Olaparib monotherapy as primary treatment in unselected triple negative breast cancer.

BACKGROUND: The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure. PATIENTS AND METHODS: In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples. RESULTS: The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response. CONCLUSION: Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624973.

Specific class of intrapartum antibiotics relates to maturation of the infant gut microbiota: a prospective cohort study.

OBJECTIVE: To evaluate the potential impact of intrapartum antibiotics, and their specific classes, on the infant gut microbiota in the first year of life. DESIGN: Prospective study of infants in the New Hampshire Birth Cohort Study (NHBCS). SETTINGS: Rural New Hampshire, USA. POPULATION OR SAMPLE: Two hundred and sixty-six full-term infants from the NHBCS. METHODS: Intrapartum antibiotic use during labour and delivery was abstracted from medical records. Faecal samples collected at 6 weeks and 1 year of age were characterised by 16S rRNA sequencing, and metagenomics analysis in a subset of samples. EXPOSURES: Maternal exposure to antibiotics during labour and delivery. MAIN OUTCOME MEASURE: Taxonomic and functional profiles of faecal samples. RESULTS: Infant exposure to intrapartum antibiotics, particularly to two or more antibiotic classes, was independently associated with lower microbial diversity scores as well as a unique bacterial community at 6 weeks (GUnifrac, P = 0.02). At 1 year, infants in the penicillin-only group had significantly lower α diversity scores than infants not exposed to intrapartum antibiotics. Within the first year of life, intrapartum exposure to penicillins was related to a significantly lower increase in several taxa including Bacteroides, use of cephalosporins was associated with a significantly lower rise over time in Bifidobacterium and infants in the multi-class group experienced a significantly higher increase in Veillonella dispar. CONCLUSIONS: Our findings suggest that intrapartum antibiotics alter the developmental trajectory of the infant gut microbiome, and specific antibiotic types may impact community composition, diversity and keystone immune training taxa. TWEETABLE ABSTRACT: Class of intrapartum antibiotics administered during delivery relates to maturation of infant gut microbiota.

Low physical activity is related to clustering of risk factors for fracture-a 2-year prospective study in children.

The study investigates the effect of physical activity (PA) on a composite score for fracture risk in pre-pubertal children. Low PA in children is related to the composite score for fracture risk and the pre-pubertal years seem to be a period when PA positively affects the score. INTRODUCTION: This study evaluates if PA in children is related to clustering of risk factors for fracture. Research questions are the following: (i) What is the effect of physical activity (PA) on single traits and a composite score for fracture risk? (ii) Could this score be used to identify the level of PA needed to reach beneficial effects? METHODS: This prospective population-based study included 269 children, aged 7-9 years at baseline while 246 attended the 2-year follow-up. We estimated duration of PA by questionnaires and measured traits that independently predict fractures. We then calculated gender specific Z-scores for each variable. The mean Z-score of all traits was used as a composite score for fracture risk. We tested correlation between duration of PA, each trait, and the composite score and group differences between children in different quartiles of PA. RESULTS: At baseline, we found no correlation between duration of PA and any of the traits or the composite score. At follow-up, we found a correlation between PA and the composite score. Physical activity had an effect on composite score, and children in the lowest quartiles of PA had unbeneficial composite score compared to children in the other quartiles. CONCLUSION: Low PA in children is related to clustering of risk factors for fracture, and the pre-pubertal years seem to be a period when PA positively affects the composite score.

Radiographers' academic development in Sweden: Towards and after a doctoral degree.

INTRODUCTION: Radiography is a young discipline and having radiographers with a doctoral degree is central for its development. Academic development of this field in Sweden has been evolving. This study explored the diagnostic radiographers' prerequisites for doctoral studies, post-doctoral employment and research activities. METHODS: Data were collected through a questionnaire designed to give insight into doctoral radiographers' qualification paths, funding, doctoral status, employment and basic demography. Sixteen radiographers participated. A conventional content analysis was used. RESULTS: The median age at dissertation defence was 53 for doctorates and 60 for licentiates. This indicates that after receiving the doctorate, there is short time left in the profession, increasing the challenge to develop the field. Most doctorates were employed within educational establishments. Unfortunately, few had supervised doctoral students, but those employed within academia contributed significantly to academic research. CONCLUSION: Compared to other Nordic countries, Sweden is at the forefront with a positive development in obtained high academic degrees. Nevertheless, there is an urgent need for post-doctorate radiographers in order to maintain the workforce to meet current and future demands. Radiographers with doctorates need to be consulted when planning research projects to establish a clear radiographic perspective. Swedish radiographers with a doctorate or licentiate have limited research time, indicating that Sweden may not invest enough in radiographic research. IMPLICATIONS FOR PRACTICE: There is a need for more doctoral positions and doctorates radiographers to supervise doctoral students. Clinical departments should recognise the benefits of having radiographic clinical research.

