Lymphocyte density determined by computational pathology validated as a predictor of response to neoadjuvant chemotherapy in breast cancer: secondary analysis of the ARTemis trial.

BACKGROUND: We have previously shown lymphocyte density, measured using computational pathology, is associated with pathological complete response (pCR) in breast cancer. The clinical validity of this finding in independent studies, among patients receiving different chemotherapy, is unknown. PATIENTS AND METHODS: The ARTemis trial randomly assigned 800 women with early stage breast cancer between May 2009 and January 2013 to three cycles of docetaxel, followed by three cycles of fluorouracil, epirubicin and cyclophosphamide once every 21 days with or without four cycles of bevacizumab. The primary endpoint was pCR (absence of invasive cancer in the breast and lymph nodes). We quantified lymphocyte density within haematoxylin and eosin (H&E) whole slide images using our previously described computational pathology approach: for every detected lymphocyte the average distance to the nearest 50 lymphocytes was calculated and the density derived from this statistic. We analyzed both pre-treatment biopsies and post-treatment surgical samples of the tumour bed. RESULTS: Of the 781 patients originally included in the primary endpoint analysis of the trial, 609 (78%) were included for baseline lymphocyte density analyses and a subset of 383 (49% of 781) for analyses of change in lymphocyte density. The main reason for loss of patients was the availability of digitized whole slide images. Pre-treatment lymphocyte density modelled as a continuous variable was associated with pCR on univariate analysis (odds ratio [OR], 2.92; 95% CI, 1.78-4.85; P < 0.001) and after adjustment for clinical covariates (OR, 2.13; 95% CI, 1.24-3.67; P = 0.006). Increased pre- to post-treatment lymphocyte density showed an independent inverse association with pCR (adjusted OR, 0.1; 95% CI, 0.033-0.31; P < 0.001). CONCLUSIONS: Lymphocyte density in pre-treatment biopsies was validated as an independent predictor of pCR in breast cancer. Computational pathology is emerging as a viable and objective means of identifying predictive biomarkers for cancer patients. CLINICALTRIALS.GOV: NCT01093235.

Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial.

BACKGROUND: The ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review. PATIENTS AND METHODS: Patients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class. RESULTS: A total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2-4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89-1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90-1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23-0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24-0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group. CONCLUSIONS: The addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer. CLINICALTRIALS.GOV NUMBER: NCT01093235.

PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes.

BACKGROUND: Expression of programmed death ligand 1 (PD-L1) in solid tumours has been shown to predict whether patients are likely to respond to anti-PD-L1 therapies. To estimate the therapeutic potential of PD-L1 inhibition in breast cancer, we evaluated the prevalence and significance of PD-L1 protein expression in a large collection of breast tumours. PATIENTS AND METHODS: Correlations between CD274 (PD-L1) copy number, transcript and protein levels were evaluated in tumours from 418 patients recruited to the METABRIC genomic study. Immunohistochemistry was used to detect PD-L1 protein in breast tumours in tissue microarrays from 5763 patients recruited to the SEARCH population-based study (N = 4079) and the NEAT randomised, controlled trial (N = 1684). RESULTS: PD-L1 protein data was available for 3916 of the possible 5763 tumours from the SEARCH and NEAT studies. PD-L1 expression by immune cells was observed in 6% (235/3916) of tumours and expression by tumour cells was observed in just 1.7% (66/3916). PD-L1 was most frequently expressed in basal-like tumours. This was observed both where tumours were subtyped by combined copy number and expression profiling [39% (17/44) of IntClust 10 i.e. basal-like tumours were PD-L1 immune cell positive; P < 0.001] and where a surrogate IHC-based classifier was used [19% (56/302) of basal-like tumours were PD-L1 immune cell positive; P < 0.001]. Moreover, CD274 (PD-L1) amplification was observed in five tumours of which four were IntClust 10. Expression of PD-L1 by either tumour cells or infiltrating immune cells was positively correlated with infiltration by both cytotoxic and regulatory T cells (P < 0.001). There was a nominally significant association between PD-L1 and improved disease-specific survival (hazard ratio 0.53, 95% confidence interval 0.26-1.07; P = 0.08) in ER-negative disease. CONCLUSIONS: Expression of PD-L1 is rare in breast cancer, markedly enriched in basal-like tumours and is correlated with infiltrating lymphocytes. PD-L1 inhibition may benefit the 19% of patients with basal-like tumours in which the protein is expressed. NEAT CLINICALTRIALSGOV: NCT00003577.

Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients.

BACKGROUND: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date. PATIENTS AND METHODS: Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival. RESULTS: In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1). CONCLUSIONS: The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.

A central review of histopathology reports after breast cancer neoadjuvant chemotherapy in the neo-tango trial.

BACKGROUND: Neo-tAnGo, a National Cancer Research Network (NCRN) multicentre randomised neoadjuvant chemotherapy trial in early breast cancer, enroled 831 patients in the United Kingdom. We report a central review of post-chemotherapy histopathology reports on the surgical specimens, to assess the presence and degree of response. METHODS: A central independent two-reader review (EP and HME) of histopathology reports from post-treatment surgical specimens was performed. The quality and completeness of pathology reporting across all centres was assessed. The reviews included pathological response to chemotherapy (pathological complete response (pCR); minimal residual disease (MRD); and lesser degrees of response), laterality, the number of axillary metastases and axillary nodes, and the type of surgery. A consensus was reached after discussion. RESULTS: In all, 825 surgical reports from 816 patients were available for review. Out of 4125 data items there were 347 discrepant results (8.4% of classifications), which involved 281 patients. These involved grading of breast response (169 but only 9 involving pCR vs MRD); laterality (6); presence of axillary metastasis (35); lymph node counts (108); and type of axillary surgery (29). Excluding cases with pCR, only 45% of reports included any comment regarding response in the breast and 30% in the axillary lymph nodes. CONCLUSION: We found considerable variability in the completeness of reporting of surgical specimens within this national neoadjuvant breast cancer trial. This highlights the need for consensus guidelines among trial groups on histopathology reporting, and the participation of histopathologists throughout the development and analysis of neoadjuvant trials.

Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials.

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses. METHODS: National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles. RESULTS: In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65-0.86), P<0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65-0.89), P=0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours. CONCLUSION: Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.

The cost-effectiveness of adjuvant chemotherapy for early breast cancer: A comparison of no chemotherapy and first, second, and third generation regimens for patients with differing prognoses.

BACKGROUND: The risk of recurrence following surgery in women with early breast cancer varies, depending upon prognostic factors. Adjuvant chemotherapy reduces this risk; however, increasingly effective regimens are associated with higher costs and toxicity profiles, making it likely that different regimens may be cost-effective for women with differing prognoses. To investigate this we performed a cost-effectiveness analysis of four treatment strategies: (1) no chemotherapy, (2) chemotherapy using cyclophosphamide, methotrexate, and fluorouracil (CMF) (a first generation regimen), (3) chemotherapy using Epirubicin-CMF (E-CMF) or fluorouracil, epirubicin, and cyclophosphamide (FEC60) (a second generation regimens), and (4) chemotherapy with FEC60 followed by docetaxel (FEC-D) (a third generation regimen). These adjuvant chemotherapy regimens were used in three large UK-led randomised controlled trials (RCTs). METHODS: A Markov model was used to simulate the natural progression of early breast cancer and the impact of chemotherapy on modifying this process. The probability of a first recurrent event within the model was estimated for women with different prognostic risk profiles using a parametric regression-based survival model incorporating established prognostic factors. Other probabilities, treatment effects, costs and quality of life weights were estimated primarily using data from the three UK-led RCTs, a meta-analysis of all relevant RCTs, and other published literature. The model predicted the lifetime costs, quality adjusted life years (QALYs) and cost-effectiveness of the four strategies for women with differing prognoses. Sensitivity analyses investigated the impact of uncertain parameters and model assumptions. FINDINGS: For women with an average to high risk of recurrence (based upon prognostic factors and any other adjuvant therapies received), FEC-D appeared most cost-effective assuming a threshold of £20,000 per QALY for the National Health Service (NHS). For younger low risk women, E-CMF/FEC60 tended to be the optimal strategy and, for some older low risk women, the model suggested a policy of no chemotherapy was cost-effective. For no patient group was CMF chemotherapy the preferred option. Sensitivity analyses demonstrated cost-effectiveness results to be particularly sensitive to the treatment effect estimate for FEC-D and the future price of docetaxel. INTERPRETATION: To our knowledge, this analysis is the first cost-effectiveness comparison of no chemotherapy, and first, second, and third generation adjuvant chemotherapy regimens for early breast cancer patients with differing prognoses. The results demonstrate the potential for different treatment strategies to be cost-effective for different types of patients. These findings may prove useful for policy makers attempting to formulate cost-effective treatment guidelines in the field of early breast cancer.

