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Cervical cancer is a common gynecologic malignancy worldwide. It is the fourth for both incidence and mortality. For cervical cancer, imaging and pathology assessments are incorporated in the revised 2018 Federation of Gynecology and Obstetrics (FIGO) staging system. Uses of imaging techniques for the pre-treatment work-up of cervical cancer have been increasing. Among imaging techniques for the evaluation of cervical cancer, ultrasound is cheaper, faster and widely available than other imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI). Advanced technique in ultrasound, such as three-dimension (3D) ultrasound and color Doppler, have improved the clinical application of ultrasound in cervical cancer. Ultrasound may provide highly accurate information on detecting tumor presence and evaluating local tumor extent if performed by ultrasound-trained gynecologists; the experience of readers is also critical for correct pretreatment staging and assessment of response to treatment. Sonographic images could be useful to predict response of neoadjuvant chemotherapy, radiotherapy, chemotherapy and concurrent chemoradiotherapy in patients with cervical cancer. This review article attempted to present the most updated specific applications of ultrasound in cervical cancer.

Dioscorea nipponica Makino has been used for the treatment of chronic bronchitis, rheumatoid arthritis, cough, and asthma. Several studies have established the antitumor effect of D. nipponica Makino extract (DNE). However, no investigations have considered the antimetastatic potential of DNE in cervical cancer cells. The present study examined the effects of DNE on cervical cancer cells treated with 12-O-tetradecanoylphorbol-13-acetate and characterized the possible molecular mechanisms. MTT assay results indicated that DNE exhibited very low cytotoxicity, and DNE significantly reduced the invasion and migration abilities of cervical cancer cells. Gelatin zymography analysis revealed that DNE significantly inhibited matrix metalloproteinase-9 (MMP-9) activity. Reverse transcription-polymerase chain reaction assay results revealed that DNE treatment inhibited the MMP-9 mRNA levels of HeLa and SiHa cells. Western blot results revealed that DNE significantly diminished the ERK1/2 phosphorylation. In conclusion, we revealed that the antimetastatic effects of DNE on cervical cancer cells are due to its inhibition of MMP-9 expression through the ERK1/2 pathway.

The purposes of the investigation were to examine the implications of long noncoding RNA growth arrest-specific transcript 5 (GAS5) in progression and clinicopathological factors of uterine cervical cancer, and patient survival in Taiwan. Genotypic distributions of two GAS5 genetic variants rs145204276 and rs55829688 were detected in 208 patients including 111 patients with invasive cancer, 97 with precancerous lesions as well as 307 control women using real-time polymerase chain reaction. It explored that patients with cervical precancerous lesion had lower rate of AGGCA deletion (Del) in both alleles (Del/Del) of GAS5 rs145204276 as compared with control women. Patients with invasive cancer did not exhibit higher rate of Del/Del. Meanwhile, there were no different genotypic distributions in rs55829688 among patients with cervical invasive cancer and those with precancerous lesions as well as control women. Moreover, cervical cancer patients with Ins (insertion, AGGCA)/Del and Del/Del (-/-) in GAS5 rs55829688 tended to have poorer hazard ratio (HR) of 5 years survival. In addition, lymph node metastasis status exerted the most significantly predictive of 5 years survival rate. Conclusively, GAS5 polymorphism rs145204276 is probably applicable to predict 5 years survival HR of cervical cancer patients. However, the mechanism elucidating the methylation status and transcription function of rs145204276 in uterine cervical cancer needs to be delineated for its unique implication in uterine cervical cancer.

Objective Symmetrical peripheral gangrene (SPG) is an uncommon but important clinical syndrome. We present a case of acute chorioamnionitis complicated with SPG. Case report A 33-year-old female (gravida 5, para 2) was admitted with preterm premature rupture of membranes (PPROM) at 20 weeks and four days of gestation. She received cervical cerclage four days ago. Seven days after the diagnosis of PPROM, she developed fever, tachypnea and tachycardia. Termination of pregnancy was decided for clinical diagnosis of sepsis. After the abortus was born, gangrene change on the nose was noticed. Afterwards, this patient developed acrocyanosis of extremities. SPG developed following sepsis with intravascular disseminated coagulation (DIC). After intensive care, the patient underwent hyperbaric oxygen therapy and fasciectomy of the left forearm. Conclusion We suggest awareness of SPG associated with acute chorioamnionitis. Early recognition of SPG, multidisciplinary care, and treatment of its underlying conditions are the mainstays of management.

Simple Summary Recent studies have shown that metformin combined with clinical chemotherapeutic drugs could cause decreased cell toxicity and attenuate tumor resistance in various types of cancer. The aim of the present study was to elucidate whether combined treatment with metformin and everolimus has a synergistic anticancer effect in human cervical cancer in vitro and in vivo. The results showed that this combined treatment synergistically inhibited the growth of human cervical cancer cell lines and xenografts in nude mice, and induced caspase-dependent apoptosis, promoting sub-G1- and G0/G1-phase arrest and enhancing mtROS production. Combined treatment also synergistically inactivated PI3K/AKT signaling and activated MAPKs signaling in cervical cancer. Our data suggested that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combined treatment provides a novel therapeutic strategy for patients with cervical cancer. Abstract Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.

