Clinicopathological significance of MMP-2 and TIMP-2 genotypes in gastric cancer

AimsSingle nucleotide polymorphisms in matrix metalloproteinase-2 (MMP-2) −1306 C/T and tissue inhibitor of metalloproteinase-2 (TIMP-2) −418 G/C abolish the Sp-1 binding site and down-regulate expression of these genes. We aim to elucidate the role of MMP-2 and TIMP-2 in clinicopathological manifestations of gastric cancer.MethodsWe enrolled 240 gastric cancer patients and 283 controls. DNA was extracted from peripheral blood leucocytes. MMP-2 and TIMP-2 genotypes were analysed by PCR-direct sequencing and PCR-RFLP method, respectively.ResultsMMP-2 and TIMP-2 genotypes were not associated with gastric cancer development. However, patients with MMP-2 −1306 C/C genotype showed higher risk of lymphatic invasion (odds ratio (OR) = 2.77, p = 0.01) and venous invasion (OR = 2.93, p = 0.012). TIMP-2 G/G genotype was associated with serosal invasion (OR = 1.89, p = 0.009), lymph node metastasis (OR = 2.19, p = 0.021), lymphatic invasion (OR = 2.87, p = 0.016) and venous invasion (OR = 2.65, p = 0.033).ConclusionOur results suggest MMP-2 and TIMP-2 genotypes play a crucial role in gastric cancer invasion, but not with development of gastric cancer.     

Predictors of the use of complementary and alternative medicine (CAM) by women at high risk for breast cancer

BackgroundFew data exist regarding the use of complementary and alternative medicine (CAM) by unaffected women at high risk of breast cancer.MethodsSelf-reported CAM use by women from multiple-case breast cancer families was obtained by questionnaire. Factors associated with CAM use were assessed using multiple logistic regression.ResultsOf 892 women, 55% (n = 489) used CAM, 6% (n = 53) specifically to prevent cancer. CAM use was independently associated with tertiary education level (OR 2.56, 95% CI 1.83–3.58, p < 0.001), greater physical activity (OR 1.05 per hour of physical activity/week, 95% CI 1.00–1.10, p = 0.049), greater anxiety (OR 1.92, 95% CI 1.16–3.16, p = 0.01), not currently smoking (OR 0.64, 95% CI 0.42–0.97, p = 0.037) and lower perceived BC risk (OR 0.82 per 20 percentage points, 95% CI 0.72–0.94, p = 0.005).ConclusionsThe majority of high-risk women use CAM, but mostly for reasons other than cancer prevention. Most predictors of CAM use are consistent with the limited literature for women at high risk for cancer.     

A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer

PurposeTo investigate the dose–response relationship and pain-relieving effect of radium-223, a highly bone-targeted alpha-pharmaceutical.MethodsOne hundred patients with castration-resistant prostate cancer (CRPC) and painful bone metastases were randomized to a single intravenous dose of 5, 25, 50 or 100 kBq/kg radium-223. The primary end-point was pain index (visual analogue scale [VAS] and analgesic use), also used to classify patients as responders or non-responders.ResultsA significant dose response for pain index was seen at week 2 (P = .035). At week 8 there were 40%, 63%, 56% and 71% pain responders (reduced pain and stable analgesic consumption) in the 5, 25, 50 and 100 kBq/kg groups, respectively. On the daily VAS, at week 8, pain decreased by a mean of −30, −31, −27 and −28 mm, respectively (P = .008, P = .0005, P = .002, and P < .0001) in these responders (post-hoc analysis). There was also a significant improvement in the brief pain inventory functional index for all dose-groups (P = .04, .01, .002 and .02, Wilcoxon signed rank test). Furthermore, a decrease in bone alkaline phosphatase in the highest dose-group was demonstrated (P = .0067). All doses were safe and well tolerated.ConclusionPain response was seen in up to 71% of the patients with a dose response observed 2 weeks after administration. The highly tolerable side-effect profile of radium-223 previously reported was confirmed.     

