GAPPS. When EGD reveals gastric polyposis localized to the gastric body and fundus, it is important to obtain a detailed family history and perform germline mutational analysis. And more, point mutation type of our family cases was a rare pattern, suggested that c.-192A>G pattern might be a pathogenic variant.

Validation of the Optimum Timing of Assessment of Tumor Infiltrating Lymphocytes During Preoperative Chemotherapy for Breast Cancer.

BACKGROUND/AIM: Tumor microenvironment (TME) assessment is considered to play an important role in the prediction of prognosis and therapeutic response following breast cancer treatment. No consensus has been reached regarding evaluation methods despite reports on the utilization of tumor-infiltrating lymphocytes (TILs) for immune TME (iTME) monitoring. Optimum timing of iTME assessment has not yet been established. PATIENTS AND METHODS: Two hundred thirty-nine patients were treated with neoadjuvant chemotherapy (NAC). During the period from diagnostic needle biopsy to NAC initiation for breast cancer, the optimal evaluation timing was examined using a receiver operating characteristic (ROC) curve analysis. RESULTS: A significant correlation between TILs and pathological complete response (pCR) was only observed in the short-term group (≤35 days) (p=0.033). Prognostic analysis revealed that in the short-term group, patients with high TIL levels had a significantly better survival prognosis relative to those with low TIL levels (>35 days) [disease-free survival (DFS): p=0.001, overall survival (OS): p=0.021]. TILs were identified as an independent factor affecting DFS in a multivariate analysis (p=0.008, hazard ratio=0.130). CONCLUSION: TIL assessment during NAC for breast cancer is a prognostic predictor only when performed at ≤35 days before NAC initiation.

Outcome of sentinel lymph node biopsy in breast cancer using dye alone: a single center review with a median follow-up of 5 years.

PURPOSE: Various techniques are used for sentinel lymph node biopsy (SLNB) in breast cancer. While subareolar injection with dye alone is a relatively easy method, few studies have reported the outcome with a follow-up period. This study presents our results of SLNB using dye alone. METHODS: Between November 2002 and December 2010, 701 patients with breast cancer underwent SLNB using subareolar injection of indocyanine green or indigo carmine. Sentinel lymph node (SLN)-negative patients were followed without axillary lymph node dissection (ALND). RESULTS: SLNs were detected in 654 of 701 patients (93.3%), and the rate increased to 98.1% over the course of the study. The mean number of SLNs removed was 1.5. There was no significant difference in the detection rate between two dyes. No adverse events resulted from the injection of dyes. Of the 654 patients, 136 (20.8%) had SLN metastasis. Five hundred patients were followed without ALND. Thirty-six patients experienced disease relapse during a median follow-up of 60 months. Thirteen patients (2.6%) had regional lymph node relapse, and eight of them could undergo salvage lymph node dissection. The 5-year disease-free and overall survival rates were 92.4 and 96.1 %, respectively. CONCLUSION: SLNB using subareolar injection with dye alone was safe and feasible even after a long follow-up.

Specific subtelomere loss on chromosome der(11)t(3;11)(q23;q23)x2 in anaplastic thyroid cancer cell line OCUT-1.

One of the most aggressive human malignancies, anaplastic thyroid carcinoma (ATC), has an extremely poor prognosis that may be explained by its genomic instability. We hypothesized that the very rapid cell turnover observed in ATC might accelerate telomere shortening and chromosomal instability associated with tumor cell malignancy. To compare and measure chromosomal aberrations and telomere shortening in the anaplastic thyroid cancer cell line OCUT-1, we applied quantitative fluorescence in situ hybridization (Q-FISH) techniques. In all 15 metaphases studied, telomere length estimates from Q-FISH of chromosomes in ATC were shorter than those of a fibroblast cell line derived from the stroma adjacent to the carcinoma. OCUT-1 cells display several chromosomal abnormalities, but have a near-normal chromosome complement of 46, XX, making it easy to analyze the karyotype. The karyotype showed 50, XX, +7, +11, der(11)t(3;11)(q23;q23)x2, del(12)(p11.2p12), +20, +1mar. We analyzed carefully the abnormalities in karyotype of OCUT-1 associated with telomere shortening on each chromosome and expression of subtelomeres. Telomere lengths in the q-arms of the abnormal chromosome del(12)(p11.2p12) were shorter than the average length in the q-arms of the normal chromosome 12 in OCUT-1. Subtelomeres on the abnormal chromosome der(11)t(3;11)(q23;q23)x2 also showed loss of signals on 11p, but there was no loss of signals in the cytogenetically normal trisomies 7 and 20 or the abnormal chromosome del(12)(p11.2p12). Subtelomeres of 3q had eight signals, one pair remaining in place on 3q and another pair on the abnormal 11p. Our findings suggest that telomere shortening and subtelomere loss are correlated with genetic instability in this anaplastic thyroid carcinoma cell line.