Simple Summary The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. Metformin exerts anticancer effects, alone or in combination with other agents, on cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Abstract Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

Pancreatic cancer is the seventh leading cause of cancer-related deaths globally. Metformin is the standard first-line of treatment for hyperglycemia in Type 2 diabetes, whereas pitavastatin is a cholesterol-lowering drug used to prevent cardiovascular diseases. Both these agents evidently exert anticancer effects on pancreatic cancer; however, it remains unclear whether cotreatment using them has additive or synergistic anticancer effects on pancreatic cancer. Thus, we herein used the ASPC-1 and PANC-1 cells and treated them with metformin and/or pitavastatin. We performed the cell viability assay, transwell migration assay, and cell cycle analysis using flow cytometry. Western blotting was used to determine protein levels. We found that cotreatment with metformin (30 mM) and pitavastatin (10 μM) significantly reduced cell viability; caused G0/G1 cell cycle arrest; upregulated the expression levels of Bax, PCNA, cleaved PARP-1, cleaved caspase-3, LC3 II, and p27 Kip1 /p21Cip1 ; and inhibited cell migration. The combination index value for cell viability indicated a synergistic interaction between metformin and pitavastatin. Moreover, cotreating the cells with metformin (30 mM) and pitavastatin (10 μM) could preserve mitochondrial function, activate AMPK, and inhibit PI3K/mTOR than treatment with metformin or pitavastatin alone. These findings clearly indicated that metformin plus pitavastatin had a synergistic anticancer effect on pancreatic cancer cells, potentially caused due to the activation of AMPK and inhibition of PI3K/mTOR signaling. Altogether, our results provide that use of metformin plus pitavastatin maybe serve as a chemotherapeutic agent for human pancreatic cancer in future.

Simple Summary Carbonic anhydrase IX (CAIX) is a hypoxia-induced protein that is highly expressed in numerous human cancers. However, the molecular mechanisms involved in CAIX and human cervical cancer metastasis remain poorly understood. Our study found that CAIX overexpression increases PFKFB4 expression and EMT, promoting cervical cancer cell migration. CAIX could contribute to cervical cancer cell metastasis and its inhibition could be a cervical cancer treatment strategy. Abstract Carbonic anhydrase IX (CAIX) is a hypoxia-induced protein that is highly expressed in numerous human cancers. However, the molecular mechanisms involved in CAIX and human cervical cancer metastasis remain poorly understood. In this study, CAIX overexpression in SiHa cells increased cell migration and epithelial-to-mesenchymal transition (EMT). Silencing CAIX in the Caski cell line decreased the motility of cells and EMT. Furthermore, the RNA-sequencing analysis identified a target gene, bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB4), which is influenced by CAIX overexpression and knockdown. A positive correlation was found between CAIX expression and PFKFB4 levels in the cervical cancer of the TCGA database. Mechanistically, CAIX overexpression activated the phosphorylation of extracellular signal-regulated kinases (ERKs) to induce EMT and promote cell migration. In clinical results, human cervical cancer patients with CAIXhigh/PFKFB4high expression in the late stage had higher rates of lymph node metastasis and the shortest survival time. Our study found that CAIX overexpression increases PFKFB4 expression and EMT, promoting cervical cancer cell migration. CAIX could contribute to cervical cancer cell metastasis and its inhibition could be a cervical cancer treatment strategy.

Human cervical cancer is the fourth most common malignancy among women worldwide, and it is expected to result in 460,000 deaths per year by 2040. Moreover, patients with cervical cancer often display drug resistance and severe side effects; therefore, the development of effective novel chemotherapeutic agents is important. In the present study, the effects of metformin, a first‑line therapeutic drug for type 2 diabetes mellitus, were evaluated in cervical cancer. Compared with the control group, metformin significantly inhibited cell viability and migration, and induced apoptosis and cell cycle arrest in human cervical cancer cell lines (CaSki and HeLa). Following metformin treatment, the protein expression levels of p‑AMP‑activated protein kinase (p‑AMPK), which promotes cell death, and the tumor suppressor protein p‑p53 were remarkably upregulated in CaSki and C33A cells compared with the control group. Furthermore, compared with the control group, metformin significantly suppressed the PI3K/AKT signaling pathway in CaSki, C33A and HeLa cells. Compound C (an AMPK inhibitor) significantly reversed the effects of metformin on CaSki, C33A and HeLa cell viability, and AMPK and p53 phosphorylation. The results of the present study suggested that metformin induced AMPK‑mediated apoptosis, thus metformin may serve as a chemotherapeutic agent for human cervical cancer.

To our knowledge, no study investigates the association of genetic variant distributions of WW domain-containing oxidoreductase (WWOX) gene with development of invasive cancer, clinicopathologic variables and patient survival in uterine cervical cancer for Taiwanese women. We therefore conducted this study to explore the clinical involvements of WWOX single nucleotide polymorphisms (SNPs) in cervical cancer. One hundred and thirty-one patients with cervical invasive cancer and 93 patients with precancerous lesions as well as 316 control women were consecutively enrolled. The genotypic frequencies of WWOX genetic variants rs73569323, rs383362, rs11545028, rs3764340 and rs12918952 were determined by real-time polymerase chain reaction. The results revealed that only WWOX SNP rs3764340 was associated between patients with cervical invasive cancer and normal controls among 5 WWOX genetic variants. Cervical cancer patients with genotypes GA/AA in WWOX SNP rs12918952 were associated with parametrium invasion and pelvic lymph node metastasis. Univariate analysis found that WWOX SNPs rs73569323 and rs11545028 were associated with patient survival, whereas multivariate analysis revealed CT/TT in rs11545028 was the only genetic variant, which could predict better overall survival, among 5 WWOX SNPs in Taiwan. In conclusion, Taiwanese women with CG/GG in WWOX SNP rs3764340 are susceptible to cervical invasive cancer. Cervical cancer patients with GA/AA in rs12918952 tend to have more risk to develop parametrium invasion and pelvic lymph node metastasis. Among 5 WWOX SNPs, rs11545028 is the only genetic variant associated with patient survival, in which CT/TT could predict better overall survival in Taiwanese women.

