Genetic variation at the Th2 immune gene IL13 is associated with IgE-mediated paediatric food allergy.

BACKGROUND: Food allergies pose a considerable world-wide public health burden with incidence as high as one in ten in 12-month-old infants. Few food allergy genetic risk variants have yet been identified. The Th2 immune gene IL13 is a highly plausible genetic candidate as it is central to the initiation of IgE class switching in B cells. OBJECTIVE: Here, we sought to investigate whether genetic polymorphisms at IL13 are associated with the development of challenge-proven IgE-mediated food allergy. METHOD: We genotyped nine IL13 "tag" single nucleotide polymorphisms (tag SNPs) in 367 challenge-proven food allergic cases, 199 food-sensitized tolerant cases and 156 non-food allergic controls from the HealthNuts study. 12-month-old infants were phenotyped using open oral food challenges. SNPs were tested using Cochran-Mantel-Haenszel test adjusted for ancestry strata. A replication study was conducted in an independent, co-located sample of four paediatric cohorts consisting of 203 food allergic cases and 330 non-food allergic controls. Replication sample phenotypes were defined by clinical history of reactivity, 95% PPV or challenge, and IL13 genotyping was performed. RESULTS: IL13 rs1295686 was associated with challenge-proven food allergy in the discovery sample (P=.003; OR=1.75; CI=1.20-2.53). This association was also detected in the replication sample (P=.03, OR=1.37, CI=1.03-1.82) and further supported by a meta-analysis (P=.0006, OR=1.50). However, we cannot rule out an association with food sensitization. Carriage of the rs1295686 variant A allele was also associated with elevated total plasma IgE. CONCLUSIONS AND CLINICAL RELAVANCE: We show for the first time, in two independent cohorts, that IL13 polymorphism rs1295686 (in complete linkage disequilibrium with functional variant rs20541) is associated with challenge-proven food allergy.

The skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants.

BACKGROUND: A defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) skin barrier gene have previously been associated with allergic conditions. OBJECTIVE: To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy. METHOD: We genotyped 71 "tag" single nucleotide polymorphisms (tag-SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components. RESULTS: SPINK5 variant rs9325071 (A⟶G) was associated with challenge-proven food allergy in the discovery sample (P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also. CONCLUSIONS: We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy.

Identification of a second substrate-binding site in solute-sodium symporters.

The structure of the sodium/galactose transporter (vSGLT), a solute-sodium symporter (SSS) from Vibrio parahaemolyticus, shares a common structural fold with LeuT of the neurotransmitter-sodium symporter family. Structural alignments between LeuT and vSGLT reveal that the crystallographically identified galactose-binding site in vSGLT is located in a more extracellular location relative to the central substrate-binding site (S1) in LeuT. Our computational analyses suggest the existence of an additional galactose-binding site in vSGLT that aligns to the S1 site of LeuT. Radiolabeled galactose saturation binding experiments indicate that, like LeuT, vSGLT can simultaneously bind two substrate molecules under equilibrium conditions. Mutating key residues in the individual substrate-binding sites reduced the molar substrate-to-protein binding stoichiometry to ~1. In addition, the related and more experimentally tractable SSS member PutP (the Na(+)/proline transporter) also exhibits a binding stoichiometry of 2. Targeting residues in the proposed sites with mutations results in the reduction of the binding stoichiometry and is accompanied by severely impaired translocation of proline. Our data suggest that substrate transport by SSS members requires both substrate-binding sites, thereby implying that SSSs and neurotransmitter-sodium symporters share common mechanistic elements in substrate transport.

Evaluation of the potential of diffusion-weighted imaging in prostate cancer detection.

