Serum levels of type IV collagen 7S and procollagen type III N-terminal propeptide in colorectal cancer patients with hepatic metastases

Background A variety of liver diseases accompany significant elevation of both type IV collagen 7S (IV-c-7S) and procollagen type III N-terminal proppeptide (P-III-P), suggesting the presence of liver fibrosis. We investigated whether metastatic liver tumors from colorectal carcinoma cause hepatic fibrosis at metastatic sites, and if serum levels of collagen precursors would suggest fibrous changes of metastatic liver tumors. Methods Peripheral venous blood was taken from 42 patients with colorectal carcinoma, before surgery or cancer chemotherapy. A commercially available PIA kit was used to measure IV-c-7S and P-III-P in sera, and immunohistochemical staining of type IV collagen expressed at hepatic metastatic lesions was performed in 15 patients with liver metastasis. Results Serum levels of both IV-c-7S and P-III-P correlated with the presence of hepatic metastasis. There were however, no significant correlations between the serum levels of those molecules and either Dukes' stage, histologic differentiation, lymph node metastasis, lung metastasis, peritoneal dissemination, or depth of colorectal wall invasion. There were significant correlations between serum levels of both IV-c-7S and P-III-P and those of carcinoembryonic antigen. Serum levels of both IV-c-7S and P-III-P and those of carcinoembryonic antigen. Serum levels of both IV-c-7S and P-III-P in the patients with multiple metastases were significantly higher than those in patients with no, or solitary, hepatic metastases. The immunohistochemical staining showed that type IV collagen was expressed at hepatic metastatic sites. Conclusion Metastatic liver tumors from colorectal cancer form liver fibrosis at metastatic sites, and accelerate the biosynthesis of type IV and type III collagen.     

Clinical Usefulness of Serum Carboxyterminal Propeptide of Type I Procollagen and Pyridinoline Cross-linked Carboxyterminal Telopeptide of Type I Collagen in Patients with Prostate Cancer

A study was undertaken to evaluate the clinical usefulness ofmeasurements of serum concentrations of the carboxyterminalpropeptide of type I procollagen (PICP) and the pyridinolinecross-linked carboxyterminal telopeptide of type I collagen(ICTP) as parameters of bone metastasis in patients with prostatecancer. Serum PICP, ICTP, prostate-specific antigen (PSA), andalkaline phosphatase (ALP) were evaluated in 82 patients withprostate cancer and 26 patients with benign prostatic hyperplasia(BPH). These markers were measured serially in 16 prostate cancerpatients during treatment. The serum levels of PICP, ICTP, ALP,and PSA were significantly higher in prostate cancer patientswith bone metastasis than in patients with either BPH or prostatecancer without bone metastasis. Although the rate of detectionof bone metastasis with PICP and ICTP was slightly lower thanthat with PSA determined by the receiver operating characteristiccurve, the correlation between both PICP and ICTP and the extentof disease was much higher than that of PSA. PICP and ICTP levelsvaried with ALP and PSA levels, the patient's clinical courseafter the start of endocrine therapy and the progression ofbone metastasis. The levels of PICP and ICTP did not changesubstantially in patients who developed local regrowth or lymphnode metastasis, and decreased as bone metastases respondedto radiotherapy. PICP and ICTP thus reflect the metastatic burdenin bone and are useful for monitoring the response of bone metastasisto therapy.     

Long term survival and the prognostic factors of advanced breast cancer patients treated with adreno-oophorectomy

Summary Longer survival data are necessary to elucidate the prognostic factors for survival in advanced breast cancer patients. Univariate and multivariate analyses were performed in 159 patients treated with adreno-oophorectomy alone as the first-line treatment for advanced or recurrent breast cancer, between 1972 and 1983. Nine clinical factors included age, menopausal status, estrogen (ER)- and progesterone receptors (PgR) in recurrent tumors, disease-free interval (DFI), number of metastatic organs, performance status, and adjuvant therapy performed. Response was evaluated according to the UICC criteria. A 31% (50/159) response with 16 CR, 34 PR, 48 NC, and 61 PD was obtained. The logistic regression model of the factors showed that ER was the single affecting factor for the response. According to the Cox proportional hazard model, ER and the dominant site of metastasis were indicated to be significant for survival. According to the landmark method, the response significantly correlated to survival. Using the backward elimination procedure of the Cox proportional hazard model in the patient group defined by the landmark time of 3 months after therapy, the survival of the patients with advanced breast cancer was shown to be primarily influenced by the tumor response which was solely affected by ER status, and the dominant site, particularly the presence of liver metastasis, independently modified the survival length. These results may be useful in future studies of total estrogen blockade trials for breast cancer.     