Reconstruction of the atrophic maxilla with interpositional bone grafting/Le Fort I osteotomy and endosteal implants: a 11-16 year follow-up.

A Le Fort I osteotomy and interpositional bone graft in combination with implants was used in the reconstruction of patients with extreme atrophy in their maxillae. Surgery was performed in a two-stage procedure. The patients in this study had conditions with reversed intermaxillary relationships with or without increased vertical intermaxillary distance. The aim of the study was to investigate treatment outcome for patients in a prospective, long-term, follow-up with a mean of 13 years (range 11-16 years), concerning implant survival rate and marginal bone loss adjacent to the surfaces of the implant. The impact of gender and smoking was also investigated. Twenty-six patients were included in the study. Of 167 implants, 24 failed. The implant estimated survival rate was 85% at the end of the follow-up. There was no significant difference between smokers and non-smokers or genders concerning implant survival. Marginal bone loss was 2.5, 2.9, 3.0 and 3.1mm from the implant-abutment junction, after 1, 2, 5 and 10 years, respectively. The bone level stabilised after 2 years. This technique results in good facial morphology, good oral function and aesthetics. All patients are still wearing their original fixed bridges.

Radiographic research in Sweden - A review of dissertations.

INTRODUCTION: Radiographers have performed research since 1988 in Sweden. The amount of doctoral and licentiate dissertations written by registered diagnostic radiographers has increased considerably since 2000. How this new field of research was established and developed has facilitated understand of the boundaries that strengthen the professional evidence base. The aim of this dissertation review was to explore the nature and the current state of radiographic research, written by registered diagnostic radiographers in Sweden. METHODS: Dissertations published between 1988 and 2017 were analysed both deductively and inductively with content analysis. RESULTS: Radiographic research focused on structural factors, clinical radiography, radiographic technology and pedagogical approaches. The findings indicated a large interest in advancing patient information, wellbeing and care during examinations. The participants were predominantly clinical patients, followed by radiographers, adults/children and the general public. The most common study designs were descriptive with a trend towards interventional studies. Interviews and questionnaires were the most common data collection methods followed by clinical examinations and documents. CONCLUSION: The analyses demonstrate that the current radiographer research has its roots in clinical practice, focusing on pragmatic aspects and applied knowledge. The findings suggest that radiographer's dissertations meet the challenges of new technologies and working practise. If the knowledge is connected to the radiographic framework, radiography can be viewed as an independent discipline with its own philosophical base. When radiographers are encouraged to conduct research, evidence based knowledge increase which strengthens the profession. Radiography, as a scientific discipline is evolving in Sweden.

Apterous is a Drosophila LIM domain gene required for the development of a subset of embryonic muscles.

The recently discovered LIM motif is found in a set of homeodomain-containing proteins thought to mediate the generation of particular cell types. Of the four LIM domain family members described to date, mec-3 and lin-11 determine cell lineages in C. elegans. Isl-1 and Xlim-1 may play similar roles in vertebrates. We have identified a Drosophila member of this class, the product of the apterous (ap) gene. During embryogenesis, ap is expressed in a small subset of fusing mesodermal precursors that give rise to 6 muscles in each abdominal hemisegment and in 5 neurons within each corresponding CNS hemisegment. Lack of ap function results in loss of ap-expressing muscles, while misexpression of ap using a heterologous promoter produces ectopic muscles.

Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism.

