[Show abstract][Hide abstract] ABSTRACT: Background: Young breast cancer survivors have specific needs related to age. Clarifying the relationships between unmet information needs and quality of life (QOL) in young breast cancer survivors can contribute to constructing a support system to enhance QOL in patients. Objective: This study aimed to identify the unmet information needs and examine the relationships between unmet information needs and QOL in young breast cancer survivors in Japan. Methods: Participants completed an information needs questionnaire containing 26 items, the World Health Organization Quality of Life InstrumentYShort Form (WHOQOL-BREF), and a demographic and medical information questionnaire. Results: Fifty participants (30.7%) were unsatisfied with "overall communication with medical professionals." The mean scores on all subscales of the WHOQOL-BREF of the participants who were satisfied with "overall communication with medical professionals" were significantly higher than those of the unsatisfied group. "follow-up tests," "treatment for recurrence of breast cancer," "strategies about communication with medical staff," and "nutrition" were significantly related with all subscales in the WHOQOL-BREF. "Secondary menopause caused by hormonal therapy" was significantly related with physical and psychological health. Conclusions: Japanese young breast cancer survivors have unmet information needs, including age-specific issues. These unmet information needs are related to QOL. In particular, "overall communication with medical professionals," which is the most unmet information need, is related to QOL. Implications for Practice: Oncology nurses should teach patients communication skills, provide adequate information, and provide education and emotional support to medical professionals to improve QOL in young breast cancer survivors.
Cancer Nursing 09/2014; Publish Ahead of Print(6). DOI:10.1097/NCC.0000000000000201 · 1.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
To clarify the clinicopathological features of breast cancer in young females, surveillance data of the Registration Committee of the Japanese Breast Cancer Society were analyzed.
The clinicopathological characteristics were compared between young (<35) patients and non-young (≥35) patients among 109,617 records registered between 2004 and 2009.
The numbers of young and non-young patients were 2,982 (2.7 %) and 106,295 (97.0 %), respectively. The young patients had more cases of a familial history of breast cancer, more subjective symptoms, fewer bilateral tumors, lower BMIs, larger tumors, more positive lymph nodes, fewer instances of an ER-positive status, more instances of an HER2-positive status, more triple-negative tumors and more advanced TNM stages. The young patients more frequently received neoadjuvant chemotherapy and breast-conserving therapy (BCT) compared with the non-young patients. Eighty percent of all patients received adjuvant therapy. The young patients were more frequently treated with chemotherapy, molecular targeted therapy and radiation therapy than the non-young patients.
In this study, young patients with breast cancer were diagnosed at more advanced stages and had more endocrine-unresponsive tumors than non-young patients. Further prognostic analyses should be conducted in this cohort.
Breast Cancer 04/2013; 21(6). DOI:10.1007/s12282-013-0466-2 · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
Identification of useful markers associated with poor prognosis in breast cancer patients is critically needed. We previously showed that expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood may be useful to predict distant metastasis in gastric cancer patients. However, expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood of breast cancer patients has not yet been studied.
Real-time reverse transcriptase-PCR was used to analyze vascular endothelial growth factor receptor-1 mRNA expression status with respect to various clinical parameters in 515 patients with breast cancer and 25 controls.
Expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood was higher in breast cancer patients than in controls. Increased vascular endothelial growth factor receptor-1 mRNA expression was associated with large tumor size, lymph node metastasis and clinical stage. Patients with high vascular endothelial growth factor receptor-1 mRNA expression also experienced a poorer survival rate than those with low expression levels, including those patients with triple-negative type and luminal-HER2(-) type disease.
Expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood may be useful for prediction of poor prognosis in breast cancer, especially in patients with triple-negative type and luminal-HER2(-) type disease.
Breast cancer research: BCR 10/2012; 14(5):R140. DOI:10.1186/bcr3345 · 5.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently, bone marrow has been considered as playing a critical role in the generation of both metastasis and recurrent disease. The accumulation of a single microRNA in the bone marrow has the potential to regulate the translation of multiple genes in cancer metastasis and may therefore serve as a prognostic marker for cancer recurrence. MicroRNA microarray analysis was performed to compare microRNA levels in bone marrow from 4 breast cancer patients with recurrent disease and 4 patients without recurrence. Accumulation of two of these microRNAs, miR-21 and miR-181a, in the recurrent breast cancer cases was validated by RT-PCR in bone marrow from 291 additional breast cancer cases. Expression of a common target gene, PDCD4, was also determined in bone marrow from 291 breast cancer cases. Increased miR-21 and miR-181a levels were significantly associated with shortened disease-free survival (DFS; p=0.0003, 0.0007) and overall survival (OS; p=0.0351, 0.0443), respectively. While low PDCD4 expression was also significantly associated with poorer DFS (p=0.036). Multivariate analysis identified bone marrow miR-21 and mR-181a levels as valuable independent prognostic factors, with correlation coefficients that were significantly higher than that of the transcript of their common target gene. Accumulation of miR-21 and miR-181a in bone marrow appears to be associated with prognosis in breast cancer patients. The much higher significant correlation with microRNA levels and prognosis suggests epistatic effects on multiple target genes in the bone marrow of breast cancer patients.