Prediction of outcome in locally advanced breast cancer by post-chemotherapy nodal status and baseline serum tumour markers

In spite of the apparent improvement in outcome in locally advanced breast cancer, the prognosis remains dismal in many patients. The aim of this study was to define prognostic subgroups within this heterogeneous entity. Between 1990 and 1999, 104 consecutive patients with locally advanced breast cancer were treated by a multimodality programme consisting of 4-6 courses of CAF induction chemotherapy followed by surgery, breast-conserving when feasible. In most cases, chemotherapy was then resumed, up to a total of eight courses, followed by locoregional radiation therapy. Patients with hormone receptor-positive tumours received tamoxifen (20 mg day(-1)) for 5 years. At a median follow-up of 57 months, the 5-year overall survival for the entire group and the disease-free survival for the 94 operated patients were 65% and 53%, respectively. Univariate analysis identified 10 prognostic factors of overall and disease-free survival, of which four retained significance on multivariate analysis: inflammatory breast cancer (P=0.0000, P=0.0004, respectively), baseline tumour markers (P=0.003 for both), post-chemotherapy number of involved nodes (P=0.003; P=0.017) and extracapsular spread (P=0.052; P=0.014). In conclusion, besides inflammatory features, baseline tumour markers and post-chemotherapy nodal status are strong predictors of outcome in locally advanced breast cancer.     

ICTP在诊断乳腺癌骨转移中的临床价值

目的：探讨ICTP在诊断乳腺癌骨转移中的临床价值。方法：用EIA法测定60例乳腺癌患者和23例健康体检者的ICTP血清水平。结果：乳腺癌骨转移患者ICTP血清水平较非骨转移和正常对照组显著升高,其诊断敏感性为77.8%,特异性为91.3%。多处骨转移患者血清ICTP阳性率和血清水平较单处骨转移患者显著升高且随着乳腺癌分期的升高,血清ICTP阳性率和血清水平也升高。结论：ICTP对乳腺癌骨转移患者的早期诊断,病情监测和临床分期判断具有重要意义。     

Glycine-extended gastrin induces matrix metalloproteinase-1- and -3-mediated invasion of human colon cancer cells through type I collagen gel and Matrigel

The effects of glycine-extended gastrin (G-Gly) on the invasion by colon cancer cells through stromal extracellular matrix and the role of metalloproteinases (MMPs) in this invasion were investigated. We found that 10(-9)-10(-6) M G-Gly significantly increased the invasiveness of 2 human colon cancer cell lines, LoVo and HT-29, both expressing the G-Gly-specific binding site but little gastrin/CCK-B receptor (gastrin receptor). LoVo cells expressed MMP-1, -2, -3 and -9. An amount of 10(-7) M G-Gly enhanced collagenase MMP-1 expression. Overexpression of enhanced green fluorescent protein (EGFP)-fused MMP-1 in LoVo cells, by cDNA transfection, enhanced invasiveness through type I collagen gel. Immunofluorescence study revealed that G-Gly increased the number of cytoplasmic vesicles containing MMP-1, some vesicles being released from the cells. The MMP-1 vesicles contained one of the ubiquitous coat proteins, Golgi-localized, gamma-adaptin ear-containing, ARF-binding proteins-2 (GGA-2). MMP-1 also colocalized with CD147 (EMMPRIN, an extracellular matrix metalloproteinase inducer in adjacent stromal cells). It was suggested that G-Gly increased the number of vesicles containing MMP-1 and that MMP-1 interacted with CD147 to increase invasion. G-Gly significantly enhanced the production of MMP-3, an activator of MMP-1 and -9, as well as gelatinase MMP-9 activity. The G-Gly-mediated MMP-9 increase was inhibited by treatment with anti-MMP-3 IgG and MMP-3 siRNA. Furthermore, G-Gly increased the proMMP-2 level, although no activated MMP-2 was found in conditioned medium in either the presence or the absence of G-Gly. By contrast, gastrin (10(-7) M) had no effect on the levels of these MMPs or the invasiveness of colon cancer cells in type I collagen gel and Matrigel. These effects of G-Gly on the activity and expression of MMPs and the invasiveness of colon cancer cells were inhibited by treating the cells with a broad-spectrum metalloproteinase inhibitor (CGS27023A) and nonselective gastrin/CCK receptor antagonists (proglumide and benzotript). But a gastrin/CCK-B receptor antagonist (YM022) did not inhibit the increased invasion by G-Gly. Together, these results demonstrate that G-Gly renders colon cancer cells more invasive by increasing MMP-1 and MMP-3 expressions via the putative G-Gly receptor and would thus be a good molecular target in a clinical setting.     