Angiomyofibroblastoma (AMF) is a distinctive, rare, benign mesenchymal tumor that often occurs in the lower genital region of women. The most commonly reported location of an AMF is in the vulvovaginal area. We describe a rare case of an AMF located in the broad ligament in a 47-yr-old woman. The patient experienced menorrhagia, dysmenorrhea, and subsequent menstrual spotting. She sought help at the National Cheng Kung University Hospital. Ultrasonography showed an echo-complex mass in the left adnexal area. The patient underwent laparoscopic surgery to remove the soft tissue mass located in the left broad ligament. The final pathology of the mass was reported as an AMF. We reviewed all of the AMF cases reported in the English-language literature found in Pubmed. This case is the first of AMF located in the broad ligament.

Matrix metalloproteinases (MMPs) play a major role in extracellular matrix remodeling and are involved in tumor cell invasion. Cancers such as childhood leukemia are characterized by their capacity to infiltrate different organs. MMP production by leukemic cells may indicate a leukemic subtype or subpopulation with a more invasive phenotype. Therefore, clarifying the action mechanisms of MMPs as prognostic predictors or MMP targeting as a therapeutic strategy is necessary. MMP-targeting drugs have been developed for the treatment of hematological malignancies. In this review, we highlight current advances in understanding the molecular mechanisms and pathological characteristics of various MMPs, as well as recent therapeutic advances targeting MMPs in childhood leukemia. Several studies have been conducted on the therapeutic efficacy of MMP inhibitors in cancer, such as collagen peptidomimetics, nonpeptidomimetic inhibitors of MMP active sites, bisphosphonates, and tetracycline derivatives. Here, we conclude that more clinical trials are necessary to estimate the role of selective MMP inhibitors in the treatment and prevention of childhood leukemia.

Cervical cancer is a global health issue and places a considerable economic and medical burden on society. Thus, a concerted effort to improve the treatment of cervical cancer is warranted. Although several treatment options are currently available for treating patients with cervical cancer, such as chemoradiation and neoadjuvant or adjuvant chemotherapy, more aggressive systemic therapies and newer therapeutic agents are under investigation. Medicinal herbs have long been used to treat diseases. In this review, we summarize studies analyzing the antitumor effects and underlying mechanisms of Chinese herbal medicines, including the effects of crude extracts and compounds in vitro or in animal models for inducing apoptosis and inhibiting invasion or metastasis. Chinese herbal medicines with therapeutic targeting, such as those that interfere with tumor growth and progression in cervical cancer, have been widely investigated. To apply Chinese herbal medicine in the treatment of cervical cancer, adequate clinical studies are required to confirm its clinical safety and efficiency. Further investigations focused on the purification, pharmacokinetics, and identification of compounds from Chinese herbal medicines in cervical cancer treatment are necessary to achieve the aforementioned treatment goals.

Purpose: The aim of the study was to determine the association between pelvic inflammatory disease (PID) and breast, colorectal, gynecologic and urinary tract cancer. Methods: The source of data was a longitudinal dataset compiled by the Longitudinal Health Insurance Database 2000 (LHID2000) which was collected by the National Health Insurance program. Cases of PID, at least two outpatient visits and one admission, were diagnosed from 2000 to 2013. The data for controls, age matched women who were not diagnosed with PID from 2000 to 2013, were also obtained. Results: A total of 47,333 PID cases and 189,332 for control group were included in the study. The ectopic pregnancy incidence rate (per 10000 person months) was 1.912 and 0.595 in the PID and control group, respectively; the rate ratio was 3.211 (confidence interval, CI = 2.931-3.519). There were significantly different in gynecologic cancers and urinary tract cancers between the PID and control group; the rate ratios (95% C.I.) were 1.903 (1.672-2.166) and 1.566 (1.211-2.025), respectively. Conclusion: Our study found that PID was associated with increased risks of gynecologic and urinary tract cancer but not colorectal or breast cancer. The information may lead to a strategy for cancer prevention and a reasonable healthcare usage through understanding PID epidemiology and controlling the inflammatory responses.

The effects of Terminalia catappa leaf extracts (TCE) have been widely investigated, including its antioxidative, anti-inflammatory, and antidiabetic activity, as well as its antimetastatic effects on several types of human cancer. However, no study has examined the antimetastatic potential of TCE in cervical cancer cells. This study aimed to elucidate the potential antimetastatic properties of ethanol extracts of Terminalia catappa in 12-O-tetradecanoylphorbol-13-acetate treated human cervical cancer cells and investigate the signaling pathway of this process. We demonstrated that TCE elicited very low cytotoxicity and significantly inhibited cellular migration and invasion in human HeLa and SiHa cervical cancer cells. Moreover, the gelatin zymography, reverse transcription-polymerase chain reaction (RT-PCR), and real-time PCR analysis revealed that the activity and mRNA level of matrix metalloproteinase-9 (MMP-9) were inhibited by TCE in a concentration-dependent manner. The Western blot results demonstrated that the highest concentration of TCE (100 μg/ml) reduced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) by 46% in the HeLa cell lines. In conclusion, it was revealed that TCE exerted antimetastatic effects on cervical cancer cells by inhibiting the expression of MMP-9 through the ERK1/2 pathway.