Telomerase activation and expression of its catalytic subunits in benign and malignant tumors of the parathyroid.

PURPOSE: Telomerase activity (TA) has been extensively studied in tumors of many organs, but not the parathyroid gland. Therefore, we investigated TA in parathyroid tumors, and examined the mRNA expression of its catalytic subunits. METHODS: We examined 17 single adenomas, one hyperplastic parathyroid gland, and one metastatic parathyroid cancer and quantified TA by fluorescence-based TRAP analysis. We also studied the expression of telomerase catalytic subunits in nine adenomas and one cancer by reverse transcription - polymerase chain reaction (RT-PCR) analysis. RESULTS: Telomerase activity was not detected in any of the adenomas or the hyperplastic gland; however, the metastatic cancer was highly positive for TA. Both human telomerase RNA ( hTR) and human telomerase-associated pretein (hTEP-1) mRNA were detected universally in every specimen tested. Conversely, human telomerase reverse transcriptase (hTERT) mRNA was not detected by the conventional electrophoresis-based technique. Faint expression of hTERT mRNA was detected by real-time RT-PCR only in the sample of parathyroid cancer. DISCUSSION: We hypothesize that TA plays a role in the malignant transformation of parathyroid disease and suggest that hTERT mRNA expression could be the key step for TA as in other malignancies. Telomerase activity and hTERT may be useful molecular targets of parathyroid cancer.

Peroxisome proliferator-activated receptor gamma activation induces cell cycle arrest via the p53-independent pathway in human anaplastic thyroid cancer cells.

Anaplastic thyroid carcinoma is one of the most aggressive human malignancies. Outcomes of intensive multimodal therapy have been far from satisfactory. Furthermore, p53 gene dysfunction, often found in this type of cancer, is known to impair the efficacy of the therapeutic agents. Specific ligands for peroxisome proliferator activated receptor gamma (PPAR-gamma) induce growth suppression in some tumor cells. In this study, we investigated the role of PPAR-gamma in anaplastic thyroid cancer cell lines (OCUT-1, ACT-1). PPAR-gamma was expressed and functional in both cell lines. Activation of PPAR-gamma with its specific ligands, troglitazone and 15-deoxy-delta 12,14-prostaglandin J2, inhibited cell growth in a dose-dependent manner through inducing G1 cell cycle arrest. P53 protein expression differed in OCUT-1 and in ACT-1, though the levels stayed constant irrespective of ligand exposure in both cell lines. In contrast, p21 and p27 proteins were induced in a dose-dependent manner in both situations. This study showed that PPAR-gamma ligands were able to induce growth suppression in anaplastic thyroid cancer cells via a p53-independent, but p21- and p27-dependent cytostatic pathway. These tumor-suppressive effects of PPAR-gamma may provide a novel approach to the treatment of anaplastic thyroid cancer.

Establishment and characterization of OCUT-1, an undifferentiated thyroid cancer cell line expressing high level of telomerase.

BACKGROUND & OBJECTIVES: Undifferentiated thyroid cancer is one of the most aggressive human malignancies, and the prognoses that have been reported are extremely poor. A number of studies have described the clinicopathologic features of this tumor and analyzed its biologic background to explain the extraordinarily aggressive nature of the tumor. Still the mechanism of cellular aggressiveness in undifferentiated thyroid cancer is not yet fully understood. METHODS: We established and characterized an undifferentiated thyroid cancer cell line, OCUT-1, derived from the surgical specimen obtained from a 74-year-old Japanese woman with advanced undifferentiated thyroid cancer. RESULTS: The cell line had already maintained over 100 passages and was stably cultured for more than a year. The cell line was observed to maintain not only its morphologic similarity to the primary cancer cells, but also its aggressive nature, including high proliferative activity, numerous genetic abnormalities, and cytokine production. Further, we have demonstrated the expression of telomerase activity in the cell, which could represent one of the responsible mechanisms for the cellular aggressiveness of this type of tumor. CONCLUSIONS: This cell line might be useful for further study concerning the correlation between telomerase activation and disease progression or anaplastic change in thyroid cancer.