Physical activity level and quality of life in long term lung cancer survivors

PurposeLung cancer is associated with a multitude of challenges, and lung cancer survivors report significantly lower quality of life (QOL) than other cancer survivors.MethodsThis study aimed to examine the relationship between physical activity level and QOL in a large sample of long term lung cancer survivors (N = 1937). Average age at diagnosis was 65 years, 92% were Caucasian, and 51% male. Surveys were completed at lung cancer diagnosis and then average 4.2 years post-diagnosis.ResultsMost survivors reported having a sedentary lifestyle at both timepoints. However, 256 survivors reported a change in physical activity level from diagnosis to follow-up. Decreased physical activity (n = 140) was associated with decreased overall, mental, physical, emotional, social, and spiritual QOL (all ps < .001) and decreased symptom control as seen in reported pain, dry coughing, coughing with phlegm, shortness of breath, and level of fatigue (all ps < .05). In contrast, increased physical activity (n = 116) was associated with improved QOL (all ps < .05), and improved symptom control as seen in frequency and severity of pain (p < .01). For all participants, those engaging in regular physical activity (30 min or more per day, at least five days per week) reported significantly higher QOL scores (all ps < .001), and better symptom control than more sedentary survivors.ConclusionsResults indicate a significant association between change in physical activity and QOL and symptom control for long term lung cancer survivors, and research exploring interventions designed to improve activity level for lung cancer survivors is further warranted.     

Comorbidity, age and overall survival in patients with advanced pancreatic cancer - results from NCIC CTG PA.3: a phase III trial of gemcitabine plus erlotinib or placebo

BackgroundThe effect of comorbidity, age and performance status (PS) on treatment of advanced pancreatic cancer is poorly understood. We examined these factors as predictors of outcome in advanced pancreatic cancer patients treated with gemcitabine +/– erlotinib.Patients and methodsComorbidity was evaluated by two physicians using the Charlson Comorbidity Index (CCI) and correlated with clinical outcome data from the NCIC Clinical Trials Group (NCIC CTG) PA.3 clinical trial.ResultsFive hundred and sixty-nine patients were included; 47% were aged ⩾65 years old, 36% had comorbidity (CCI > 0). In multivariate analysis, neither age (p = 0.22) nor comorbidity (p = 0.21) was associated with overall survival. The baseline presence of better PS and lower pain intensity scores was associated with better overall survival (p < 0.0001 and p = 0.01, respectively). An improvement in survival with the addition of erlotinib therapy was seen in patients age <65 (adjusted hazard ratio (HR) 0.73, p = 0.01) or in the presence of comorbidity (adjusted HR 0.72, p = 0.03). However, neither age nor CCI score was predictive of erlotinib benefit after test for interaction. Patients treated with gemcitabine plus erlotinib who were ⩾65 years of age or those with comorbidity had a higher rate of infections ⩾grade 3.ConclusionLow baseline pain intensity and better PS were associated with improved overall survival, while age and comorbidity were not independent prognostic factors for patients treated with gemcitabine-based therapy.     

Impact of late treatment-related radiotherapy toxicity, depression, and anxiety on quality of life in long-term breast cancer survivors

IntroductionThis study aimed to assess the impact of late treatment toxicity (especially radiotherapy toxicity), chemoradiotherapy treatment type (concurrent or sequential), depression and anxiety on overall, physical and emotional quality of life (QoL) in long-term breast cancer survivors.MethodWe assessed 117 patients (mean follow-up since the end of treatment = 8.1 years) for late radiotherapy toxicity (LENT-SOMA scale), patient and doctor ratings of breast cosmetic outcomes, QoL (EORTC QLQ-C30), depression and anxiety (Hospital and Anxiety Depression scale).ResultsIn univariate analyses, factors associated with significantly decreased QoL were: use of sequential treatment and decreased overall QoL (P = 0.002) and emotional QoL (P = 0.02); few radiotherapy late toxicity symptoms (pain and decreased physical QoL, P = 0.01; fibrosis and decreased emotional QoL, P = 0.04); probable depression or probable anxiety and decreased overall, physical and emotional QoL (P ≤ 0.005). In multivariate analyses, probable depression and probable anxiety were the most stronger predictors for decreased QoL in the overall, physical and emotional domains (P ≤ 0.02).ConclusionImproving screening for and treatment of depression and anxiety might improve QoL in long-term breast cancer survivors.     