International Journal of Oncology 04/2011; 38(4):955-62. DOI:10.3892/ijo.2011.926 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CD47 plays a variety of roles in intercellular signaling. Herein, we focused on the clinicopathologic significance of CD47 expression in human breast cancer. Our data suggest that the correlation between CD47 and signal regulatory protein α (SIRPA) expression may play a key role in the progression of breast cancer.
Quantitative real-time PCR was used to evaluate CD47 mRNA and SIRPA mRNA expression in bone marrow and in peripheral blood from 738 cases of breast cancer.
In patients with high levels of CD47 expression in the bone marrow, survival was significantly poorer compared with patients with low levels of CD47 expression [disease-free survival (DFS), P = 0.0035; overall survival (OS), P = 0.015]. Furthermore, high CD47 expression group in a multivariate analysis showed significance as an independent variable for poorer prognosis in DFS (P = 0.024). In the peripheral blood, however, high CD47 expression in patients was not an independent and significant prognostic factor for DFS and OS in a multivariate analysis. CD47 expression was strongly correlated with SIRPA expression in both the bone marrow (P < 0.0001) and peripheral blood (P < 0.0001) of breast cancer patients.
This is one of the first studies to show that a host factor in bone marrow confers prognostic importance. CD47 is an important biomarker in breast cancer, and functions as a prognostic factor for DFS. Moreover, we suggest that the poor prognosis of breast cancer patients with high expression of CD47 is due to an active CD47/SIRPA signaling pathway in circulating cells.
Clinical Cancer Research 09/2010; 16(18):4625-35. DOI:10.1158/1078-0432.CCR-10-0349 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The clinical significance of isolated tumor cells (ITC) in peripheral blood (PB) and bone marrow (BM) as predictive markers in the recurrence or metastasis of breast cancer has not yet been determined. In the current study, we focused on the urokinase plasminogen activator receptor (u-PAR) gene as a powerful indicator of the potential to relapse after surgery.
We examined CK-7 and CK19 as an ITC marker and u-PAR as a candidate indicator for metastasis in PB and BM from 800 cases of breast cancer by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR). Serum tumor markers, carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3), were compared with u-PAR or CK status.
CK7 in PB was positive in 262 cases that showed a poorer disease-free survival (DFS) than 478 CK7(-) cases (P < 0.05). The 153 cases of u-PAR(+) in BM showed significantly poorer DFS and overall survival (OS) than did the 579 cases of u-PAR(-) in BM (P < 0001 and P < 0.0001, respectively). In PB, a significant difference was also observed between 330 cases of u-PAR(+) and 437 cases of u-PAR(-) (P < 0.0001). The hazard ratio (HR) for prediction of recurrence was significantly higher in u-PAR (P < 0.0001; HR 0.0519) than the level of three serum tumor markers.
u-PAR expresses in cancer cells during the dormant phase. The current findings revealed that the expression levels of u-PAR in PB and BM evaluated preoperatively indicate the potential to relapse or metastasize after surgery.
[Show abstract][Hide abstract] ABSTRACT: Research on the impact of breast cancer on Asian women's sexual lives is extremely scarce. This study investigated the sexual changes experienced by breast cancer patients in Japan following surgery, and their sexuality-related information needs.
An anonymous, cross-sectional survey of breast cancer out-patients was conducted in 2005. Data from 85 subjects, who were without recurrence and reported being sexually active pre-surgery, were analyzed.
Subjects were mainly in their 40's and 50's, and the median time since surgery was 43 months. Seventy-three (85.9%) had resumed sex after surgery with the median time being 3.5 months after surgery. Among 73 who resumed sex, 43 reported that the frequency of sex decreased, and 72 reported at least one sexually related change. The multiple logistic regression analysis revealed that those who had perceived the sexual relationship with their partner important before surgery (OR, 6.705; 95%CI, 1.320-34.051; p = 0.022) were more likely to maintain the same frequency of sex as before surgery. Perceived changes in respondents' sexual relationship did not necessarily result in deterioration of the couple's overall relationship. Regarding sexuality-related information needs, respondents wished to have information on treatment-induced sexual changes as well as sexual and general inter-couple communication strategies.