Accuracy of unidimensional and volumetric ultrasound measurements in predicting good pathological response to neoadjuvant chemotherapy in breast cancer patients.

Pathological complete response (pCR) is an important predictor of long-term survival in patients with breast cancer receiving neoadjuvant chemotherapy (NAC). At present, the accuracy of traditional radiological assessments during treatment in predicting pCR is poor. Unidimensional and 3D volumetric ultrasound measurements prior to, after 4 cycles (mid-treatment), and at the end of 8 cycles (end-treatment) of chemotherapy were available from a subset of 55 patients enrolled in Neo-tAnGo, a National Cancer Research Network (NCRN) UK neoadjuvant chemotherapy breast cancer trial. Proportional changes in longest diameter (LD) and volume as well as absolute residual size thresholds were examined for their ability to predict pCR or pCR plus minimal residual disease (pCR/MRD). Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) and likelihood ratios (LRs) were calculated. Receiver-operator characteristic (ROC) curves and logistic regression models were also constructed. At mid-treatment, neither complete radiological response, nor proportional LD or volume changes were found predictive of final pCR. A small residual tumour volume (≤ 1 cm³ vs. > 1 cm³) at mid-treatment, however, was associated with pCR/MRD (P = 0.014). Sensitivity, specificity, PPV, NPV, LR+ and LR- values were 61%, 77%, 61%, 77%, 2.62 and 0.51, respectively. The area under the ROC curve was 0.689 (P = 0.03). Volume ≤ 1 cm³ at mid-treatment was found significant in a logistic regression (OR: 0.194, P = 0.011). At end-treatment, no ultrasound measurements were found predictive of pCR or pCR/MRD. In conclusion, proportional tumour size changes (the basis of the RECIST criteria) were not found predictive of good pathological response, although residual volume ≤ 1 cm³ at mid-treatment was found to be predictive of pCR/MRD. However, multiple volume and LD thresholds were examined and uncorrected P values presented, increasing the possibility of type I errors. Replication in an independent dataset is required.

NEAT: National Epirubicin Adjuvant Trial--toxicity, delivered dose intensity and quality of life.

The NEAT trial reported considerable benefit for ECMF (epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil) of 28% for relapse-free survival (RFS) and 30% for overall survival (OS), when compared with classical CMF in early breast cancer. To assess tolerability, toxicity, dose intensity and quality of life (QoL) analyses were undertaken. All 2021 eligible patients had common toxicity criteria (CTC), delivered chemotherapy and supportive treatments details and long-term morbidities recorded. The QoL substudy used multiple validated measures. ECMF produced low CTC scores, although higher than CMF for nausea, vomiting, alopecia, constipation, stomatitis (P<0.001), infection (P=0.001) and fatigue (P=0.03). Supportive treatments required, however, were similar across randomised treatments. On-treatment deaths were more common with CMF (13) than ECMF(5). Optimal course-delivered dose intensity (CDDI > or =85%) was received more often by ECMF patients (83 vs 76%: P=0.0002), and was associated with better RFS (P=0.0006). QoL over 2 years was equivalent across treatments, despite minimally worse side effects for ECMF during treatment. ECMF benefit spanned all levels of toxicity, CDDI and QoL. There are no reported acute myeloid leukaemias or cardiac dysfunctions. ECMF is tolerable, deliverable, and significantly more effective than CMF, with no serious long-term toxicity or QoL detriment.

tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast cancer: a prospective pulmonary, cardiac and hepatic function evaluation.

tAnGo is a large randomised trial assessing the addition of gemcitabine(G) to paclitaxel(T), following epirubicin(E) and cyclophosphamide(C) in women with invasive higher risk early breast cancer. To assess the safety and tolerability of adding G, a detailed safety substudy was undertaken. A total of 135 patients had cardiac, pulmonary and hepatic function assessed at (i) randomisation, (ii) mid-chemotherapy, (iii) immediately post-chemotherapy and (iv) 6 months post-chemotherapy. Skin toxicity was assessed during radiotherapy. No differences were detected in FEV(1) or FVC levels between treatment arms or time points. Diffusion capacity (TL(CO)) reduced during treatment (P<0.0001), with a significantly lower drop in EC-GT patients (P=0.02). Most of the reduction occurred during EC and recovered by 6-months post treatment. There was no difference in cardiac function between treatment arms. Only 11 patients had echocardiography/MUGA results change from normal to abnormal during treatment, with only five having LVEF<50%. Transient transaminitis occurred in both treatment arms with significantly more in EC-GT patients post-chemotherapy (AST P=0.03, ALT P=0.003), although the majority was low grade. There was no correlation between transaminitis and other toxicities. Both treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis levels. Despite these being greater with EC-GT, both regimens appear well tolerated.

Questioning specialists' attitudes to breast cancer follow-up in primary care.

BACKGROUND: National Institute for Clinical Excellence (NICE) guidelines recommend discharging asymptomatic breast care patients 3 years after diagnosis. A role for General Practitioners (GPs) and breast care nurses is proposed, together with skills training, but it remains unclear for how long breast cancer patients should be followed up, what tests should be done, and who should be conducting the follow-up. We therefore surveyed Breast Cancer Specialists. DESIGN: A 20-point questionnaire was sent to 562 Specialists registered in the Cancer Research Clinical Trials Unit database, with questions on case-load, perceptions of follow-up, local policy and opinions on greater primary care involvement. RESULTS: The most commonly acknowledged purpose of follow-up was detection of treatment-related morbidity. Eighty four percent of respondents adhered to a locally developed protocol with only 9% conforming to NICE guidelines. The median follow-up was 5 years. Significant factors predicting delayed discharge were younger age (P < or = 0.0001); poorer Nottingham Prognostic Index (P = 0.003); treatment factors (P = 0.002); and patient risk factors (P = 0.003). Centres with higher case-loads (>200/year) were more likely to discharge earlier. Reduced workload was perceived as the main benefit of discharge, while lack of GP oncological experience and loss of outcome data were concerns. CONCLUSIONS: Specialists favour a risk adjusted discharge strategy and increased oncology infrastructure in primary care.

Impaired endothelial function in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) patients suffer from excess cardiac deaths due to accelerated atherosclerosis. Endothelial dysfunction is a marker of early atherosclerosis. We tested the hypothesis that SLE patients have impaired endothelial function and assessed the relationship between endothelial function and clinical outcome over the subsequent five years. Thirty-six female SLE patients were compared with 22 healthy age and sex matched controls. Endothelial dependent vasodilatation (EDD) was assessed at the brachial artery in response to shear stress. Endothelium-independent dilatation induced by glyceryl trinitrate was also measured. Patients were followed for up to five years and the development of damage in the cardiovascular and other systems recorded. SLE patients showed significantly impaired endothelial function (median EDD 5.6%, IQR 3.1-7.2%) compared with healthy controls (median EDD 8.0%, IQR 6.3-9.3%; P = 0.001). Endothelium independent dilatation did not differ between the two groups. Endothelial function was significantly worse in postmenopausal compared with premenopausal women (median EDD 6.6%, IQR 3.9-7.8% versus 3.1%, IQR 2.6-5.1%; P = 0.016). Total cholesterol was inversely correlated with endothelial function in SLE patients (Spearman correlation r = -0.422, P = 0.025). There was no relationship between endothelial function and the development of damage in any organ system, including the cardiovascular system during patient follow-up. Patients with SLE have impaired endothelial Lupus (2007) 16, 84-88.