Humoral immune responses to MUC1 in women with a BRCA1 or BRCA2 mutation

IntroductionBreast cancer patients with early disease and a natural humoral response to MUC1 have a favourable prognosis, suggesting a possible role of MUC1 antibodies (ab) in controlling haematogenous tumour dissemination and outgrowth. The aim of the study was to evaluate humoral immune responses to MUC1 in women at hereditary high risk of breast cancer to investigate whether this immune response could play a role in the prevention of disease.Materials and methodsCA15.3 (U/mL), and IgG and IgM ab to MUC1 (arbitrary units per mL, Arb-U/mL) were measured in serum samples obtained from 422 women at hereditary high risk of breast/ovarian cancer, of whom 127 BRCA1/2 carriers, attending the Familial Cancer Clinic of the VU University Medical Centre, and from 370 age-matched healthy controls. Serum samples obtained from women who developed breast cancer (N = 12) or breast cancer recurrence (N = 17), and from women who underwent prophylactic mastectomy (N = 12) and had no breast lesions were also tested.ResultsCA15.3 ranked significantly higher in mutation carriers than in controls (P = 0.03). MUC1 IgG ab levels ranked significantly lower in BRCA1/2 mutation carriers than in controls (P = 0.003). MUC1 IgG levels were not significantly different (P = 0.53) between women who developed primary breast cancer (median 0.72 Arb-U/ml, range 0.52–2.44 Arb-U/ml) and women who underwent prophylactic mastectomy and had no breast lesions (median 1.04 Arb-U/ml, range 0.43–2.88 Arb-U/ml).ConclusionSerum levels of natural IgG ab to MUC1 are lower in BRCA1/2 mutation carriers than in healthy controls. Furthermore, in contrast to previous results in women with sporadic breast cancer, no elevated MUC1 IgG ab were seen in women at hereditary high risk who developed breast cancer. Prophylactic immunotherapy with MUC1 substrates may be a strategy to reduce the risk of breast cancer in BRCA1/2 mutation carriers, strengthening tumour immune surveillance.     

Postmastectomy radiotherapy reduces locoregional recurrence in elderly women with high-risk breast cancer

AimsClinical trials of adjuvant radiotherapy after mastectomy have largely excluded women aged 70 years or over, even though they comprise 30% of the breast cancer population. This study examined outcomes in elderly women with high-risk breast cancer treated with or without postmastectomy radiotherapy (PMRT).Materials and methodsData were analysed for 233 women aged 70 years or over with high-risk breast cancer (tumours >5 cm or ≥4 positive axillary nodes) treated with mastectomy and referred to the British Columbia Cancer Agency from 1989 to 1997. Tumour and treatment characteristics were compared between two cohorts: women treated with PMRT (n = 147) vs women treated without PMRT (n = 86). Univariate and multivariate analyses of 10-year Kaplan–Meier locoregional recurrence (LRR), distant recurrence, breast cancer-specific survival and overall survival were carried out.ResultsMedian follow-up time was 5.5 years. The distribution of tumour sizes was similar in the two groups. Compared with women treated without PMRT, higher proportions of women who underwent PMRT had four or more positive nodes (83% vs 67%, P = 0.01) and positive surgical margins (14% vs 4%, P = 0.02). Systemic therapy, used in 94% of women, was comparable in the two cohorts (P = 0.63). Elderly women treated with PMRT had significantly lower LRR compared with women treated without PMRT (16% vs 28%, P = 0.03). No differences in distant recurrence, breast cancer-specific survival or overall survival were observed in the two treatment groups (all P > 0.05). On multivariate analysis, the omission of PMRT and the presence of high-grade histology were significant predictors of LRR, whereas an increasing number of positive nodes was significantly associated with distant recurrence and overall survival.ConclusionsIn women aged 70 years or over with tumours greater than 5 cm or four or more positive nodes, significantly lower LRR was observed in women treated with radiotherapy compared with women treated without radiotherapy. PMRT should be considered in the management of elderly women with these high-risk characteristics.     