This research revealed that breast cancer patients in Japan experience various sexual problems following breast cancer treatment. Sexuality-related information should be provided to all patients, regardless of patients age or type of surgery, as a part of routine treatment information giving.
[Show abstract][Hide abstract] ABSTRACT: With the development of the CellSearch System, it has become possible to measure circulating tumor cell (CTC) levels with high reproducibility, and the CTC test is currently being used clinically for patients with metastatic breast cancer in the United States. It is imperative that the clinical significance of the CTC test also be examined in Japan.
Using the CellSearch System, CTC levels were evaluated in 57 healthy individuals and patients with benign breast disease; 30 patients with primary breast cancer (stages 1-3); and 38 patients with metastatic breast cancer. First, the relationship between CTC levels and the presence of metastasis was examined using a cutoff score of 2 CTCs per 7.5 ml whole blood. Then, the patients with metastatic breast cancer were divided into two groups, using a cutoff score of 5 CTCs per 7.5 ml blood, and progression-free survival (PFS) and overall survival (OS) were compared in the two groups.
When the clinical cutoff score was set at 2 CTCs per 7.5 ml blood, 0% of the healthy individuals and patients with benign breast disease (0/57), 3.3% of the patients with primary breast cancer (1/30), and 50% of the patients with metastatic breast cancer (19/38) were identified as as having 2 CTCs per 7.5 ml blood. Additionally, with a cutoff score of 5 CTCs, 11 patients were reported to have 5 or more CTCs and both PFS (P = 0.0036) and OS (P = 0.04) were worse for this patient population than for the population with fewer than 5 CTCs.
As concluded in a similar clinical trial in the United States, for patients with breast cancer, measuring CTC levels can be both an accurate indicator of metastases and an important measure of patient prognosis.
International Journal of Clinical Oncology 07/2008; 13(3):252-6. DOI:10.1007/s10147-007-0748-9 · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Akt is a serine/threonine kinase that has been demonstrated to play an important role in survival when cells are exposed to different apoptotic stimuli. Recent studies show that aberrant activation of Akt in breast carcinoma is associated with a poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway is currently attracting considerable attention as a new target for effective therapeutic strategies. We investigated the incidence of Akt activation in 252 primary breast carcinomas and relationships among the activation of Akt, HER2 overexpression, hormone receptor expression, and alteration of the PTEN gene. Eighty-four cases (33.3%) were positive for pAkt expression. pAkt was significantly associated with HER2 overexpression (p<0.0001) and LOH at the PTEN gene locus (p<0.01). There was an inverse correlation between pAkt and PR (p<0.05). We also retrospectively examined the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer. Of these 36 metastatic breast cancer cases, 12 cases (33.4%) were considered to show positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated worse efficacy than in pAkt-negative patients (p<0.01). In addition, the clinical benefit was the smallest in the patients positive both for HER2 and pAkt (p<0.01). The clinical benefit rate of estrogen deprivation therapy with AI or LH-RH agonist was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (p<0.05), and there was a tendency for the clinical benefit of SERM to be smaller in the pAkt-positive patients (p=0.09). These findings therefore suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings indicate that the activation of Akt in the downstream pathway of HER2 plays an important role in resistance to endocrine therapy for breast cancer. Our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.
Breast Cancer 04/2006; 13(2):137-44. DOI:10.2325/jbcs.13.137 · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this retrospective study, the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer was investigated. Thirty-six metastatic breast cancer patients, treated with endocrine therapy, were evaluated for the activation of Akt by an immunohistochemical assessment of the expression of phosphorylated Akt at Ser 473 (pAkt). The relationship between the efficacy of endocrine therapy and Akt activation, HER2 status and hormone receptor expression was also investigated. Of these 36 cases, 12 cases (33.4%) were considered to show a positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated a worse efficacy than in pAkt-negative patients (P<0.01). pAkt positivity was also associated with a poorer objective response (P<0.05). The clinical benefit rate was lower in HER2 positive groups than in HER2 negative group (P<0.05). In addition, the clinical benefit was the smallest in both the HER2 and pAkt-positive patients (P<0.01). Regarding the endocrine agents, the clinical benefit of estrogen deprivation therapy with aromatase inhibitor or luteinising hormone-releasing hormone agosists was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (P<0.05). In addition, there was a tendency for clinical benefit of selective estrogen receptor modulator to be smaller in the pAkt-positive patients (P=0.09). These findings, therefore, suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings suggest that the activation of Akt in the downstream pathway of HER2 plays an important role in the resistance to endocrine therapy for breast cancer. Although our study was small in scope and retrospective in design, our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.