BACKGROUND: Tamoxifen is hydroxylated by cytochrome P450 (CYP) 2D6 to the potent metabolites 4-hydroxytamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam), which are both conjugated by sulphotransferase (SULT)1A1. Clinical studies indicate that CYP2D6 and SULT1A1 genotypes are predictors for treatment response to tamoxifen. Therefore, we examined the relationship between CYP2D6 genotype, SULT1A1 genotype, SULT1A1 copy number and the pharmacokinetics of tamoxifen. PATIENTS AND METHODS: The serum levels of tamoxifen and metabolites of 151 breast cancer patients were measured by high-pressure liquid chromatography-tandem mass spectrometry. The CYP2D6 and SULT1A1 polymorphisms and SULT1A1 copy number were determined by long PCR, PCR-based restriction fragment length polymorphism, DNA sequencing and fluorescence-based PCR. RESULTS: The levels of 4OHtam, 4OHNDtam and N-demethyltamoxifen were associated with CYP2D6 predicted enzymatic activity (P < 0.05). The SULT1A1 genotype or copy number did not influence the levels of tamoxifen and its metabolites. However, the ratios of N-demethyltamoxifen/tamoxifen and N-dedimethyltamoxifen/N-demethyltamoxifen were related to SULT1A1 genotype. CONCLUSION: CYP2D6 and SULT1A1 genotypes may partly explain the wide inter-individual variations in the serum levels of tamoxifen and its metabolites. We propose that therapeutic drug monitoring should be included in studies linking CYP2D6 and SULT1A1 genotypes to clinical outcome.

Trends that have influenced the Swedish radiography profession over the last four decades.

INTRODUCTION: The expansion of the radiography profession in recent decades has widened the scope of radiographic practice. This has raised questions about which trends have had an impact on the profession over the years. The study aim was to explore trends that have influenced the radiography profession over the last four decades. METHODS: A qualitative design was used. Eleven focus group interviews inspired by the Scenario Planning Method were conducted at 11 diagnostic radiology departments in public hospitals in Sweden. The target group consisted of 48 registered radiographers. To analyse the data, qualitative content analysis was used. RESULTS: Thematic data analysis revealed three broad categories; technological development and radiation doses, current status of the radiography profession and specialisation leading to expert knowledge. Each category derived from two or three sub-categories. CONCLUSION: The results demonstrate significant trends of influences on the radiography profession in Sweden over the last four decades. New methods and technology and control of radiation doses have had a favourable effect on the development of the radiography profession. Nevertheless, current status such as shortage of radiographers has had an adverse way. Specialisation leading to expert knowledge has an influence on career advancement and a specialist education regulated by the law, might be a prerequisite for the development of the radiography profession.

Professional development for radiographers and post graduate nurses in radiological interventions: Building teamwork and collaboration through drama.

INTRODUCTION: The rapid development within Interventional Radiology presents new challenges. Hybrid operating rooms consist of interventional radiology, open surgery, computed tomography, magnetic resonance imaging and other techniques. This means that several disciplines and professionals need to work in new constellations creating a multidisciplinary team around the patient. In accordance with this development, higher professional education must provide new pedagogic strategies to successfully address the knowledge expected in today's complex working life. AIM: To explore the use of Applied Drama as a learning medium, focusing on the use of Forum Theatre, to foster team work and collaboration in the field of radiography and learning. METHODS: A qualitative approach, closely related to Ethnography, was utilized. RESULT: The Drama Workshop utilising Forum Theatre created a dynamic learning environment and enabled the participants from three professions to understand each other's priorities better. The use of drama within health care education allows the students to take different roles in order to find the best way to co-operate. CONCLUSION: Forum Theatre is a useful learning medium in order to promote teamwork and collaboration in the radiological intervention field. By choosing a personal working experience, Forum Theatre seem to engage the participants at a deeper level and to experience various communication strategies and how the outcome changed depending on the approach. This can lead to improved teamwork and collaboration.

The effect of exercise on fatigue and physical functioning in breast cancer patients during and after treatment and at 6 months follow-up: A meta-analysis.

Breast cancer is the leading cause of cancer in women worldwide. Exercise interventions may improve physical and psychological factors during and after active breast cancer treatment. The aim of this systematic review was to assess the current knowledge regarding the efficacy of physical exercise with respect to fatigue and self-reported physical functioning. Systematic searches in Cochrane Library, Medline, Embase, Cinahl, PsycINFO, AMED and PEDro. After assessing the quality of the studies, we identified 25 randomized controlled trials that included 3418 breast cancer patients. An increase in physical functioning and a decrease in fatigue were observed after a physical exercise intervention, with an SMD of 0.27 (0.12, 0.41) and -0.32 (-0.49, - 0.14), respectively. There were slightly higher improvements in physical functioning and fatigue when the patients received the intervention after adjuvant breast cancer treatment. The 6-month follow-up data showed a small favourable difference for the physical exercise group for both physical functioning and fatigue. This systematic review found that an exercise intervention program can produce short-term improvements in physical functioning and can reduce fatigue in breast cancer patients. However, more studies are needed to confirm the time-dependent observations in this study.

Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment.

Several metabolites of tamoxifen, including 4-hydroxy-N-desmethyltamoxifen (metabolite BX), 4-hydroxytamoxifen (metabolite B), N-desmethyltamoxifen (metabolite X), the primary alcohol (metabolite Y), and N-desdimethyltamoxifen (metabolite Z) were identified and their concentrations determined in fluids and feces from patients receiving chronic tamoxifen treatment. The biological samples investigated were serum, pleural, pericardial and peritoneal effusions, cerebrospinal fluid, saliva, bile, feces, and urine. In serum, tamoxifen itself, and the metabolites X and Z were the prevailing species, but significant amounts of the metabolites Y, B, and BX were also detected. About 3 h after drug intake tamoxifen as well as Y, B, BX, X, and Z showed a peak in serum. This may be explained by efficient metabolism of the metabolite precursor before being distributed to peripheral compartments. Upon drug withdrawal all metabolites showed first-order elimination curves which paralleled that of tamoxifen suggesting that their rate of elimination exceeded that of tamoxifen and that the serum levels are production rate limited. The protein binding of tamoxifen and its major serum metabolites (Y, X, Z) was determined and found to be higher than 98%. Albumin was the predominant carrier for tamoxifen in human plasma. The concentrations of tamoxifen and its metabolites in pleural, pericardial, and peritoneal effusions equalled those detected in serum, corresponding to an effusion/serum ratio between 0.2 and 1. Only trace amounts of tamoxifen and metabolite X were detected in cerebrospinal fluid (CSF/serum ratio less than 0.02). In saliva, concentrations of tamoxifen and X exceeded the amounts of free drug in serum, suggesting active transport or trapping of these compounds in the salivary gland. Bile and urine were rich in the hydroxylated, conjugated metabolites (Y, B, and BX), whereas in feces unconjugated metabolite B and tamoxifen were the predominating species.

Profound suppression of plasma estrogens by megestrol acetate in postmenopausal breast cancer patients.

Twelve postmenopausal women suffering from advanced breast cancer had plasma estrogens, androgens, cortisol, and gonadotropins determined before therapy and during treatment with megestrol acetate (MA) in oral doses escalated from 40 to 160 mg. The plasma clearance and production rate of estrone and estrone sulfate were determined before treatment and after 4 weeks of therapy with 160 mg MA. Treatment with MA suppressed plasma levels of dehydroepiandrosterone sulfate, androstenedione, and cortisol in a dose-dependent manner to <10% of pretreatment values. Plasma testosterone, estradiol, estrone, and estrone sulfate were suppressed to 18-29% of pretreatment values, whereas the gonadotropins were suppressed to 35-52%. The plasma clearance rates of estrone and estrone sulfate were increased by a mean value of 23.7% (P < 0.01) and 23.5% (P < 0.025), whereas the production rates were reduced by 76.7% (P < 0.0005) and 76.1% (P < 0.0005), respectively. Our findings indicate that MA causes profound suppression of adrenal steroid production but in addition suppresses ovarian secretion of androgens in postmenopausal breast cancer patients. The reduction in plasma estrogens is comparable to values obtained with commonly used aromatase inhibitors and may be responsible for its antitumor effects in breast cancer.

A 3-year prospective follow-up study of implant-supported fixed prostheses in patients subjected to maxillary sinus floor augmentation with a 80:20 mixture of deproteinized bovine bone and autogenous bone Clinical, radiographic and resonance frequency analysis.