To date, few studies have explored the effects of single nucleotide polymorphisms (SNPs) of the receptor for advanced glycation end products (RAGE) in uterine cervical cancer. Therefore, we conducted this study to investigate the involvement of RAGE SNPs in cervical cancer. In total, 117 patients with cervical invasive cancer, 84 with precancerous lesions, and 320 normal women were recruited consecutively. Real-time polymerase chain reaction was used to examine the genotypic frequencies of RAGE SNPs. The results indicated that among the four RAGE SNPs, only the GT/TT genotype of rs184003 was distributed differently between patients with cervical neoplasias and the normal controls, with GG as a reference. Moreover, cervical cancer patients with genotypes TA/AA in rs1800624 exhibited a lower risk of parametrium invasion, moderate-to-poor cell differentiation, and pelvic lymph node metastasis. In conclusion, RAGE SNPs rs1800624 was associated with some clinicopathological variables in cervical cancer.

Up to date, no study explores the relationship of single nucleotide polymorphisms (SNPs) of long non-coding RNAs HOTAIR (lncRNAs HOTAIR) with cancer recurrence and patient survival in uterine cervical cancer for Taiwanese women. We therefore designed this study to investigate the clinical roles of lncRNAs HOTAIR SNPs in cervical cancer. One hundred and sixteen patients with cervical invasive cancer and 96 patients with preinvasive lesions as well as 318 control women were consecutively recruited. LncRNAs HOTAIR SNPs rs920778, rs12427129, rs4759314 and rs1899663 were analyzed and their genotypic frequencies were examined by real-time polymerase chain reaction. The results indicated that there were no genotypic differences between patients with cervical neoplasia and normal controls as well as among patients with invasive and invasive cancer, and normal controls. However, genotype GG in lncRNAs HOTAIR SNP rs920778 was demonstrated to be a predictor for poorer cancer recurrence probability [p=0.001, hazard ratio (HR): 7.25, 95% CI: 2.19-23.96]. Furthermore, cervical cancer patients with genotype GG in lncRNAs HOTAIR rs920778 had worse overall survival (p=0.002, HR: 7.22, 95% CI: 2.09-24.92). No significant associations exhibited between lncRNAs HOTAIR SNP rs920778 and clinicopathological parameters. In conclusion, this studied lncRNAs HOTAIR SNPs are not associated with cervical carcinongensis. However, lncRNAs HOTAIR SNP rs920778 may be regarded as an independent predictor of cancer recurrence probability and overall survival in cervical cancer patients.

The treatment of cancer is an important issue in both developing and developed countries. Clinical use of ultrasound in cancer is not only for the diagnosis but also for the treatment. Focused ultrasound surgery (FUS) is a noninvasive technique. By using the combination of high-intensity focused ultrasound (HIFU) and imaging method, FUS has the potential to ablate tumor lesions precisely. The main mechanisms of HIFU ablation involve mechanical and thermal effects. Recent advances in HIFU have increased its popularity. Some promising results were achieved in managing various malignancies, including pancreas, prostate, liver, kidney, breast and bone. Other applications include brain tumor ablation and disruption of the blood-brain barrier. We aim at briefly outlining the clinical utility of FUS as a noninvasive technique for a variety of types of cancer treatment.

Background Phloretin, a dihydrochalcone flavonoid, possesses anti-inflammatory activity and inhibits the growth of various cancers. However, the flavonoid's effect on cervical cancer metastasis and angiogenesis remains unknown. Purpose In this study, we provide molecular evidence associated with the antimetastatic and antiangiogenic effects of phloretin. Methods In this study, the anti-invasive effect of phloretin (0–60 μM) in cervical cancer cells was evaluated using the Matrigel invasion assay, gelatin zymography, cell-matrix adhesion assay, wound healing assay, and Western blotting. Antiangiogenic potential of phloretin (0–100 μM) was assessed by the Matrigel tube formation assay. The in vivo antitumor effect of phloretin (10 or 20 mg/kg) was fed by oral gavage and determined using subcutaneous inoculation and tail vein injection in immunodeficient nude mice. Results Phloretin (60 μM) showed marked suppression of invasion and migration through downregulation of matrix metalloproteinase (MMP)-2, MMP-3, and cathepsin S in human SiHa cervical cancer cells. Phloretin (60 μM) reversed the epithelial-mesenchymal transition induced by transforming growth factor-β1 and downregulated mesenchymal markers, such as fibronectin, vimentin, and RhoA. Phloretin (100 μM) treatment significantly inhibited the aldehyde dehydrogenase 1 activity of SiHa cells, reduced the self-renewal properties and stemness signatures of CD44 and Sox-2 in sphere-forming cervical cancer-derived tumor-initiating cells, and inhibited the invasion, MMP-2 activity, and tube formation capacity of human umbilical vein endothelial cells. The ability of phloretin (20 mg/kg) to suppress lung metastasis and tumor growth in SiHa cells was evidenced by tail vein injection and subcutaneous inoculation in a tumor xenograft model. Conclusion In summary, the findings indicate that phloretin inhibits the metastatic and angiogenic abilities and cancer stemness of SiHa cells, thereby suggesting that this flavonoid is a promising therapeutic agent for the treatment of human cervical cancer cells.