The efficacy of zoledronic acid in breast cancer adjuvant therapy: a meta-analysis of randomised controlled trials

BackgroundThe effect of zoledronic acid in breast cancer adjuvant therapy concerning improvement of patient survival has yet to be confirmed. We performed a meta-analysis of published and unpublished randomised controlled trials with the aim of accurate evaluation between clinical outcome and the association of the addition of zoledronic acid to adjuvant therapy.MethodsWe searched PubMed (from 1966 to present) and online abstracts from the proceeding Annual Meetings of the American Society of Clinical Oncology (ASCO) (years 1992–2010) and online abstracts from San Antonio Breast Cancer Symposium (years 2004–2010). A total of five eligible studies including 3676 subjects and 3678 controls met our search criteria and were evaluated. Random and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. The primary study end-points were the disease free survival (DFS). Secondary end-points were overall survival (OS), distant or loco-regional recurrence free survival and bone metastasis free survival.FindingsCompared with the control arm, adjuvant breast cancer treatment with zoledronic acid did not significantly improve overall survival, disease free survival, bone metastasis free survival, distant and locoregional recurrence free survival. However, in the postmenopausal subgroup, the addition of zoledronic acid to standard therapy could significantly improve DFS (relative risk (RR) = 0.763, 95% confidence interval (CI) 0.658–0.884, p < 0.001) and reduce the risk of distant (RR = 0.744, 95% CI 0.611–0.906, p = 0.003) and locoregional recurrence (RR = 0.508, 95% CI 0.340–0.760, p = 0.001).InterpretationAdjuvant zoledronic acid did not significantly improve the prognosis of breast cancer patients. Due to the highly variable definitions of menopause utilised in different studies, we hypothesise that zoledronic acid may have a potential effect on postmenopausal patients. Additional studies are needed to evaluate the value of adjuvant treatment of zoledronic acid in premenopausal counterparts, differing disease stages and various pathological types of breast cancer.     

Sphingosine kinase-1 activity and expression in human prostate cancer resection specimens

PurposeSphingosine kinase-1 (SphK1) was shown in preclinical models and non-genitourinary cancers to be instrumental in cancer progression, adaptation to hypoxia and in tumour angiogenesis. No data were available in human prostate cancer. The present study was designed to assess SphK1 expression and activity in radical prostatectomy specimens and to research correlations with clinical features.Materials and methodsTransverse section of fresh tissue was obtained from 30 consecutive patients undergoing laparoscopic prostatectomy. SphK1 enzymatic activities of tumour and normal counterpart were determined. Relationships with PSA, Gleason sum, pathological stage, resection margin status and treatment failure were researched. SphK1 pattern of expression was then assessed on tissue microarray.ResultsA significant 2-fold increase in SphK1 enzymatic activity(11.1 ± 8.4 versus 5.9 ± 3.2 (P < 0.04)) was observed in cancer. The upper quartile of SphK1 activity was associated with higher PSA (16.7 versus 6.4 ng/ml, P = 0.04), higher tumor volumes (20.7 versus 9.8, P = 0.002), higher rates of positive margins (85.7% versus 28.6%, P = 0.01) and surgical failure (71.4% versus 9.5%, P = 0.003) than the lower three quartiles. Odds ratios (OR) for treatment failure showed a strong relationship with SphK1 activity (OR: 23.7, P = 0.001), positive resection margins (OR: 15.0, P = 0.007) and Gleason sum (?4 + 3, OR: 8.0, P = 0.003). Tissue microarrays showed discrete epithelial expression that varied with Gleason sum with significant relationship between SphK1 expression and higher Gleason sum.ConclusionIn complement to preclinical literature, the demonstrated relationships between SphK1-increased activity in cancer and relevant clinical features confirm a central role for SphK1 in prostate cancer that herald promising avenues in risk-assessment and treatment.     