Patient and tumour characteristics, management, and age-specific survival in women with breast cancer in the East of England

Background:

Breast cancer relative survival (BCRS), which compares the observed survival of women with breast cancer with the expected survival of women for the whole population of the same age, time period, and geographical region, tends to be poorer in older women, but the reasons for this are not clear. We examined the influence of patient and tumour characteristics, and treatment on BCRS to see whether these could explain the age-specific effect.

Methods:

Data for 14 048 female breast cancer patients diagnosed from 1999 to 2007, aged 50 years or over were obtained from the Eastern Cancer Registration and Information Centre. We estimated relative 5- and 10-year survival for patients in four age groups (50–69, 70–74, 75–79, and 80+ years). We also modelled relative excess mortality (REM) rate using Poisson regression adjusting for patient characteristics and treatment. The REMs derived from these models quantify the extent to which the hazard of death differs from the hazard in the reference category, after taking into account the background risk of death in the general population. We compared the results with those obtained for breast cancer-specific mortality, analysed using multivariate Cox regression.

Results:

Median follow-up time was 4.7 years. Relative 5-year survival was 89, 81, 76, and 70% for patients aged 50–69, 70–74, 75–79, and 80+ years, respectively. Corresponding relative 10-year survival was 84, 77, 67, and 66%. Unadjusted REM was 1.93, 2.74, and 3.88 for patients aged 70–74, 75–79, and 80+ years, respectively, (50–69 years as reference). The equivalent hazard ratios from the Cox model were 1.88, 2.45, and 3.81. These were attenuated after adjusting for confounders (REM – 1.49, 1.36, and 1.23; Cox – 1.47, 1.50, and 1.76).

Conclusion:

We confirmed poorer BCRS in older women in our region. This was partially explained by known prognostic factors. Further research is needed to determine whether biological differences or suboptimal management can explain the residual excess mortality.     

The effect of the I1307K APC polymorphism on the clinicopathological features and natural history of breast cancer.

The I1307K polymorphism in APC has been found to predispose to colorectal cancer in Ashkenazi Jews, and has recently been associated with an increased risk for breast cancer in the same population. In that study, we genotyped 205 paraffin-embedded breast cancers from Ashkenazi Jewish women diagnosed below the age of 65. We now present an extended analysis, with clinicopathological correlations between carriers of I1307K and non-carriers. Twenty-four of 209 cases (11.5%, 95% confidence interval 7.5-16.6) were found to carry the I1307K polymorphism. When stratifying the data by other relevant clinicopathological variables, we observed no association between the presence of this polymorphism and age at diagnosis (P = 0.52), grade (P = 0.074), tumour size (P = 0.99), lymph node status (P = 0.82), oestrogen receptor status (P = 0.23) or P53 immunoreactivity (P = 0.80). The breast-cancer specific 5-year survival for women with I1307 K polymorphism was 88.9% compared with 81.6% in women without I1307K (P = 0.34). Using microdissected samples and direct sequencing, no somatic mutations were observed in any of the 24 I1307K-positive cases. Single-strand conformation analysis of 158 of the I1307K-negative breast cancers that were available for study revealed no mobility shifts. We conclude that the presence of the I1307K polymorphism does not appear to be associated with any particular clinicopathological feature of breast cancer and importantly, does not affect the prognosis.     

Clinical significance of interstitial collagen deposition at the invading edge in oral cancer: Immunohistochemistry for type I collagen

Background Changes in interstitial collagen in human oral cancer have not yet been fully studied. We examined the relationship between the degree of interstitial collagen deposition at the invading edge of the tumor, and the clinical and pathologic findings in oral squamous cell carcinoma. We also investigated the therapeutic implication of the changes in distribution patterns of collagen deposition by comparing biopsy specimens and surgical specimens. Methods Immunohistochemical staining was performed by the streptavidin-biotin method using antibody against human type I collagen for visualizing interstitial collagen in 50 biopsy and 45 surgical specimens. Results Carcinomas with scanty interstitial collagen in biopsy specimens tended to have highly malignant characteristics. Large carcinomas with scanty deposition both in biopsy and surgical specimens were likely to have positive resection margins in spite of radical surgery. Conclusion Immunostaining patterns for type I collagen of oral squamous cell carcinomas can provide information of importance in determining safe resection margins.     

Population-based comparison of prognostic factors in invasive micropapillary and invasive ductal carcinoma of the breast

Background:

Invasive micropapillary carcinoma (IMPC) is a variant of breast carcinoma with a higher propensity for lymph node metastases compared with invasive ductal carcinoma (IDC).