European Journal of Cancer 03/2006; 42(5):629-35. DOI:10.1016/j.ejca.2005.11.025 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The clinical significance of occult micrometastasis (O.M) remains unknown. We investigated it in peripheral blood (P.B.) and bone marrow (B.M.) in breast cancer patients with surgery. First, we investigated the expression levels of 7 representative molecular markers for detecting O.M (CEA, CK-7, CK-18, CK-19, CK-20, MAM and MUC-1) in 27 cancer and 8 non-epithelial cell lines using quantitative RT-PCR (QRT-PCR), and showed that the expression level of CK-7 was higher in every cancer cell line than in the non-epithelial cell lines. Next, we studied the clinical significance of O.M in P.B. and B.M. by QRT-PCR for CK-7 in breast cancer patients with surgery. Based on comparison with 17 non-cancer controls, 37 (18.0%) and 100 (48.5%) of the 206 patients were positive for CK-7 in P.B. and B.M., respectively. In 98 cases observed over 24 months after surgery, the CK-7-positive group in P.B. had poorer disease-free survival (DFS) than the negative group (p<0.01). The CK-7-positive group in P.B. showed poorer DFS than the negative group in 132 lymph node-negative cases (p=0.01), and moreover, in 61 lymph node-negative cases observed over 24 months after surgery, the CK-7-positive group in P.B. showed poorer DFS than the negative group (p<0.0001). In B.M., no significant difference in DFS was found between the CK-7-positive and CK-7-negative groups. QRT-PCR for CK-7 could be a useful and universal method for detecting O.M, and the quantitative detection of CK-7 in P.B. would have a prognostic value as a marker of early recurrence in breast cancer patients with surgery.
International Journal of Oncology 04/2005; 26(3):721-30. DOI:10.3892/ijo.26.3.721 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Comparing differential gene expression profiles established by cDNA microarray between normal cells (N), primary carcinoma cells (T), and metastatic carcinoma cells (M) may determine those critical genes directly associated with progression and metastasis of breast cancer. Total RNA was extracted by laser microdissection (LMD) from 20 slices of T, N and M from 6 cases. After amplification by a T7-based system, differentially expressed genes between T, N and M were identified by cDNA microarray. In addition, to clarify the mechanism for altered gene expression, we determined the methylation status by sequencing after bisulfite treatment for intriguing genes. As a result, the expression of motility related protein-1 (MRP-1/CD9), peripheral myelin protein-22 (PMP-22), and caspase 3 (CASP-3) were down-regulated in M compared to T. We focused especially on MRP-1 and found that the expression status of MRP-1 was significantly inversely associated with stage of disease in 56 cases of breast cancer (P<0.05), and the relapse free survival in 5 years was significantly higher in MRP-1 positive cases than those negative cases (P<0.05). Conversely, overexpression, by 11-fold, of signal transduction and translation factors were observed in T compared to N. The cancer specific methylation was observed only in CASP-3 in a case. In conclusion, the establishment of the present assay allows us to detect genes directly associated with each cell population within tumor tissue and gives us clues to identify metastasis-related genes comprehensively in clinical breast cancer cases.
[Show abstract][Hide abstract] ABSTRACT: To date, the biological approach to breast cancer, such as pathologic subtype genetic analysis has been well investigated, and is considered to be the most important approach to under breast cancer treatment. Recently, the importance of a team approach to multidisciplinary medical treatment and holistic medical treatment has been recognized. The five following points are important: 1) recognition of patients' needs, 2) clarifying responsibility, 3) respect for each other, 4) maintaining good communication, 5) updating the system. Our original 'team approach path' is useful as a communication tool between a patient and the staff. Patient satisfaction is the purpose and a team approach is one method of carrying out medical treatment led by a patient as well as the medical treatment and informed decision based on narrative.
Breast Cancer 02/2005; 12(1):21-5. DOI:10.2325/jbcs.12.21 · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Few surrogate markers are available for predicting the survival benefit from chemotherapy in primary breast cancer. We examined tumor growth kinetics by assessing cytokeratin 18 neo-epitope (CK18NE), an apoptosis marker detected by M30 antibody and Ki-67 antigen, a proliferation marker detected by MIB-1 antibody in 72 primary breast cancer patients who underwent pre-operative anthracycline-based chemotherapy. Increase in M30 index and decrease in MIB-1 index after the exposure of 2 to 4 cycles of chemotherapy correlated significantly with pathological tumor response. Univariate survival analysis, conducted in the subgroup of 42 patients who underwent CAF (cyclophosphamide, adriamycin and 5-FU) therapy alone, showed that the patients with the high levels of M30 index (>35 counts/1000 tumor cells) and the low levels of MIB-1 index (<140 counts/1000 tumor cells) after chemotherapy had a remarkably favorable prognosis as compared with patients in other categories. In addition, the alteration in growth kinetics by the treatment showed a significant prognostic value. Multivariate analysis also confirmed that the post-treatment growth kinetics was an independent prognostic indicator. These findings suggest that the alteration in growth kinetics revealed by CK18NE and MIB-1 might be a surrogate marker for predicting the survival benefit from chemotherapy in primary breast cancer.