Resumption or persistence of menstruation after cytotoxic chemotherapy is a prognostic factor for poor disease-free survival in premenopausal patients with early breast cancer

BackgroundWe investigated the relationship between resumption or persistence of menstruation after cytotoxic chemotherapy (RM) and disease-free survival (DFS) in premenopausal patients with early breast cancer.MethodsMedical records from 872 patients who received cytotoxic chemotherapy for stage I to III breast cancer were retrospectively reviewed.ResultsThe median patient age was 41 years (range, 21–54) and the median follow-up duration was 6.2 years (range, 0.7–10.4). Six hundred ninety-two patients (79.4%) were hormone receptor (HR) positive and the majority of these received tamoxifen therapy after completing chemotherapy. The chemotherapy-induced amenorrhea (CIA) rate was 76.7% (n = 669), and 51.8% (n = 452) experienced RM during the follow-up period. One hundred twenty-one (13.9%) patients had persistent menstruation without CIA. DFS was significantly affected by younger age at diagnosis (≤35 years) (P = 0.013), tumor size > 2 cm (P < 0.001), node positivity (P < 0.001), HR negativity (P < 0.001), HER2 positivity (P = 0.010), and RM (P < 0.001). HR negativity [hazard ratio 1.7, 95% confidence interval (CI) 1.2–2.4, P = 0.006], tumor size > 2 cm (hazard ratio 2.1, 95% CI 1.4–3.0, P < 0.001), node positivity (hazard ratio 3.0, 95% CI 2.0–4.7, P < 0.001), and RM (hazard ratio 1.8, 95% CI 1.2–2.7, P = 0.004) remained significant factors for DFS on multivariate analysis.ConclusionsA considerable proportion of premenopausal patients treated with chemotherapy experienced RM after CIA. RM was a poor prognostic factor for DFS in premenopausal patients with early breast cancer.     

Recreational and household physical activity at different time points and DNA global methylation

BackgroundDNA methylation patterns are heritable but can change over time and in response to exposures. Lower global DNA methylation, which may result in increased genomic and chromosomal instability, has been associated with increased cancer risk. Physical activity is a modifiable factor that has been inversely related to the risk of cancer. Changes in DNA methylation may be a mechanism by which lifestyle and environment factors influence disease. We investigated the relationship between DNA methylation and physical activity in a sample of women enroled in The Sister Study, a large United States (U.S.) cohort study of women aged 35–74 years with a family history of breast cancer.MethodsGlobal DNA methylation was measured using bisulphite-converted DNA and pyrosequencing of a LINE-1 repetitive sequence in the peripheral blood of 647 non-Hispanic white women. Physical activity (average hours per week) was retrospectively assessed for three time periods: childhood (ages 5–12), teenage years (ages 13–19) and the previous 12 months.FindingsCompared with women with physical activity levels below the median for all three time periods, those at or above the median physical activity for one (β = 0.20, 95% confidence interval (CI): ?0.10, 0.49), two (β = 0.22, 95% CI: ?0.08, 0.52) or all three (β = 0.33, 95% CI: 0.01, 0.66) time periods had increased global methylation.InterpretationMaintaining higher levels of physical activity over these three time periods was associated with increased global DNA methylation, consistent with reported associations between exercise and decreased cancer risk.     

Functional status declines among cancer survivors: Trajectory and contributing factors

ObjectiveThis study aimed to quantify functional status (FS) trajectories pre- and post-diagnosis of cancer, FS trajectories among cancer-free individuals, and factors affecting FS.Materials and MethodsSelf-reported FS, scored from 0 (worst) to 100 (best), of Atherosclerosis Risk in Communities (ARIC) Study cohort participants diagnosed with incident cancer (lung (N = 303), breast (N = 374), prostate (N = 529), colorectal (N = 228)), and cancer-free participants (N = 11,155) over 15 years was examined. FS was evaluated in two ways: 1) until death or follow-up year 15 (Model 1) and 2) same as survivorship model except that a FS value of zero was used for assessments after death to follow-up year 15 (Model 2). Mean FS at discrete time points were used to generate FS trajectories. Differences in repeated measures of FS were assessed using linear growth models.ResultsWithin one year after diagnosis, FS scores declined compared to the cancer-free group, except for prostate cancer. FS continued to decline beyond one year after lung or colorectal cancer diagnosis. FS was lower in all cancer groups, except prostate, compared to the cancer-free group (Model 1: lung − 4.76, breast − 2.28, colorectal − 2.55; Model 2: lung − 2.36, breast − 2.46, colorectal − 2.31). Predictors of decreased FS score independent of cancer diagnosis included low education, comorbidities, obesity, smoking, lack of health insurance, and age.ConclusionFS in all incident cancer groups declined during the first year post-diagnosis, which could be due to intensive treatments. Targeting factors related to FS declines could improve health outcomes for patients with cancer.     