Background: Our study aimed to assess the endometrial cancer risk after tamoxifen adjuvant treatment for female breast cancer patients in Taiwan. Materials and Methods: A total of 74,280 breast cancer patients between January 1997 and December 2004 were included in the study; 39,411 received tamoxifen treatment and 34,869 did not. Tamoxifen-associated endometrial cancer was defined as endometrial cancer that occurred in patients at least 6-month after the diagnosis of breast cancer, who underwent tamoxifen treatment. Results: A total of 222 patients developed endometrial cancer, and of these,153 (69 %) were seen in patients with tamoxifen treatment, and 69 (31%) were seen in patients without the use of tamoxifen. The incidence of endometrial cancer was 0.388% (153/39,411) in patients with tamoxifen treatment, while was 0.198% (69/34,869) in patients without tamoxifen treatment. Logistic regression analysis demonstrated that tamoxifen use and age over 35 years were significantly correlated with development of endometrial cancer (p

Background: The direct impact of medical expenses on breast cancer incidence and mortality rate has not been sufficiently addressed. The purpose of this study is to investigate the potential correlation between the incidence and mortality rate of breast cancer and the medical expenses in Taiwan. Materials and Methods: Breast cancer cases were identified from the National Health Insurance Research Database (NHIRD) with corresponding to International Classification of Diseases, and the Ninth Revision (ICD-9) code 174, 1740-1749, 175, 1750 and 1759 from January 1999 to December 2006. Age-specific incidences were estimated by population data obtained from the Department of Statistics, Ministry of the Interior. Medical expenses, including outpatient and inpatient services, were also retrieved from the NHIRD. Results: The incidence increased from 20.06 per 100,000 in 1999 to 30.34 per 100,000 in 2006; the total expenses increased from 1,449,333,521 in 1999 to 4,350,400,592 Taiwan dollars in 2006. The age-standardized mortality rate for female breast cancer remained essentially unchanged, while the age-standardized incidence increased steadily (except 2002-2003). Among the top 20 coexisting ICD-9 codes for expenses, four are directly on cancers, while 16 are on other diseases or symptoms, which are not necessarily caused by breast cancer. Conclusions: Significantly increased medical expenditure on breast cancer failed to bring down its mortality and incidence rate. The finding has implications for healthcare policy planners in proposing strategies for breast cancer control and allocating the resources.

Background : Our previous studies revealed that leukocyte infiltration into aged or injured myoepithelial cell layers is a key trigger for breast tumor invasion and metastasis. Our current study further assessed the possibility that leukocyte aggregates may harbor detached individual tumor cell or clusters of tumor cells. Materials and methods : Tissue sections from patients with pregnancy-associated breast cancer (PABC) and controls were subjected to morphological and immunohistochemical assessment with a panel of leukocyte and tumor cell related markers. Results : A total of 63 leukocyte aggregates were detected in the 20 PABC cases studied. Of these, 55 (87%) were distributed within normal or hyperplastic lobules adjacent to invasive lesions. Over 70% of these leukocyte aggregates harbored detached individual tumor cell or cell clusters with malignant properties, including strong p53 positivity, elevated proliferation, reduced cell surface adhesion molecules, and cytological resemblance to adjacent invasive cancer cells. A significant number of these tumor cells or condensed chromosomes of mitotic tumor cells were observed to conjoin with the plasma membrane of leukocytes. Similar alterations were seen in leukocyte aggregates within the inter-lobular space and in non-PABC with a lower frequency. Conclusions : These findings suggest that leukocyte infiltration may trigger dissemination of tumor cells from their primary site, and that leukocyte aggregates may serve as a reservoir for disseminated tumor cells that may be physically dragged to distant sites by leukocytes during their migration.

Antenatal clinical breast examinations (ANCBEs) performed by physicians or nurses during prenatal care visits are recommended by the Department of Health in Taiwan. This study aimed to assess the level of acceptance of ANCBE in Taiwan and the determinants associated with behavior toward them. This was a clinic-based study conducted from 30 November 2008 to 30 April 2009 by using a structured questionnaire for 492 pregnant women. Only 2.8% of the patients received ANCBE, and 95.9% were not aware of the availability of ANCBE. History of breast surgery and awareness of ANCBE availability were significantly associated with receiving ANCBE ( P < .001). Furthermore, multiparity was statistically different for the awareness of ANCBE availability ( P = .04). Acceptance of ANCBE was determined by personal history of breast surgery and awareness of ANCBE availability.

Invasive lobular cancer (ILC) tends to be significantly larger in size with significantly more positive lymph nodes, whereas ILC has a significantly more favorable outcome, compared to stage-matched invasive ductal carcinoma (IDC). The mechanism accounting for such differences remains elusive. Based on morphological, immunohistochemical, and molecular studies of over 1,000 cases of human breast cancers, we hypothesize that the differences may result from the structural and/or functional differences of their surrounding myoepithelial cell layers, which dictate lobular and ductal tumor cells to follow different pathways of invasion or metastasis. The background, rationale, supportive data, and implications of our hypothesis are presented and discussed.

Our previous studies revealed that a single Wilms' tumor 1 (WT-1) immunohistochemistry can be used to elucidate both the myoepithelial cells and blood vessels of human breast tumors. As the human ovary is rich in blood vessels, and WT-1 has been used as a biomarker for ovarian tumors, our current study attempted to assess if a single WT-1 immunohistochemistry has dual usages in evaluation of ovarian tumor and endothelial cells. Paraffin-embedded tissue sections were prepared from 20 cases of ovarian tumors. A set of four consecutive sections from each case were subjected to immunohistochemistry with a mouse monoclonal antibody against the human WT-1 protein, a well defined ovarian tumor marker, CA-125, and a endothelial cell phenotypic marker, CD34, respectively. From each case, 4-5 randomly selected fields were photographed, and expression of these molecules in the same structures were compared. Distinct WT-1 immunoreactivities were seen in both ovarian tumor and endothelial cells. Over 90% of WT-1 positive tumor and endothelial cells were positive for CA-125 and CD34, respectively. Similarly, over 90% of CA-125 or CD34 positive cells co-express WT-1 in tumor or endothelial cells, respectively. Our findings suggest that a single WT-1 immunohistochemistry can be used to assess both the tumor cells and micro-vascular density in ovarian tumors. Our findings also suggest that as WT-1 is expressed in both tumor and endothelial cells, the development of therapeutic agents to target WT-1 may provide an effective treatment option for ovarian cancer.