BACKGROUND: Conventional T2-weighted (T2W) imaging alone has a poor sensitivity for prostate cancer detection. PURPOSE: To evaluate combined T2W and diffusion-weighted magnetic resonance imaging (DW-MRI) versus T2W MRI alone for identifying tumor in patients with prostate cancer. MATERIAL AND METHODS: Fifty-four consecutive patients with prostate cancer (46 stage 1 and 2, 8 stage 3) and sextant biopsies within the previous 3 months were studied. Endorectal MR images were analyzed by two radiologists (1 experienced, 1 trainee) blinded to patient information and histopathology. T2W images were scored first, followed by combined T2W and isotropic apparent diffusion coefficient (ADC) maps calculated from DW-MRI (b = 0, 300, 500, and 800 s/mm(2)). Gland apex, middle, and base for each side were scored negative, indeterminate, or positive for tumor. Imaging data for each sextant were compared with histology. Sensitivity, specificity, and interobserver agreement were calculated. RESULTS: Sensitivity and specificity for tumor identification significantly improved from 50% and 79.6% (T2W alone, experienced observer) to 73.2% and 80.8% (P<0.001), respectively. For the trainee observer, there was no improvement (44.3% and 72% T2W alone vs. 45.1% and 69.2% T2W plus ADC maps). Interobserver agreement was moderate for T2W imaging alone (kappa 0.51) and fair for T2W plus ADC maps (kappa 0.33). CONCLUSION: In an experienced observer, DW-MRI together with T2W imaging can significantly improve tumor identification in prostate cancer.

Good clinical response of breast cancers to neoadjuvant chemoendocrine therapy is associated with improved overall survival.

BACKGROUND: We present extended follow-up from a prospective randomised trial evaluating the role of neoadjuvant chemoendocrine therapy in the treatment of operable breast cancer. PATIENTS AND METHODS: 309 women were randomised to primary surgery followed by eight cycles of adjuvant mitoxantrone, methotrexate with tamoxifen (2MT) or 2MT with mitomycin-C (3MT) versus the same regimen for four cycles before followed by four cycles after surgery. For this analysis the median follow-up of patients was 112 months. RESULTS: After 10 years follow-up there is still no statistically significant difference in disease-free survival (DFS) (71% versus 71%) or overall survival (OS) (63% versus 70%) when comparing adjuvant versus neoadjuvant treatment, respectively. Of 144 evaluable patients in the neoadjuvant arm, 74 achieved a good clinical response and 70 patients achieved a poor clinical response. Good responders had a superior DFS (80% versus 64%, P=0.01) and OS (77% versus 63%, P=0.03) compared to poor responders. CONCLUSIONS: At 10 years, neoadjuvant and adjuvant treatment continue to have equivalent OS and DFS. Good clinical response to neoadjuvant chemotherapy is associated with superior DFS and OS. This supports the use of clinical response of primary breast cancer to neoadjuvant therapy as a surrogate marker of survival benefit.

Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients.

The aim of this study was to evaluate pretreatment clinical features and biological markers together with changes in these factors as predictors of response and relapse in patients receiving tamoxifen for primary breast cancer. Fine-needle aspiration cytology of the primary breast cancer was performed before tamoxifen treatment in 54 patients and repeated after therapy on day 14, day 60, or on both days in a subset of 35 patients. These samples were evaluated for estrogen receptor (ER), progesterone receptor (PgR), Ki67, S-phase fraction and ploidy. The overall response to tamoxifen was 57% (31 of 54 patients). Pretreatment ER and PgR significantly predicted for response by univariate analysis (P < 0.0001 and P < 0.003, respectively). By multivariate analysis, ER expression was the only independent predictor of response, and it was associated with 27 times the likelihood of response (95% confidence interval, 6-136). Increase in PgR and decrease in Ki67 on day 14 significantly predicted for response to tamoxifen (P < 0.03 and P < 0.04, respectively). Lack of ER, clinical node-positive disease, and failure to decrease Ki67 on day 14 were significantly associated with increased risk of relapse (P < 0.05). By multivariate analysis, ER expression was the only independent predictor of relapse (P < 0.005). Pretreatment and early changes in molecular marker expression may assist in the prediction of response and clinical outcome in primary breast cancer patients receiving tamoxifen.

Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma.