The number of positive nodes and the ratio of positive to excised nodes are significant predictors of survival in women with micrometastatic node-positive breast cancer

BackgroundTo evaluate the prognostic impact of the number of positive nodes and the lymph node ratio (LNR) of positive to excised nodes on survival in women diagnosed with nodal micrometastatic breast cancer before the era of widespread sentinel lymph node biopsy.MethodsSubjects were 62,551 women identified by the Surveillance Epidemiology and End Results database, diagnosed with pT1–2pN0-1 breast cancer between 1988 and 1997. Kaplan–Meier breast cancer-specific survival (BCSS) and overall survival (OS) were compared between three cohorts: node-negative (pN0, n = 57,980) nodal micrometastasis all ⩽2 mm (pNmic, N = 1818), and macroscopic nodal metastasis >2 mm but <2 cm (pNmac, n = 2753). Nodal subgroups were examined by the number of positive nodes (1–3 versus ⩾4) and the LNR (⩽0.25 versus >0.25).ResultsMedian follow-up was 7.3 yr. Ten-year BCSS and OS in pNmic breast cancer were significantly lower compared to pN0 disease (BCSS 82.3% versus 91.9%, p < 0.001 and OS 68.1% versus 75.7%, p < 0.001). BCSS and OS with pNmic disease progressively declined with increasing number of positive nodes and increasing LNR. OS with pNmic was similar to pNmac disease when matched by the number of positive nodes and by the LNR. Both pN-based and LNR-based classifications were significantly prognostic of BCSS and OS on Cox regression multivariate analysis.ConclusionNodal micrometastasis is associated with poorer survival compared to pN0 disease. Mortality hazards with nodal micrometastasis increased with increasing number of positive nodes and increasing LNR. The number of positive nodes and the LNR should be considered in risk estimates for patients with nodal micrometastatic breast cancer.     

Effect of lymphoid volume irradiation on radiation-induced lymphopenia in head and neck cancers

PurposeRadiotherapy induces significant and prolonged lymphopenia in head and neck cancer patients with poorer outcomes and reduced survival. Irradiated volumes may be correlated with lymphopenia with a potential impact on immunotherapy efficacy. We assessed associations between volumes treated with radiotherapy and the nadir of the lymphocyte count in patients with head and neck cancer.Materials and methodsWe conducted a monocentric retrospective study in patients with head and neck cancer treated with radiation. Univariate analysis used regression analysis to model nadir lymphocyte count and radiotherapy volumes; multivariate analysis then modelled factors associated with nadir lymphocyte count.ResultsOf the 77 included patients, 97% presented lymphopenia during radiotherapy with an average nadir of 431 cells/mm³ at a median of 40 days after the beginning of treatment. The volume of high-risk radiotherapy and gross tumour volume were correlated with nadir lymphocyte count with a Spearman coefficient of −0.267 (P = 0.019) and −0.387 (P = 0.001), respectively. After multivariate linear regression, high-risk radiotherapy was significantly associated with nadir lymphocyte count with a regression coefficient of −0.32 (per cubic centimetre) [95% CI = −0.60; −0.03] (P = 0.028).ConclusionHigh-risk radiotherapy was significantly associated with nadir lymphocyte count in patients with head and neck cancer treated with radiation. Sparing lymphoid volumes from irradiation by elective nodal irradiation or proton therapy may limit lymphopenia and needs to be investigated in combination with immunotherapy.     