Our previous studies revealed that pregnancy associated breast cancer (PABC) had significantly reduced nuclear p63 expression in myoepithelia, while intense cytoplasmic p63 expression in associated epithelia. Our current study assessed these epithelia using immunohistochemistry with a panel of aggressiveness and invasiveness related markers and comparative genomic hybridization (array-CGH) with over 30,000 DNA probes. These epithelia showed several unique alterations, including (1) immunohistochemical and morphological resemblance to invasive cancer, (2) significant gain in copy numbers of DNA coding genes for morphogenesis, angiogenesis, and metastasis, and (3) significant loss in copy numbers of DNA coding genes for tumor suppressors, cell adhesion, and macromolecular complex assembly or intra-cellular trafficking. Detected array-CGH alterations correlated well with in vivo expression of a number of corresponding proteins tested. These findings suggest that aberrant sub-cellular localization of p63 expression in normal or hyperplastic appearing epithelial cells may significant contribute to increased invasiveness and aggressiveness of these cells.

Human breast cancer represents a group of highly heterogeneous lesions consisting of about 20 morphologically distinct subtypes with substantially different molecular and/or biochemical signatures, clinical courses, and prognoses. This study analyzed the possible correlation between the morphological presentations of breast cancer and two hypothesized models of carcinogenesis, in order to identify the intrinsic mechanism(s) and clinical implications of breast cancer heterogeneity.

This study assessed the accuracy of three-dimensional (3-D) power Doppler ultrasound in differentiating between benign and malignant breast tumors by using a support vector machine (SVM). A 3-D power Doppler ultrasonography was performed on 164 patients with 86 benign and 78 malignant breast tumors. The volume-of-interest (VOI) in 3-D ultrasound images was automatically generated from three rectangular regions-of-interest (ROI). The vascularization index (VI), flow index (FI) and vascularization-flow index (VFI) on 3-D power-Doppler ultrasound images were evaluated for the entire volume area, computer extracted VOI area and the area outside the VOI. Furthermore, patient's age and VOI volume were also applied for breast tumor classifications. Each ultrasonography in this study was classified as benign or malignant based on the features using the SVM model. All the tumors were sampled using k-fold cross-validation (k = 10) to evaluate the diagnostic performance with receiver operating characteristic (ROC) curves. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of SVM for classifying malignancies were 94%, 69%, 73%, 92% and 81%, respectively. The classification performance in terms of A z value for the ROC curve of the features derived from 3-D power Doppler is 0.91. This study indicates that combining 3-D power Doppler vascularity with patient's age and tumor size offers a good method for differentiating benign andmalignant breast tumors. (E-mail: ylhuang@thu.edu.tw (Y.-L.H.); darren_chen@cch.org.tw (D.-R.C.))

Objective: Logistic regression analysis (LRA), Support Vector Machine (SVM) and a neural network (NN) are commonly used statistical models in computeraided diagnostic (CAD) systems for breast ultrasonography (US). The aim of this study was to clarify the diagnostic ability of the use of these statistical models for future applications of CAD systems, such as three-dimensional (3D) power Doppler imaging, vascularity evaluation and the differentiation of a solid mass. Materials and Methods: A database that contained 3D power Doppler imaging pairs of non-harmonic and tissue harmonic images for 97 benign and 86 malignant solid tumors was utilized. The virtual organ computer-aided analysis-imaging program was used to analyze the stored volumes of the 183 solid breast tumors. LRA, an SVM and NN were employed in comparative analyses for the characterization of benign and malignant solid breast masses from the database. Results: The values of area under receiver operating characteristic (ROC) curve, referred to as Az values for the use of non-harmonic 3D power Doppler US with LRA, SVM and NN were 0.9341, 0.9185 and 0.9086, respectively. The Az values for the use of harmonic 3D power Doppler US with LRA, SVM and NN were 0.9286, 0.8979 and 0.9009, respectively. The Az values of six ROC curves for the use of LRA, SVM and NN for non-harmonic or harmonic 3D power Doppler imaging were similar. Conclusion: The diagnostic performances of these three models (LRA, SVM and NN) are not different as demonstrated by ROC curve analysis. Depending on user emphasis for the use of ROC curve findings, the use of LRA appears to provide better sensitivity as compared to the other statistical models.

Purpose The authors assessed the characteristics of benign and malignant solid breast tumors in harmonic three-dimensional (3D) power Doppler imaging and proposed decision models to classify benign and malignant breast tumors. Materials and methods A total of 86 malignant and 97 benign harmonic 3D power Doppler US images were analyzed. All the harmonic 3D power Doppler images were obtained using a Voluson730 US system (GE, Zipf, Austria) equipped with a RSP 6–12 transducer and tissue harmonic imaging modalities. Imaging analysis was performed using the Virtual Organ Computer-aided Analysis (VOCAL)-imaging program. Histogram indices, the vascularization index (VI), flow index (FI) and vascularization-flow index (VFI), were calculated for the intra-tumor and for shells with an outside thickness of 3 mm surrounding the breast tumors. The receiver operating characteristic (ROC) curves were calculated to estimate the diagnostic performances. Results The results revealed that the choice of decision model comprised the parameters of patient age, intra-tumor VI, and tumor volume to classify benign and malignant breast tumors. The area under the ROC curve (Az) was 0.910, accuracy was 81.4%, and sensitivity and specificity were 81.4% and 81.4%, respectively. The parameter intra-tumor VI was the choice for all of the histogram indices in differentiating between malignant and benign lesions. Conclusion The decision model, which was composed of patient age, tumor volume and intra-tumor VI, and a cut-off value for intra-tumor VI at the upper end of patient age and tumor volume, was recommended in clinical application.