Criterion validity of the BBUSQ-22: a questionnaire assessing bowel and urinary tract symptoms in women.

To evaluate the criterion validity of the Birmingham Bowel and Urinary Symptoms Questionnaire (BBUSQ-22). Forty-four women presenting with urinary or bowel symptoms to a urogynaecology/functional bowel clinic, completed three disease-specific questionnaires (Birmingham Bowel and Urinary Symptoms Questionnaire, Sheffield Prolapse Symptoms Questionnaire and King's Health Questionnaire) and two generic questionnaires (SF-36 and EuroQol). Wilcoxon rank sum tests, Spearman's rank correlations and multiple regression analyses were undertaken. All clinically hypothesised correlations between the questionnaires' domains were found significant, and all domains hypothesised to be predictors of the BBUSQ-22 domains were proven to be prognostic, without explaining too much variability to doubt their uniqueness. The similarity among the measures has been proved without such relationships being too strong to call into question the distinctiveness of the concepts being measured. Overall, criterion validity is demonstrated, and the clinical usefulness of the addition this questionnaire makes to the area is highlighted.

A prospective double blind placebo-controlled randomized trial of ultrasound in the physiotherapy treatment of shoulder pain.

OBJECTIVE: To compare the effectiveness of manual therapy and ultrasound (US) with manual therapy and placebo ultrasound (placebo US) in the treatment of new episodes of unilateral shoulder pain referred for physiotherapy. METHODS: In a multicentre, double blind, placebo-controlled randomized trial, participants were recruited with a clinical diagnosis of unilateral shoulder pain from nine primary care physiotherapy departments in Birmingham, UK. Recruitment took place from January 1999 to September 2001. Participants were 18 yrs old and above. Participants all received advice and home exercises and were randomized to additionally receive manual therapy plus US or manual therapy plus placebo US. The primary outcome measure was the Shoulder Disability Questionnaire (SDQ-UK). Outcomes were assessed at baseline, 2 weeks, 6 weeks and 6 months. Analysis was by intention to treat. RESULTS: A total of 221 participants (mean age 56 yrs) were recruited. 113 participants were randomized to US and 108 to placebo US. There was 76% follow up at 6 weeks and 71% at 6 months. The mean (95% CI) reduction in SDQ scores at 6 weeks was 17 points (13-26) for US and 13 points (9-17) for placebo US (P = 0.06). There were no statistically significant differences at the 5% level in mean changes between groups at any of the time points. CONCLUSIONS: The addition of US was not superior to placebo US when used as part of a package of physiotherapy in the short-term management of shoulder pain. This has important implications for physiotherapy practice.

The SDF-1 G > A polymorphism at position 801 plays no role in multiple myeloma but may contribute to an inferior cause-specific survival in chronic lymphocytic leukemia.

The growth and circulation of B lymphocytes is largely under the control of bone marrow stromal cells, cytokines and chemokines. The gene responsible for the pivotal B cell growth factor, stromal derived factor-1 (SDF-1), has recently been shown to contain a single nucleotide polymorphism G > A at position 801 which leads to higher SDF-1 secretion. This polymorphism is common in the normal population and has been shown to play a potential role in the development of both HIV and non-HIV related non-Hodgkin's lymphoma. We therefore undertook a large single-centre study to ascertain its role in the pathogenesis of two other common B-cell malignancies, notably chronic lymphocytic leukemia (CLL- 197 patients) and multiple myeloma (126 patients). We show that the 801 G > A polymorphism plays no role in the incidence of multiple myeloma or CLL nor the outcome in multiple myeloma. By contrast, it trends towards an inferior cause-specific survival in CLL.

Development and psychometric testing of a symptom index for pelvic organ prolapse.