Cosmesis, late sequelae and local control after breast-conserving therapy: influence of type of tumour bed boost and adjuvant chemotherapy

AimsTo study the influence of various factors affecting cosmetic outcome and late sequelae in a large cohort of women treated with breast-conserving therapy.Materials and methodsBetween 1980 and 2000, 1022 pathological stage I/II breast cancer patients underwent breast-conserving therapy. On the basis of the type of tumour bed boost they received after whole breast radiotherapy, these women were assigned to three groups: (A) low dose rate (LDR) brachytherapy of 15–20 Gy (n = 383); (B) high dose rate (HDR) brachytherapy of 10 Gy (optimised) in a single fraction (n = 153); (C) electron beam 15 Gy/six fractions (n = 460). Systemic adjuvant therapy was given to 757 women, of whom 570 received adjuvant chemotherapy.ResultsCosmesis at the last follow-up was good or excellent in 77% of women. Post-radiation worsening of cosmesis was observed in 11.5% of women and was similar in the three boost groups. Moderate to severe late breast sequelae were observed in 22% of women in group B, which was significantly higher than the 12% in group A (P = 0.002) and 9% in group C (P = 0.0001). The actuarial 5-year local control rate was 91% and was 90, 92 and 93% in groups A, B and C, respectively. Tumour size (P = 0.049) and adjuvant chemotherapy (P = 0.04) were the significant factors affecting cosmetic outcome on univariate analysis. On multivariate analysis, adjuvant chemotherapy was the only factor leading to worsening in the cosmetic outcome, with P = 0.03 (hazard ratio 1.65 [95% confidence interval 1.05–2.59]).ConclusionThe type of tumour bed boost did not have a significant effect on the worsening of cosmetic outcome. However, there were significantly more late breast sequelae in women treated with single fraction HDR implants. Chemotherapy had an adverse effect on the cosmetic outcome, but the late breast sequelae and local control rates were comparable.     

Lack of TIMP-1 tumour cell immunoreactivity predicts effect of adjuvant anthracycline-based chemotherapy in patients (n = 647) with primary breast cancer. A Danish Breast Cancer Cooperative Group Study

PurposeA number of prospective studies have shown that adjuvant CEF significantly improves disease-free and overall survival as compared to CMF in breast cancer patients. Our aim was to determine whether the benefit of epirubicin versus methotrexate differs according to TIMP-1 tumour cell immunoreactivity.Experimental designTissue micro arrays from 647 patients randomly assigned to CMF or CEF in DBCG trial 89D were included. The primary end-point was invasive disease-free survival (IDFS). A central assessment of tissue inhibitor of metalloproteinases 1 (TIMP-1) status was performed using immunohistochemistry (IHC). Tumours were regarded as TIMP-1 positive if epithelial breast cancer cells were stained using the anti-TIMP-1 monoclonal antibody VT7.ResultsBy central assessment 75% of tumours were classified as tumour cell TIMP-1 positive. Among CEF-treated patients, individuals with TIMP-1 negative tumours had a significant longer IDFS than patients with TIMP-1 positive tumours (p = 0.047). The multivariate Cox regression analysis of IDFS showed that CEF was superior to CMF among patients with TIMP-1 negative tumours (hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.31–0.84, p = 0.0085), while no significant difference could be demonstrated among patients with TIMP-1 positive tumours (HR = 0.88; 95% CI: 0.68–1.13, p = 0.32). A non-significant TIMP-1 status (positive or negative) versus treatment (CMF or CEF) interaction was detected for IDFS (p = 0.06) and OS (p = 0.21).ConclusionLack of TIMP-1 tumour cell immunoreactivity seems to predict a favourable effect of epirubicin-containing adjuvant therapy in primary breast cancer. However, an independent study is awaited to validate the potential predictive value of TIMP-1 immunoreactivity.     

Mammographic changes resulting from benign breast surgery impair breast cancer detection at screening mammography