Objectives To evaluate the use of three-dimensional (3D) power Doppler ultrasound in the differential diagnosis of solid breast tumors using a neural network model as a classifier. Methods Data from 102 benign and 93 malignant breast tumor images that had pathological confirmation were collected consecutively from January 2003 to February 2004. We used 3D power Doppler ultrasound to calculate three indices (vascularization index (VI), flow index (FI) and vascularization flow index (VFI)) for the tumor itself and for the tumor plus a 3-mm shell surrounding it. These data were applied to a multilayer perception (MLP) neural network model and we evaluated the model as a classifier to assess the capability of 3D power Doppler sonography to differentiate between benign and malignant solid breast tumors. Results The accuracy of the MLP model for classifying malignancy was 84.6%, the sensitivity was 90.3%, the specificity was 79.4%, the positive predictive value was 80.0% and the negative predictive value was 90.0%. When the neural network was used to combine the three 3D power Doppler indices, the area under the receiver–operating characteristics curve was 0.89. Conclusions 3D power Doppler ultrasound may serve as a useful tool in distinguishing between benign and malignant breast tumors, and its capability may be increased by using a MLP neural network model as a classifier. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

Aim: The current study assessed the potential impact of diabetes type 1 and type 2 for female breast cancer risk. Materials and Methods: The health information and medical record of the entire adult female residents in Taiwan were retrieved from Taiwan's National Health Insurance Research Database. Multivariate Cox proportional hazard regression models and descriptive statistics were used to identify potential correlations between type 1/2 diabetes and breast cancer. In addition, this study statistically assessed the possible association of diabetes and breast cancer risk with age, insurance amount (quality of care), and regions. Results: The diabetic status of the entire adult female population was assessed between 2001 and 2003. Of 10,827,079 adult females, 4,738 (0.04%) were diagnosed with type 1 and 830,546 (7.7%) with type 2 diabetes, and 9, 991,795 (92.3%) were free of diabetes. From 2004 to 2010, a total of 57,283 cases of breast cancer were detected, with an average breast cancer incidence rate of 0.53% in the generation population. The actual breast cancer incidence rate was 0.30% (14 of 4,738) in patients with type 1 diabetes, 1.10% (9,105 of 830,546) in patients with type 2 diabetes, and 0.48% (48,164 of 9,991,795) in patients free of diabetes. The breast cancer incidence rate is significantly higher (p < 0.001) in patients with type 2 diabetes than that in patients with type 1 diabetes and in patients free of diabetes. After adjusting for the covariates of age, insurance cost, and region, hazard ratios (HRs) for the association between breast cancer risk and types 1 and 2 DM were 1.01 (CI = 0.60-1.71) and 1.13 (CI = 1.10-1.16), respectively. Women with type 2 diabetes were at a significantly higher risk for development of breast cancer compared with those free of diabetes, but there appeared to have no significant increase in risk for those with type 1 diabetes. Our study also revealed that age, insurance amount (quality of care), and region are significantly associated with diabetes and breast cancer risk (p

Background Our previous studies have suggested that the primary impact of immune cell infiltration into the normal or pre-invasive tissue component is associated with the physical destruction of epithelial capsules, which may promote tumor progression and invasion. Our current study attempted to further verify our previous observations and determine the primary type(s) of infiltrating immune cells and the possible mechanism associated with physical destructions of the epithelial capsules. Methods In total, the study was conducted with 250 primary breast and prostate tumors, the primary immune cell of cytotoxic T-lymphocytes (CTL), Natural killer cells (NK) and Mast cells were analyzed by immunohistochemistry, fluorescent labeling and apoptosis assay. qRT-PCR was used for gene expression analysis. Our current study assessed the physical disruption of these immune cells and potential impact on the epithelial capsule of human breast and prostate tumors. Results Our study yield several clinically-relevant findings that have not been studied before. (1) A vast majority of these infiltrating immune cells are distributed in the normal-appearing or pre-invasive tissue components rather than in invasive cancer tissues. (2) These cells often form rings or semilunar structures that either surround focally-disrupted basal cell layers or physically attach to the basal cells. (3) Basal cells physically associated with these immune cells generally displayed distinct signs of degeneration, including substantially elevated apoptosis, necrosis, and reduced tumor suppressor p63 expression. In contrast, luminal cells overlying focally disrupted basal cell layers had a substantially increased proliferation rate and elevated expression of stem cell markers compared to their adjacent morphologically similar counterparts that overlie a non-disrupted capsule. Conclusion Our findings suggest that at the early stage of tumor invasion, CTL, NK and Mast cells are the main types of tumor infiltrating immune cells involved in focal degenerative products in the tumor capsules. The primary impact of these infiltrating immune cells is that they are associated with focal disruptions of the tumor capsule, which selectively favor tumor stem cells proliferation and invasion.