BACKGROUND: Laboratory evidence suggests that many anticancer agents exert their effect by altering the ratio between apoptosis and cellular proliferation. The objective of this clinical study was to examine in vivo changes in apoptotic index (AI), Bcl-2 expression, proliferation (Ki-67 and S-phase fraction [SPF]), and ploidy as potential indicators of chemoresponsiveness. METHODS: Twenty-eight women with primary operable breast carcinoma received 2M (mitoxantrone 11 mg/m2, methotrexate 35 mg/m2 every 3 weeks) for 4 cycles before surgery/radiotherapy, and an additional 2 cycles were given after surgery. Clinical response was assessed after four cycles of treatment according to World Health Organization criteria. Changes in molecular markers were assessed from biopsies obtained by fine-needle aspiration performed before treatment, repeated after 24 and/or 72 hours (T1), and on Days 7 and 21 after the first cycle of chemotherapy. Flow cytometric analysis was used to assess SPF, ploidy, and AI (in situ DNA nick end labeling assay) whereas Ki-67 and Bcl-2 were evaluated by immunocytochemical analysis. RESULTS: The overall response rate was 61% (17 of 28 patients), with a 14% (4 of 28 patients) complete response rate. Patients with diploid carcinomas (P = 0.04) with high Ki-67 (P = 0.0001) and SPF (P = 0.09) were more likely to respond to treatment. Median AI increased by 3.4% with interquartile (IQ) range of 3.2 in responders, compared with only -0.1% (IQ range, 2.2) in nonresponders at T1 (P = 0.03). Median Ki-67 decreased by -12.0% (IQ range, 22.9) in responders and increased by 18.5% (IQ range, 15.1) in nonresponders on Day 21 (P = 0.003). Median Bcl-2 scores increased by 1.0 (IQ range, 4.0) in responders and were unchanged at 0.0 (IQ range, 0.5) in nonresponders (P = 0.08). Changes in SPF or ploidy were not significantly predictive of response. CONCLUSIONS: The results of this preliminary study support evidence that chemotherapy may increase apoptosis, decrease Ki-67, and increase Bcl-2 expression in primary breast carcinomas that subsequently respond to therapy. Methodology allowing morphological confirmation of apoptosis would be advantageous.

Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer.

PURPOSE: To determine whether pretreatment clinical features and molecular markers, together with changes in these factors, can predict treatment response and survival in patients with primary operable breast cancer who receive neoadjuvant therapy. PATIENTS AND METHODS: Mitoxantrone, methotrexate (with or without mitomycin), and tamoxifen chemoendocrine therapy was administered to 158 patients before surgery. Clinical response was assessed after four cycles of treatment. Fine-needle aspiration cytology for estrogen receptor (ER), progesterone receptor (PgR), c-erbB-2, p53, bcl-2, Ki67, S-phase fraction (SPF), and ploidy were performed pretreatment and repeated on day 10 or day 21 after the first cycle of treatment. RESULTS: Good clinical response (GCR, defined as complete response or minimal residual disease) was achieved in 31% of patients (49 of 158). Tumor size, nodal disease, response, ER, PgR, c-erbB-2, p53, bcl-2, Ki67, SPF, and ploidy were analyzed as predictors of survival. By univariate analysis, node-positive disease (P =.05), lack of ER (P <.05) and PgR (P <.05), and failure to attain GCR (P =.008) were associated with a significantly increased risk of relapse. A significantly increased risk of death was associated with node-positive disease (P =.02), lack of ER expression (P =.04), and failure to attain GCR. By multivariate analysis, GCR was an independent predictor for survival (P =.05). ER expression (P =.03), absence of c-erbB-2 (P =.03), and a decrease in Ki67 on day 10 or day 21 of the first cycle (P <.05) significantly predicted for subsequent GCR. CONCLUSION: Molecular markers may be used to predict the likelihood of achieving GCR, which seems to be a valid surrogate marker for survival.

Reduction in angiogenesis after neoadjuvant chemoendocrine therapy in patients with operable breast carcinoma.