A wide range of symptoms are commonly ascribed to pelvic organ prolapse including pain, awareness of lump, bowel, bladder and sexual dysfunction. The aim of this work was to develop and validate an instrument to quantify symptoms related to pelvic organ prolapse. Consultation with symptomatic women and specialists in coloproctology, urology, gynaecology and sexual health resulted in a questionnaire with 25 questions. In total, 203 women participated in a psychometric testing of this instrument, 152 cases with prolapse and 51 controls without. The content validity, criterion validity, reliability and responsiveness of the questionnaire were evaluated. The questionnaire proved a reliable and valid instrument for the assessment of symptoms related to uterovaginal prolapse. It is also sensitive to change.

Review of second-line chemotherapy for advanced gastric adenocarcinoma.

Palliative chemotherapy has been shown to improve survival compared with best supportive care alone in patients with unresectable or recurrent gastric cancer. However, patients receiving chemotherapy eventually develop progressive disease. At this stage, no standard second-line chemotherapy can be offered. No randomised-controlled trial data suggest a benefit of second-line chemotherapy compared with supportive care alone. We review the published data concerning the use of second-line chemotherapy in gastric adenocarcinoma. Response rates to second-line therapy in phase II trials are similar to those seen for other cancers that are more commonly retreated. In addition, data suggest that patients who respond to second-line therapy consistently survive longer compared with non-responders, and, perhaps more importantly, symptomatic benefit may be obtained from second-line therapy.

The effect of biological effective dose on time to symptom progression in metastatic renal cell carcinoma.

AIMS: Renal cell carcinoma is commonly thought to be a radioresistant malignancy. Retrospective studies report conflicting results on the effect of radiotherapy dose escalation on response and time to progression in symptomatic metastatic disease; studies using the linear quadratic model have used alpha/beta ratios that are inappropriate for slow growing tumours. We aim to describe our experience with palliative radiotherapy in this context, relating Biological Effective Dose to outcome. MATERIALS AND METHODS: From December 1995 to April 2001, 143 independent palliative radiotherapy treatments were delivered to 78 patients in a single institution. Retrospective data was obtained on the radiotherapy schedule used, symptom response and time to symptom progression. The biological effective dose (BED) was calculated using alpha/beta ratios of 3 and 7 Gy (BED3 and BED7). The Log-Rank test was used to assess any differences in time to progression, and the Cox Proportional Hazards analysis to determine prognostic factors of time to progression. RESULTS: Overall symptomatic response rate was 73%, with most responses being partial (67%). Forty-three (38%) patients had symptomatic progression after a median follow-up of 425 days. BED (BED3 or BED7) was not significantly different across response types (complete, partial or no response; P=0.90 and 0.88, respectively) and was not predictive for time to symptomatic progression (P=0.99 for BED3 and P=0.70 for BED7). Patients with bone metastases received less total dose (P=0.001), less BED (BED3, P=0.0013, and BED7, P=0.0005) and had a significantly longer time to progression than other sites of metastases (hazard ratio (HR) 0.4; 95% confidence interval (CI) 0.2-0.7; P=0.004). Initial treatment with interferon-alpha alone in patients presenting with metastatic disease, before palliative radiotherapy, was also associated with a shorter time to symptom progression (HR 4.6; 95% CI 1.5-14.1; P=0.007). On removal of these criteria, brain metastases became a significant predictor of progression time, with an HR of 2.5 (95% CI 1.0-5.9; P=0.05), showing an increased risk of progression with brain metastases compared with metastases elsewhere. Time from primary diagnosis to development of metastatic disease was not predictive of time to symptom progression (P=0.29). CONCLUSION: Despite the widespread assumption that renal cell carcinoma is radioresistant, retrospective assessment showed high response rates to palliative radiotherapy. On the basis of our data, higher BED does not seem to be a predictor of response or of duration of response in the palliative treatment of renal cell carcinoma. Palliation of bone pain seems to be particularly durable compared with the palliation of symptoms at other sites of metastases. A trend for shorter duration of palliative effect of whole-brain radiotherapy was noted.