PurposeTo study possible explanations for lower screening performance after previous benign breast surgery.Patients and methodsWe included a consecutive series of 351,009 screening examinations in 85,274 women, obtained between January 1, 1997 and January 1, 2009. The examinations of women with screen detected cancers (SDC) or interval cancers (IC), diagnosed after previous benign breast surgery, were reviewed by two screening radiologists. They determined the presence and degree of post surgical changes, classified breast density and determined whether mammographic interpretation was hampered by tissue characteristics. They also assessed whether the cancer had already been visible at a previous screen.ResultsScreening sensitivity was lower in women with prior benign breast surgery than without (63.5% (115/181) versus 73.5% (1643/2236), p = 0.004). A total of 115 SDCs and 66 ICs were diagnosed in breasts after previous benign breast surgery. Post surgical mammographic alterations in the breast segment where cancer was diagnosed were more distinct in ICs than in SDCs (p = 0.001). Women with post surgical mammographic changes at the location of the breast cancer had an increased interval cancer risk (OR = 2.12, 95% confidence interval (CI) = 1.05–4.26). Limited mammographic interpretation due to tissue characteristics was mentioned, only in three SDCs and one IC. The proportions of SDCs and ICS that were already visible at a previous screen were comparable for women with and without prior surgery (SDC: 47.5% versus 43.8%, p = 0.3, IC: 50.0% versus 48.4%, p = 0.8).ConclusionPrevious benign breast surgery decreases screening sensitivity and this is likely due to postoperative mammographic changes.     

What influences clinicians’ operative preferences for women with breast cancer? An application of the discrete choice experiment

IntroductionLittle is known regarding cancer clinicians’ treatment preferences.AimDetermine the impact of pre-operative variables over specialist breast clinicians’ operative preferences using discrete choice experiment methodology.MethodsCross-sectional survey of operative preferences to hypothetical scenarios based on: patient age, bra cup size, cancer size, site and focality.Results73% response rate (68/93). Multinomial logistic regression across scenarios (n = 1695) with allowance for response clustering, comparing equal preference for mastectomy and breast conservation surgery (BCS) with preference for mastectomy or BCS. Increasing patient age, cancer size, central site, multi-focality and reducing cup size, all associated with preference for mastectomy, over equal preference, over BCS (p < 0.001). Doctors preferred specific treatments, females and nurses avoided mastectomy (p = 0.015 and p < 0.001 respectively).ConclusionsClinician preferences were predominantly treatment guideline congruent, but significantly influenced by patient age, clinician gender and occupation. This methodology is capable of elucidating treatment preferences and could be applied elsewhere where treatment options and practice variability exist.     

Protective effects of berberine on radiation-induced lung injury via intercellular adhesion molecular-1 and transforming growth factor-beta-1 in patients with lung cancer

PurposeTo investigate the protective effects of berberine on radiation-induced lung injury (RILI) in non-small cell lung cancer (NSCLC) patients treated with radiotherapy.Patients and methodsIn this randomised, double-blind study, 90 patients with NSCLC were divided into two groups. The trial group received radiation therapy plus berberine, and the control group received radiation therapy plus a placebo for 6 weeks. Soluble intercellular adhesion molecular-1 (sICAM-1) and transforming growth factor-beta-1 (TGF-β1) were measured. RILI and pulmonary function were evaluated at 6 weeks and 6 months after treatment, respectively.ResultsOf the 90 patients enroled, 43 in the control group and 42 in the trial group completed the study. The incidence of RILI was significantly lower in the trial group at 6 weeks and 6 months than that in the control group (45.2% versus 72.1% and 35.7% versus 65.1%, respectively, both P < 0.05). sICAM-1 levels in the trial group were significantly lower at weeks 6 and 12 (373.64 ± 89.33 versus 459.53 ± 123.59 and 447.83 ± 111.21 versus 513.91 ± 150.46, both P < 0.01), and plasma TGF-β1 levels were lower at week 3 and 6 (5.43 ± 1.47 versus 6.22 ± 1.78 and 5.93 ± 2.39 versus 7.67 ± 2.74, P < 0.05 and 0.01, respectively) in comparison with the control group. Significant differences were observed in FEV1 (P = 0.033) and DLCO (P = 0.003) between patients receiving berberine and those receiving placebo. Independent-samples T-test showed reductions from baseline FVC at week 6 (P < 0.05), and FEV1 and DLCO at month 6 (P < 0.05 and 0.01, respectively) in the trial group were significantly smaller than that in the control group.ConclusionBerberine significantly reduced the incidence of RILI, improved PF and decreased the levels of sICAM-1 and TGF-β1. The exact mechanisms remain to be further explored.