BACKGROUND: The intensity of angiogenesis, as measured by microvessel density, is a strong independent predictor of survival in breast carcinoma patients. The impact of chemotherapy and/or endocrine therapy on this process is unknown. METHODS: Histologic samples from patients randomized to a trial of neoadjuvant (NEO) versus adjuvant (ADJ) chemoendocrine therapy for operable breast carcinoma were obtained. Samples from 195 patients (90 NEO samples and 105 ADJ samples) were analyzed. Immunostaining was performed with the CD34 monoclonal antibody and the scoring of microvessels was performed using the Chalkley method. RESULTS: The median score of the NEO patients was 5.7 (95% confidence interval [CI], 5.3-6.0) and the median score of the ADJ patients was 6.3 (95% CI, 6-6.7) (P=0.025). Using previously validated scoring categories, there were fewer samples with a poor prognosis (score > or =7) in the NEO group (26%) compared with the ADJ group (32%) (P=0.04). CONCLUSIONS: The results of the current study suggest that NEO chemoendocrine therapy causes a reduction in microvessel density in primary breast carcinomas, which could be secondary to tumor regression or due to a direct effect on angiogenesis.

Quantitative changes in cytological molecular markers during primary medical treatment of breast cancer: a pilot study.

AIM: To quantify the changes in biological molecular markers during primary medical treatment in patients with operable breast cancer and to assess their possible relationship with response to treatment. METHODS: The treatment group consisted of 31 patients with operable breast carcinomas, median age 57 years (range 41-67), treated with four 3-weekly cycles of chemotherapy with Mitoxantrone, methotrexate (+/- mitomycin C), and tamoxifen before surgery. Fine needle aspiration (FNA) was used to obtain samples from patients prior to and at 10 or 21 days post-treatment. The following molecular markers were assessed: estrogen receptor (ER), progesterone receptor (PgR), p53, Bcl-2, and Ki67 measured by immunocytochemistry, and ploidy and S-phase fraction (SPF) by flow cytometry. To evaluate the reproducibility of the technique, repeat FNA was performed in a separate non-treatment control group of 20 patients and the same molecular markers assessed, two weeks after the first sample with no intervening treatment. RESULTS: The non-treatment control group showed a high reproducibility for the measurement of molecular markers from repeat FNA. In the treatment group there was a non-significant reduction in SPF and a significant reduction (p = 0.005) in Ki67. Patients who responded to neoadjuvant therapy were more likely to have a reduction in these two markers than those who failed to respond. Similarly, a reduction in ER scores was observed between the first and second samples (p = 0.04). For PgR, the change between the first and second samples was not significant although there was a significant difference between responders and non-responders (p = 0.03). All nine patients with an increase in PgR were responders. No significant changes in p53 or Bcl-2 were observed during treatment. CONCLUSION: Molecular markers can be adequately measured from FNA samples prior to and during neoadjuvant therapy. Changes in cellular proliferation and hormone receptors have been shown that may be related to tumour response. These relationships should be assessed in a larger cohort of patients.

A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer.

BACKGROUND: A prospective randomised trial was undertaken to evaluate the role of neoadjuvant chemoendocrine therapy prior to surgery in primary operable breast cancer. PATIENTS AND METHODS: Three hundred nine women (median age 56 years, range 27-70) with primary operable breast cancer confirmed on fine needle aspiration (FNA) cytology were recruited to this study. They were treated with a combination of mitozantrone and methotrexate (+/- mitomycin-C) combined with tamoxifen (2MT). Patients received eight cycles of 2MT (four prior to surgery in the neoadjuvant group) and tamoxifen for five years with appropriate surgery and radiotherapy. The two groups were comparable for age, menopausal status, stage and surgical requirements. RESULTS: The clinical response rates to neoadjuvant therapy were as follows: 22% complete response (CR), 29% minimal residual disease (MRD), 33% partial response (PR), 15% no change (NC) and only two patients had clinical evidence of progressive disease. Surgical requirements were reduced from 31 patients (22%) of the adjuvant group having mastectomy to 14 (10%) in the neoadjuvant group (P < 0.003). At a median follow-up of 48 months (range 10-70 months) there is no statistically significant difference between the two groups in terms of local relapse, metastatic relapse or overall survival. Symptomatic and haematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy. CONCLUSION: This randomised trial has shown a significant reduction in the surgical requirements for mastectomy, after treatment with neoadjuvant chemoendocrine therapy, with no deterioration in local or distal relapse.

Variation in endometrial thickening in women with amenorrhea on tamoxifen.