Methods:

Retrospective analysis of 636 IMPC and 297 735 IDC cases in the Surveillance, Epidemiology and End Results database comparing disease-specific survival (DSS) and overall survival (OS) between IMPC and IDC.

Results:

A higher percentage of IMPC cases (52.0%) had nodal metastases compared with IDC cases (34.6%). The 5-year DSS and OS for IMPC was 91.8% and 82.9%, respectively compared with 88.6% and 80.5% for IDC, respectively. For both IMPC and IDC, oestrogen-receptor positivity was associated with better survival, while having four or more positive lymph nodes or larger tumour size correlated with worse survival. Radiotherapy provided a survival benefit for both histological types.

Conclusions:

Despite IMPC''s higher propensity for lymph node metastasis, IMPC has DSS and OS that compare favourably with IDC.     

Capecitabine and paclitaxel combination chemotherapy for inoperable or recurrent breast cancer: a phase I dose-finding study by the Kinki Breast Cancer Study Group

Background The combination of capecitabine and paclitaxel (XP) has demonstrated synergistic antitumor activity in preclinical models. Three-weekly XP regimens have demonstrated excellent efficacy in phase II and III trials in metastatic breast cancer. We conducted a dose-finding study to identify the recommended 4-weekly XP regimen in patients with inoperable or recurrent breast cancer for phase II evaluation. Methods Eligible patients had inoperable or recurrent breast cancer previously treated with chemotherapy (but not capecitabine or paclitaxel) in the (neo)adjuvant or metastatic setting. Each 4-week treatment cycle consisted of escalating doses of capecitabine (628 or 829 mg/m² twice daily [b.i.d.] on days 1–21) and paclitaxel (80 or 90 mg/m² on days 1, 8, and 15). Dose-limiting toxicities (DLT) were evaluated during the first two cycles. Results Nine patients were treated. At dose level 1 (capecitabine 628 mg/m² b.i.d. plus paclitaxel 80 mg/m²), one patient experienced a DLT (grade 3 non-hematologic toxicity). There were no further DLTs at dose level 1 or 2. Although the MTD was not reached, dose level 2 (capecitabine 829 mg/m² b.i.d., days 1–21, plus paclitaxel 80 mg/m², days 1, 8, and 15, every 28 days) is recommended for phase II evaluation, taking into consideration the single-agent doses used in Japan and the doses identified in Western studies of 3-weekly XP. The overall response rate was 44%; all patients treated at dose level 2 achieved a partial response. Conclusions This 4-weekly XP regimen was well tolerated, active in patients with pretreated advanced breast cancer, and could be given as outpatient treatment. These results are consistent with findings of phase II and III trials evaluating 3-weekly regimens, and indicate that further investigation of a 4-weekly XP regimen is warranted.     

Premenopausal levels of circulating insulin-like growth factor I and the risk of postmenopausal breast cancer

Increased levels of insulin-like growth factor I (IGF-I) may directly stimulate breast cell proliferation and promote growth and survival of transformed cells. Higher levels of IGF-I have been associated with increased risk of premenopausal breast cancer but not postmenopausal breast cancer. We investigated whether circulating levels of IGF-I prior to menopause are associated with breast cancer diagnosed after menopause in a population-based nested case-control study. Female cohort participants were enrolled in 1974 (n = 15,192) and 1989 (n = 18,724) and blood was drawn. Cases were women diagnosed with primary breast cancer at ages > or =50, of whom 152 were premenopausal at blood draw. One control was matched to each case on cohort participation, age, ethnic group, menopausal status and date of blood draw. Levels of IGF-I and IGF binding protein 3 (IGFBP-3) were measured using enzyme-linked immunoabsorbent assays. The association between IGF-I and breast cancer was determined using conditional logistic regression, adjusting for IGFBP-3. IGF-I levels decreased with age (p = 0.0001). Prior to age-stratification, IGF-I levels neither measured before nor after menopause were associated with postmenopausal breast cancer. After age-stratification, associations were suggested in the youngest premenopausal age group (upper vs. lowest third: odds ratio (OR) = 5.31, 95% confidence intervals (CI) = 0.85-33.13; p trend = 0.06) and oldest postmenopausal age group (upper vs. lowest third: OR = 3.41, 95% CI = 0.66-17.71; p trend = 0.13). The association between circulating levels of IGF-I and postmenopausal breast cancer risk may be modified by age. Increased levels of circulating IGF-I may be of particular interest in the younger premenopausal women and older postmenopausal women. Age-stratification should be undertaken in larger investigations of IGF-I levels as predictors of postmenopausal breast cancer.     