The aim of this study was to compare the diagnostic performance of nonharmonic ultrasound (US) and tissue harmonic imaging (THI) using three-dimensional (3D) power Doppler sonographic technique to classify benign and malignant breast tumors by vascularization. From January 2003 to February 2004, we evaluated 200 patients and one of lobular carcinoma in situ was excluded from the malignant category. One hundred and ninety-nine subjects were enrolled. All subjects with one or more breast masses were studied with 3D power Doppler US nonharmonic and harmonic technologies. Sixteen of 199 subjects were excluded because masses exceeded 3 cm limit of our US probe's footprint (n = 5) or no harmonic Doppler information (n = 11). A total of 97 benign and 86 pathologically proven malignant breast tumor images were analyzed. 3D power Doppler US imaging was performed using a Voluson730 US system. Three histogram indices, the vascularization index (VI), flow index (FI) and vascularization-flow index (VFI), on both nonharmonic and harmonic images were calculated for the intratumor and for shells with an outside thickness of 3 mm surrounding the breast lesion. A multilayer perception (MLP) neural network classifier used the vascularity indices to determine whether the breast tumors are benign or malignant. The receiver operating characteristic (ROC) curves are performed to estimate the diagnostic performances for nonharmonic and harmonic methods. ROC curve analysis used overall age, volume, VI, FI and VFI for both intratumor and shells with an outside thickness of 3 mm surrounding the breast lesions in nonharmonic US and THI. The area under the ROC curve (A(Z)) was 0.9086 and 0.9009 (p = 0.3770). The sensitivity was 90.7% and 83.7% (p = 0.72), respectively, and the specificity was 92.8% and 92.8% (p = 1.00), respectively. In conclusion, the performance of 3D power Doppler US with respect to the characterization of solid breast masses as benign or malignant was not significantly improved with tissue harmonic imaging.

The aim of this study was to assess tumor vascularity through three dimensional (3D) power Doppler breast ultrasound (US) and propose a decision model for the classification of benign and malignant breast tumors. Patient recruitment for this study was performed consecutively during a 13-mo period (January 2003 to February 2004). A total of 102 benign and 93 malignant solid breast images were analyzed. Three-dimensional power Doppler US imaging was performed using a Voluson730 ultrasound system equipped with a relative stopping power index (RSP) 6 to 12 transducer. The Virtual Organ Computer-aided Analysis (VOCAL)-imaging program (version 2.1) was used to analyze the stored volume. Histogram indices of the vascularization index (VI), flow index (FI) and vascularization-flow index (VFI) for the intra-tumor and for shells with a thickness of 3 mm surrounding the breast lesion were calculated and showed that for both, malignancy had a higher VI, FI and VFI than benignancy, with statistical significance. Multivariate and stepwise logistic regression revealed the model (including patient age, volume and intra-tumor FI in 3D power Doppler vascularity) to be the best choice for malignant breast tumor characterization. The receiver operating characteristics (ROC) index for the performance of the model was 0.926. Histogram indices for the intra-tumor FI in the 3D power Doppler scan are a good choice of parameter for differentiating between malignant and benign tumors with respect to the power of sensitivity, no matter whether one index is suggested or the patients' age and volume are considered.

Our previous studies have led to a novel hypothesis that aberrant leukocyte infiltration is a trigger for tumor invasion. Our hypothesis and supporting data have been published in multiple peer-reviewed journals. Our current studies attempted to further expand our previous observations, and to test a novel hypothesis that aberrant leukocyte infiltration may also represent a trigger for tumor metastasis. Tissue sections from human breast, prostate, cervical, and lung tumors were analyzed with multidisciplinary approaches with a panel of tumor metastasis-related biomarkers. Our study revealed that pre-invasive tumors surrounded by or immediately adjacent to leukocyte aggregates displayed a number of unique features: [1] significantly reduced expression of cell surface adhesion molecules, [2] significantly elevated blood vessels and lymphatic ducts at the intersection between the tumor core and leukocyte aggregates, [3] the presence of isolated individual tumor cells or cell clusters within the leukocyte aggregates, [4] physical attachment or fusion of tumor cell membrane and condensed chromosomes of mitotic tumor cells with leukocytes, and [5] the presence of co-joined tumor cells and leukocytes within vascular structures or lymphatic ducts. Together, our findings suggest that leukocyte infiltration may trigger tumor metastasis through three correlated mechanisms: (1) to physically disrupt the inter-cellular junctions and cell surface adhesion molecules, [2] to interfere with the mitotic process or physically drag tumor cells to different sites during their migration, and [3] to stimulate growth of vascular structures that facilitate tumor metastasis. (Supported in part by grants DAMD17-01-1-0129, DAMD17-01-1-0130, PC051308 from Congressionally Directed Medical Research Programs, grant BCTR0706983 from The Susan G. Komen Breast Cancer Foundation, and grant 2008-02 from The US Military Cancer Institute and Henry M. Jackson Foundation to Dr. Yan-gao Man, and by grant 2006CB910505 from The Ministry of Chinese Science and Technology Department to Drs. Xichen Zhang and Yan-gao Man). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2250.

Cancer remains a leading cause of death in Taiwan, and the prevalence of breast cancer has increased in recent years. The early detection and diagnosis of breast cancer is the key to ensuring prompt treatment and a reduced death rate. Mammography and ultrasound (US) are the main imaging techniques used in the detection of breast cancer. The heterogeneity of breast cancers leads to an overlap in benign and malignant ultrasonography images, and US examinations are also operator dependent. Recently, computer-aided diagnosis (CAD) has become a major research topic in medical imaging and diagnosis. Technical advances such as tissue harmonic imaging, compound imaging, split screen imaging and extended field-of-view imaging, Doppler US, the use of intravenous contrast agents, elastography, and CAD systems have expanded the clinical application of breast US. Breast US CAD can be an efficient computerized model to provide a second opinion and avoid interobserver variation. Various breast US CAD systems have been developed using techniques which combine image texture extraction and a decision-making algorithm. However, the textural analysis is system dependent and can only be performed well using one specific US system. Recently, several researchers have demonstrated the use of such CAD systems with various US machines mainly for preprocessing techniques designed to homogenize textural features between systems. Morphology-based CAD systems used for the diagnosis of solid breast tumors have the advantage of being nearly independent of either the settings of US systems or different US machines. Future research on CAD systems should include pathologically specific tissue-related and hormonerelated conjecture, which could be applied to picture archiving and communication systems or teleradiology.