Tamoxifen is reported to increase the risk of endometrial cancers mostly in postmenopausal women. In the Royal Marsden chemoprevention programme, we noted that premenopausal women at the start of tamoxifen/placebo who developed amenorrhea may be at special risk of endometrial cancer. The aim of this report was to investigate recently amenorrheic women by measuring plasma estradiol (E2), follicular stimulating hormone (FSH), and endometrial thickness (ET) by transvaginal ultrasound (TVUS). ET readings and E2 levels were available in the same proportion of women on tamoxifen or placebo. Women on placebo developed amenorrhea with upper limit of E2 readings of 450 pmol/L. In both postmenopausal women and recently amenorrheic women with low E2 (< or = 450 pmol/L), tamoxifen significantly increased endometrial thickening (p < 0.0001 and < 0.005 respectively). Conversely, tamoxifen did not result in endometrial thickening in women with high E2 (> 450 pmol/L), with a trend to lower ET readings (p = 0.07). Finally, all five women who developed endometrial cancer were premenopausal at the start of tamoxifen/placebo. Two of these five women were asymptomatic with increased ET readings (17 mm and 17 mm) and low E2 levels (32 and 51 pmol/L). These results indicate that women who develop amenorrhea on tamoxifen may be at special risk of endometrial cancer. Tamoxifen causes endometrial thickening in amenorrheic women with low E2 but has an opposite antiestrogenic effect in women with high E2. We recommend that women who develop amenorrhea on tamoxifen especially in the presence of endometrial thickening, low E2 levels, and/or gynaecological symptoms warrant further investigations.

Cytological evaluation of biological prognostic markers from primary breast carcinomas.

This study was undertaken to evaluate our ability to detect multiple molecular markers of prognosis and response to treatment in fine needle aspirates (FNA) from patients with primary breast carcinomas. 147 patients with operable primary breast carcinomas who had been recruited to a randomized trial of primary medical therapy (PMT) versus adjuvant chemoendocrine therapy were analysed. FNAs were taken prior to therapy and from this multiple slides were produced using cytospin cytocentrifugation and stored at -80 degrees C for subsequent immunocytochemical analysis (ICA). ICA was performed for oestrogen receptor (ER), progesterone receptor (PgR), p53, Ki67, and Bcl-2. Part of the aspirate was snap frozen and used for flow cytometric analysis of ploidy and S-phase fraction (SPF). In a subgroup of 50 patients who had surgery prior to systemic therapy, as well as FNAs, sections were also taken from paraffin-embedded blocks and stained by ICA for ER, PgR and p53 for validation. In these patients ER was additionally measured by enzyme immunoassay (EIA) from frozen tissue taken at surgery. ER, PgR, p53, Bcl-2, and Ki67 were successfully detected by ICA while ploidy and SPF were successfully measured by flow cytometry from FNA material. The percentage positive values obtained were reasonable and as follows: 74% for ER, 70% for PgR, 36% for p53, 80% for Bcl-2,68% of tumours were aneuploid and 32% diploid. Significant relationships between these measurements were observed in accordance with expectations. The concordance for ER, PgR, and p53 from FNA when compared to ICA of matching histological sections was 91.5%, 75.5%, and 75% respectively. For ER the concordance between measurement by ICA of cytological and histological samples and by EIA of frozen tissue was 82.5% and 84% respectively. These results indicate that multiple molecular markers can be adequately tested on cytological preparations from primary breast tumours. These markers can be used to determine prognosis and predict response to PMT.

Prediction of response to neoadjuvant chemoendocrine therapy in primary breast carcinomas.