International Journal of Oncology 08/2004; 25(2):397-405. DOI:10.3892/ijo.25.2.397 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The combination effect of docetaxel and capecitabine on tumour response rate and survival was demonstrated recently in metastatic breast cancer patients. This combination was based on an experimental hypothesis that taxane can increase tumour sensitivity to the effect of capecitabine through the upregulation of thymidine phosphorylase (TP), which is responsible for the metabolism of 5-fluorouracil (5-FU) and its derivatives, including capecitabine. To examine the alteration in TP expression before and after neoadjuvant chemotherapy, 92 patients with primary breast cancer (T2-4N0-1M0) were enrolled in this study; 14 were treated with adriamycin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC); 58 with 5-FU, adriamycin, and cyclophosphamide (FAC) or 5-FU, epirubicin, and cyclophosphamide (FEC); and 20 with FEC followed by docetaxel/taxotere (TXT-containing regimen). Thymidine phosphorylase upregulation was seen in 54.4% and 32.6% of patients in tumour cells and stromal cells, respectively. Increases in TP expression were found only in the AC/EC and TXT-containing regimen groups. In conclusion, it was strongly suggested that unlike 5-FU-containing regimens, the taxane and AC combination therapies upregulate TP expression in primary breast cancer. Thymidine phosphorylase upregulation by several anticancer drugs implies the importance of individualised strategies for sensitisation of tumour tissues to 5-FU and its derivatives.
British Journal of Cancer 07/2004; 90(12):2338-43. DOI:10.1038/sj.bjc.6601845 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This article reviews the current state of efforts targeting human epidermal growth factor receptor-2 (erbB2/HER2)in breast cancer therapy. The results of recently conducted clinical studies with trastuzumab and several other compounds are presented. Trastuzumab, a humanised monoclonal antibody(mAb)directed against the extracellular domain of HER2, has been shown to be active against HER2-overexpressing metastatic breast cancer, either as a single agent or when used in combination with chemotherapy. In preclinical models, trastuzumab has shown additive and even synergistic anti-tumor activity with the chemotherapeutic agents. In a large, randomised, phase III trial, the combination of trastuzumab and chemotherapy was shown to improve the response rate and survival in patients with metastatic breast cancer. The high incidence of cardiotoxicity seen with the combination of trastuzumab plus anthracycline drugs prompted several clinical studies combining trastuzumab with other chemotherapeutic agents, including taxanes, vinorelbine and platinum salts. This article summarises the available data on trastuzumab-based combination chemotherapies and novel drugs targeting HER2 and signal transduction molecules for the treatment of breast cancer.
Breast Cancer 02/2004; 11(2):105-15. DOI:10.1007/BF02968288 · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidermal growth factor receptor (EGFR) and c-erbB-2 are 2 of the 4 members of the erbB receptor family that play a role in signaling by forming heterodimers between family members.
The immunohistochemical expression of EGFR and c-erbB-2 was determined on 670 women who underwent operation for primary breast cancer.
According to the combination of EGFR and c-erbB-2, 670 patients were classified into 4 groups: EGFR(-)/c-erbB-2(-) (417 patients); EGFR(+)/c-erbB-2(-) (136 patients); EGFR(-)/c-erbB-2(+) (72 patients); and EGFR(+)/c-erbB-2(+) (45 patients). Univariate analyses on disease-free and overall survival showed a significant difference among these 4 groups, whereas the difference between patients with positive and negative expression of EGFR was not statistically significant in patients with positive expression of c-erbB-2. A multivariate analysis indicated the combination of EGFR and c-erbB-2 to be an independently significant prognostic factor for disease-free and overall survival.
Breast cancer with both a positive EGFR and c-erbB-2 expression had the worst prognosis, whereas the prognostic value of c-erbB-2 was stronger than that of EGFR in breast cancer.
Surgery 03/2003; 133(2):219-21. DOI:10.1067/msy.2003.32 · 3.38 Impact Factor