Prognostic value of health‐related quality‐of‐life parameters in early‐stage breast cancer: an 8‐year follow‐up study

Objective: The purpose was to investigate whether self‐reported health‐related quality‐of‐life (HRQOL) parameters at time of diagnosis and/or 1‐year follow‐up are prognostic for disease‐free survival (DFS) in early‐stage breast cancer patients. Methods: Data from 195 women, diagnosed with early‐stage breast cancer, who had filled in the EORTC QLQ‐C30 and the Hospital Anxiety and Depression Scale (HADS) at time of diagnosis and 1 year after surgery, were analyzed. Results: After a median follow‐up of 8.2 years (range 0.09–9.45), 27 (14.1%) deaths and 22 (11.5%) recurrences were observed. Using Cox multivariate regression analysis, appetite loss reported 1‐year following surgery (HR 2.92, 95% CI 1.50–5.66), p=0.002) was significantly predictive for shorter DFS, even after controlling for age and depression. None of the clinical or biological prognostic factors was found to have a confounding effect. Conclusion: The findings indicate that loss of appetite probably is of prognostic value in addition to well‐recognized clinical and biological data, in early‐stage breast cancer. Copyright © 2010 John Wiley & Sons, Ltd.     

Claudin 19 inhibits the malignant potential of breast cancer cells by modulating extracellular matrix-associated UBE2C/Wnt signaling

Claudin proteins are a major component of the tight junctions between cells, which are involved in a variety of human diseases, including cancer. This study aimed to investigate the functional role of claudin 19 (CLDN19) in human breast cancer progression. Here, we firstly found that CLDN19 was downregulated in breast tumor tissues than normal control, and loss of CLDN19 predicted poor patient survival in patients with breast cancer, by utilizing the Cancer Genome Atlas Program (TCGA) dataset analysis. To further validate the tumor suppressive effects of CLDN19, we established CLDN19 overexpressed MDA-MB-231 and T47D cells. And overexpression of CLDN19 resulted in suppression of cell growth/migration in breast cancer cells cultured in 3D environment or in vivo. Mechanistically, we demonstrated that CLDN19 downregulated ubiquitin conjugating enzyme E2 C (UBE2C) expression, which further suppressed Wnt/β-catenin pro-survival signaling pathway activation induced by extracellular matrix (ECM), in 3D environment or in vivo. Altogether, our study revealed a tumor suppressive role of CLDN19, which hindered ECM/UBE2C/Wnt signaling activation in breast cancer, and offered novel insight for tumor diagnosis and targeted therapy.     

A prospective study of the significance of gene and chromosome alterations as prognostic indicators of breast cancer patients with lymph node metastases

In 150 surgically resected primary breast carcinomas that had axillary lymph-node metastases, we examined the incidence of loss of heterozygosity on chromosomes 16p, 16q, 17p, 17q, and 18q, point mutation of the p53 tumor-suppressor gene, nuclear immunoreaction of p53 protein, and amplifications of the c-erbB-2 and int-2 oncogenes by Southern blotting, single-strand conformation polymorphism analysis, and immunohistochemistry. We analyzed the association of these factors and conventional prognostic parameters with outcome of the patients, using Cox's univariate and multivariate analyses. The univariate analysis revealed that nuclear p53 immunoreaction, p53 mutation, and c-erbB-2 amplification as well as the number of metastatic lymph nodes, histological grade, and hormone-receptor statuses were significant prognostic indicators for both recurrence and cancer death. p53 immunoreaction was correlated more strongly with a poor prognosis than p53 mutations. The combination of p53 and c-erbB-2 effectively identified the high-risk patient group, and even among Grade 3 cases the subgroup with these alterations tended to have poorer clinical outcomes. The multivariate analysis including p53, c-erbB-2, and conventional factors. Lymph node status, grade, and p53 had independent impacts on the survival of patients. Under identical adjuvant systemic therapies, prognoses differed between the patient groups with and without alterations of p53 or c-erbB-2. Appropriate combinations of conventional factors with nuclear p53 immunoreaction and c-erbB-2 amplification would help to identify highly aggressive node-positive breast carcinomas and would aid stratification of patient groups in randomized clinical trials of adjuvant systemic therapies.     

Phase I study of weekly nab‐paclitaxel combined with S‐1 in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer

We conducted a phase I study of a weekly nab‐paclitaxel and S‐1 combination therapy in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S‐1 dose (65 or 80 mg/m²) and nab‐paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose‐limiting toxicity was observed in one patient at Level 3 (100 mg/m² nab‐paclitaxel on days 1, 8, and 15 with 80 mg/m² S‐1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3–4 treatment‐related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression‐free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long‐term administration of this combination therapy.