Our aim was to determine whether biological molecular markers can predict response to neoadjuvant chemoendocrine therapy in patients with early breast cancer. Ninety patients (median age 56 years; range, 28-69 years) with primary operable breast carcinoma were studied. They were treated with four 3-weekly cycles of chemotherapy with mitozantrone, methotrexate (+/- mitomycin C), and tamoxifen prior to surgery. Fine-needle aspiration was used to obtain samples from patients prior to therapy, and the following parameters were assessed: estrogen receptor (ER), progesterone receptor (PgR), p53, Ki67, Bcl-2, and c-erbB-2 measured by immunocytochemistry, and ploidy and S-phase fraction (SPF) by flow cytometry. The tumors of 78% of the subjects responded (complete response, 9%; partial response, 69%) and 22% did not (no change, 20%; progressive disease, 2%). Response rates according to disease stage and patient age were as follows: T1, 74%; T2, 79%; T3/T4, 78%; age 50, 79% (P = not significant). Response rates for other parameters were as follows: ER-positive, 82%, and -negative, 70%; PgR-positive, 86%, and -negative, 71%; p53-positive, 74%, and -negative, 81%; Bcl-2-positive, 85%, and -negative 61%; c-erbB-2-positive, 57%, and -negative, 93%; Ki67 high, 77%, and low, 81%; SPF high, 77%, and low, 77%; aneuploid, 71%; and diploid, 85%. Only the difference for c-erbB-2 was statistically significant (P = 0.007). A trend for higher response rates to neoadjuvant chemoendocrine therapy for tumors that were positive for ER, PgR, and Bcl-2 was observed but did not reach statistical significance. Tumors negative for c-erbB-2 had a higher response rate, which was statistically significant. In contrast, Ki67, ploidy, SPF, and p53 failed to predict for response.

Hypofractionated stereotactic radiotherapy in the management of recurrent glioma.

PURPOSE: This study aimed to assess the efficacy and toxicity of hypofractionated stereotactic radiotherapy (SRT) in the management of patients with recurrent glioma. METHODS AND MATERIALS: From January 1989 to July 1994, 36 patients with glioma were treated at the time of recurrence. Twenty-nine had recurrent high-grade astrocytoma, 3 high-grade oligodendroglioma, 1 high-grade ependymoma, and 3 pilocytic astrocytoma. Hypofractionated stereotactic radiotherapy was given using either three noncoplanar arcs or four to six noncoplanar fixed beams at 5 Gy/fraction, to doses ranging from 20 to 50 Gy initially on a dose escalation program. Two patients received 20 Gy, 8 received 30 Gy, 10 received 35 Gy, 10 received 40 Gy, 5 received 45 Gy, and 1 received 50 Gy, treating 5 days/week. RESULTS: The median survival of 29 patients with recurrent high-grade astrocytoma was 11 months from the time of SRT. This compared to a median survival of 7 months for a cohort matched for age, performance status, and initial histologic grade who received nitrosourea-based chemotherapy at recurrence (p < 0.05). Initial low-grade astrocytoma histology was the only favorable prognostic factor for survival on univariate analysis. Three patients with recurrent oligodendroglioma remain alive 11, 23, and 34 months after SRT. Three children treated for recurrent pilocytic astrocytoma remain alive 14, 41, and 55 months following SRT. Presumed radiation damage, defined as reversible steroid-dependent toxicity, was observed in 13 patients (36%) and required reoperation in 2 (6%). A total dose of >40 Gy was a major predictor of radiation damage (p < 0.005). CONCLUSION: Hypofractionated SRT is a noninvasive, well-tolerated, outpatient-based method of delivering palliative, high-dose, focal irradiation.

The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy postmenopausal women participating in a randomised, controlled tamoxifen prevention study.

BACKGROUND: The role of hormone replacement therapy (HRT) in women who have been treated for breast cancer remains controversial. The addition of tamoxifen may protect these women from any proliferative effect of exogenous oestrogen on the breast. The aim of this analysis was to determine if tamoxifen and HRT may be safely administered together. METHODS: We studied the interaction between HRT and tamoxifen on serum cholesterol, fibrinogen, antithrombin III (AT III) and bone mineral density (BMD) in postmenopausal healthy women enrolled in a randomised tamoxifen chemoprevention trial. RESULTS: Tamoxifen decreased serum cholesterol by a mean of 13% from pretreatment values (n = 153). The addition of HRT to tamoxifen did not result in further reduction in serum cholesterol (n = 20). HRT alone led to a reduction of serum cholesterol by a mean of 5% in 14 women on placebo. The addition of tamoxifen to HRT resulted in further reduction in serum cholesterol by a mean of 7% (n = 44). Significant reductions of plasma fibrinogen by 14% and AT III by 8% were seen in women who received tamoxifen. There were no further significant changes in these coagulation factors in women on tamoxifen/HRT combinations. Tamoxifen resulted in an annual increase in BMD of the femur and spine by 2% and 1.5%, respectively, when compared to placebo (n = 38). The addition of HRT to tamoxifen resulted in further 2% annual increase in BMD of the femur. CONCLUSIONS: We conclude that there were no significant adverse intereactions with tamoxifen and HRT in this small series of patients. The combination results in a reduction of serum cholesterol, increase in BMD especially in the femur and appears not to have any adverse effect on coagulation factors. Multicentre studies should be conducted to evaluate the effect of this combination on relieving menopausal symptoms, disease relapse and overall survival in women who have received treatment for breast cancer.

Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer.

PURPOSE: To evaluate in a randomized clinical trial systemic chemoendocrine therapy used as primary (neo-adjuvant) treatment before surgery in women with primary operable breast cancer. PATIENTS AND METHODS: Patients aged less than 70 years with clinically palpable, primary operable breast cancer diagnostically confirmed by fine-needle aspiration cytology (FNAC) and suitable for treatment with surgery, radiotherapy, cytotoxic chemotherapy, and tamoxifen were considered eligible. Patients randomized to neoadjuvant treatment received four cycles of chemo-therapy for 3 months before surgery followed by another four cycles after surgery, and were compared with patients randomized to adjuvant therapy who received eight cycles of chemotherapy over 6 months after surgery. RESULTS: Of 212 patients who were randomized to receive either adjuvant (n = 107) or neoadjuvant (n = 105) chemoendocrine therapy, 200 are now assessable for response. The two groups are comparable for age, menopausal status, disease stage, and surgical requirements. The overall clinical response rate was 85%, with a complete histologic response rate of 10%. There was a significant reduction in the requirement for mastectomy in patients who received neoadjuvant treatment (13%) as compared with those who received adjuvant therapy (28%) (P < .005). Symptomatic and hematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy. The median follow-up period for patients in this trial is 28 months, during which time four patients have relapsed locally and 20, including one of the local relapses, have developed metastatic disease, 19 of whom have died. The follow-up period is too brief to evaluate relapse rate or survival duration. CONCLUSION: This trial confirms previous reports of a high rate of response to neoadjuvant therapy, but is the first to include small primary cancers and to show, in the context of a randomized trial, a reduction in the requirement for mastectomy. Until disease-free and overall survival data are available from the larger National Surgical Adjuvant Breast and Bowel Project (NSABP)-18 trial, such neoadjuvant treatment cannot be recommended outside of a clinical trial.

Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer.

The role of chemotherapy in the palliation of patients with advanced stage (IIIB and IV non-small-cell lung cancer (NSCLC) remains controversial. We have carried out a chemotherapy study emphasising symptom relief, a topic not normally discussed in previous similar studies. A total of 120 patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) were treated with a moderate-dose palliative chemotherapy regimen consisting of mitomycin C 8 mg m-2 i.v. on day 1 (alternate courses), vinblastine 6 mg m-2 i.v. on day 1 and cisplatin 50 mg m-2 i.v. on day 1 (MVP), repeating every 21 days for a maximum of six courses. Thirty-eight of 118 assessable patients (32%) achieved an objective response. Patients with locally advanced disease (stage IIIB) had a significantly better response rate (52%) than those with metastatic disease (25%) (P < 0.01). In 76 out of 110 (69%) patients, with tumour-related symptoms including 24 out of 31 patients (78%) with locally advanced disease, symptoms completely disappeared or substantially improved. In only 15 patients (14%) did symptoms progress during treatment. Symptomatic improvement was achieved after one course of chemotherapy in 61% and after two courses in 96% of responding patients. The schedule was well tolerated. Only 19% developed WHO grade 3/4 nausea/vomiting, and only 3% developed significant alopecia. Other toxicities were minimal. MVP is a pragmatic inexpensive chemotherapy regimen that offers useful symptom palliation in patients with advanced NSCLC and merits a 1-2 course therapeutic trial in such patients. The schedule should also be assessed as primary (neoadjuvant) chemotherapy before radical radiotherapy for locally advanced NSCLC in a randomised trial.