The purpose of this prospective clinical study was to evaluate the 3-year outcome of 30 maxillary sinus floor augmentations with an autogenous bone-deproteinized bovine bone mixture (20:80). A total of 108 dental implants were placed after 6 months of graft healing. After another 6 months, the occlusion was restored with fixed prostheses and followed for 3 years of functional loading. Clinical and radiographic examinations of the sinuses and implants, including computerized tomography (CT) were performed. The stability of the implants was evaluated by means of resonance frequency analyses (RFA). After 3 years of functional loading with fixed bridges, 15 of 108 implants were lost giving a cumulative survival rate (CSR) of 86%. All followed patients, except one, had fixed bridges in function after 3 years of loading. The mean marginal bone loss was 1.3+/-1.1 mm after 3 years. RFA showed a mean implant stability quotient (ISQ) value of 66+/-4.1 after 3 years with no significant difference between implants in grafted and residual bone. Examination with CT showed that 67% of the maxillary sinuses were healthy prior to treatment and 71% after 3 years of loading. It was concluded that grafting of the maxillary sinus with a mixture of autogenous bone and deproteinized bovine bone is a reliable procedure.

Monitoring of implant stability in grafted bone using resonance frequency analysis. A clinical study from implant placement to 6 months of loading.

The aim of this prospective study was to compare implants placed in grafted and normal non-grafted maxilla by means of resonance frequency analysis (RFA), clinical stability and implant failure. Twenty-nine patients with severe atrophy of the edentulous maxilla were treated with autogenous bone grafts as onlay (24 patients) or as interpositional grafts in conjunction with a Le Fort I osteotomy (five patients) 6 months prior to placement of 222 implants. Ten non-grafted patients treated with 75 Brånemark implants in the edentulous maxillae served as a control group. RFA was performed at implant placement, abutment connection and after 6 months of bridge loading. Seventeen (8%) implants were lost in the grafted bone and one (1%) in normal bone. RFA revealed a similar pattern in both grafted and normal maxillae, i.e. increasing resonance frequency (RF) with time (Wilcoxon Signed Rank test for paired data). Twenty implants that were rotation mobile (low primary stability) at the time of insertion showed a significantly lower value at implant placement according to RFA (Mann-Whitney U-test, P = 0.020). The RF for the failed implants revealed a tendency towards lower values (Mann-Whitney U-test, P = 0.072), compared to the successful implants. It is concluded that implants placed in grafted bone when using a two-stage technique achieve a stability similar to that of implants placed in normal non-grafted bone.

Influence of dexaminoglutethimide, an optical isomer of aminoglutethimide, on the disposition of estrone sulfate in postmenopausal breast cancer patients.

Aminoglutethimide (AG) has been the most widely used aromatase inhibitor in breast cancer patients to date. Commercially, AG (Orimeten) is available as a racemate (DL-AG). Previous studies suggested the stereoisomers of AG (D-AG and L-AG) to differ considerably in their affinities and potencies to inhibit different cytochrome P-450-dependent enzymes, with D-AG being the potent aromatase inhibitor. DL-AG, apart from being an aromatase inhibitor, is known to enhance the metabolism of plasma estrone sulfate (E1S). In the present study we compared the effects of D-AG (500 mg daily) and DL-AG (1000 mg daily) on plasma estrogen levels and estrone (E1) and E1S clearance rates, determined after the injection of [14C]E1 and [3H]E1S, in a cross-over study involving 12 postmenopausal breast cancer patients. Treatment with DL-AG and D-AG suppressed plasma E1S to 18.6% and 15.0% of pretreatment levels, whereas E1 and estradiol E2 levels fell to 18.6% and 23.4% of their pretreatment levels during treatment with DL-AG and to 17.7% and 23.4% during treatment with D-AG, respectively. Thus, both treatment options suppressed all estrogens measured to a similar extent. The clearance rate of E1S increased from a mean pretreatment value of 5.9 to 14.0 and 10.0 L/h during treatment with DL-AG and D-AG, respectively (P < 0.05, comparing the two on-treatment situations), whereas the production rate of E1S decreased from a pretreatment value of 1.44 to 0.64 nmol/h with DL-AG and 0.36 nmol/h with D-AG (P < 0.05, comparing on-treatment values). These findings are consistent with the hypothesis that the D- as well as the L-form of AG may enhance the clearance rate of E1S. The finding of a higher estrogen production rate during treatment with DL-AG compared to D-AG probably reflects an increased plasma level of the estrogen precursor androstenedione (mean levels of androstenedione of 2.54 and 1.27 nmol/L during treatment with D-AG and DL-AG, respectively; P < 0.05).

Spontaneous periodic hypothermia.

We studied a patient with spontaneous periodic hypothermia, agenesis of corpus callosum (Shapiro's syndrome), polydipsia polyuria, and hyponatremia. Endocrine evaluation of hypothalamic-pituitary unit, thyroid, adrenals and gonads was normal. Results of a water deprivation test implied primary polydipsia. Four of 10 reported cases of Shapiro's syndrome had abnormalities in water metabolism. In view of the known effects of arginine vasopressin in thermoregulation, the recurrent hypothermia of this syndrome and the abnormalities of water metabolism may have a common pathogenetic mechanism.

Weekly doxorubicin with or without high-dose medroxyprogesterone acetate in hormone-resistant advanced breast cancer. A randomised study. The Norwegian Breast Cancer Group.

In a randomised study, 218 patients with advanced breast cancer, resistant to hormone therapy, received either doxorubicin 20 mg every week (Awkly) alone or Awkly combined with high doses (1000 mg daily) of oral medroxyprogesterone acetate (HD-MPA). Of the 210 evaluable patients, the response rates were 26% [95% confidence interval (CI) 18-34%] for Awkly and 38% (95% CI 29-47%) for Awkly + HD-MPA (P = 0.08). There was no significant difference with regard to duration of response. Median survival was 11 months in both groups. Considerable toxicity was seen from HD-MPA, particularly weight gain and fluid retention. The present study provides evidence that, in concordance with preclinical studies and a previous randomised study, interaction between chemotherapy and HD-MPA may exist in breast cancer normally resistant to hormone therapy. For further studies, other gestagens and/or a dose reduction could be investigated.

Effects of treatment with megestrol acetate on the insulin-like growth factor system: time and dose dependency.

This study was designed to evaluate time and dose dependency of alterations in insulin-like growth factor (IGF)-I, free IGF-I and the functional status of IGF-binding protein (IGFBP)-3 in breast cancer patients during treatment with megestrol acetate (MA). In 16 patients receiving MA 160 mg daily, total IGF-I levels increased gradually (significant after 3 days on treatment) by a maximum of 2.66-fold after 5-6 months on treatment. However, free (readily dissociable) IGF-I levels increased to a smaller extent (1.23-2.15-fold). This discrepancy may be due to an increase in intact IGFBP-3 determined by Western ligand blotting (WLB). Similar findings were observed in 12 patients treated with MA in escalating doses from 40-800 mg daily. A dose-dependent increase in IGF-I was observed up to a dose level of 120 mg daily. We conclude that treatment with MA caused a profound increase in plasma levels of total IGF-I accompanied by a moderate increase in free IGF-I. This may explain the anabolic effects of MA in patients suffering from cachexia, but refute the hypothesis that alterations in the IGF-system may contribute to the antitumour effects of MA in breast cancer patients.

A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer.

The aim of this study was to compare the efficacy and tolerability of the new aromatase inhibitor 'ARIMIDEX' (anastrozole) with megestrol acetate in the treatment of advanced breast cancer in postmenopausal women. Anastrozole is a new potent and highly selective non-steroidal aromatase inhibitor. We conducted a prospective randomised trial comparing two doses of anastrozole (1 and 10 mg orally once daily) with megestrol acetate (40 mg orally four times daily) in postmenopausal patients with advanced breast cancer who progressed after prior tamoxifen therapy. All patients were analysed for efficacy as randomised (intention to treat) and for tolerability as per treatment received. Of the 378 patients who entered the study, 135 were randomised to anastrozole 1 mg, 118 to anastrozole 10 mg, and 125 patients to megestrol acetate. After a median follow-up of 192 days, response rate which included complete response, partial response and patients who had disease stabilisation for 6 months or more was 34% for anastrozole 1 mg, 33.9% for anastrozole 10 mg and 32.8% for megestrol acetate. There were no statistically significant differences between either dose of anastrozole and megestrol acetate in terms of objective response rate, time to objective progression of disease or time to treatment failure. The three treatments were generally well tolerated, but more patients on megestrol acetate reported weight gain, oedema and dyspnoea as adverse events while more patients on anastrozole reported gastro-intestinal disorders, usually in the form of mild transient nausea. Patients on anastrozole did not report higher incidences of oestrogen withdrawal symptoms. Anastrozole is an effective and well tolerated treatment for postmenopausal patients with advanced breast cancer. The higher 10 mg dose did not result in additional clinical benefit, but was well tolerated reflecting the good therapeutic margin with anastrozole. Based on this data, anastrozole 1 mg should be the recommended therapeutic dose.