PAM-50 predicts local recurrence after breast cancer surgery in postmenopausal patients with ER+/HER2- disease: results from 1204 patients in the randomized ABCSG-8 trial.

BACKGROUND: The aim of this study was to investigate whether the PAM-50-based 46-gene assay carries prognostic value for risk of local recurrence of breast cancer. METHODS: The Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8 RCT compared 5 years of tamoxifen with tamoxifen for 2 years followed by anastrozole for 3 years in postmenopausal women with endocrine receptor-positive breast cancer. This study included patients from the trial who had breast-conserving surgery for whom tumour blocks were available for PAM-50 analysis. RESULTS: Tumour blocks from 1204 patients who had breast-conserving surgery were available for the PAM-50 analysis, and 1034 of these received radiotherapy. After a median follow-up of 10.8 years, 23 local events had been observed, corresponding to an overall local recurrence risk of 2.2 per cent. Univariable competing-risk analysis demonstrated that patients at low risk according to PAM-50 analysis (risk-of-recurrence (ROR) score less than 57) had a significantly lower incidence of local recurrence than those in the high-risk group at 5 years (0.1 (95 per cent c.i. 0 to 0.7) versus 2.2 (0.9 to 4.6) per cent respectively; subhazard ratio (SHR) 17.18, 95 per cent c.i. 2.06 to 142.88; P = 0.009) and 10 years (0.9 (0.4 to 2.0) versus 3.8 (1.9 to 6.6) per cent; SHR 4.76, 1.72 to 13.17; P = 0.003). Multivariable analyses that included ROR score, age, tumour size, nodal status, type of surgery, tumor grade, and trial-specific endocrine therapy confirmed that ROR score was an independent prognostic factor for risk of local recurrence. Analysis of the women randomized to radiotherapy or control after breast conservation showed that PAM-50 was not predictive of radiotherapy effect. CONCLUSION: PAM-50 can be used as a prognostic tool for local recurrence risk in postmenopausal women with hormone receptor-positive breast cancer treated with endocrine therapy. The test was not predictive for the benefit of radiotherapy.

A clinical validation study of MammaPrint in hormone receptor-positive breast cancer from the Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG-8) biomarker cohort.

BACKGROUND: MammaPrint is a prognostic assay based on gene expression in tumors from patients with early breast cancer. MammaPrint has been extensively validated and Food and Drug Administration cleared in fresh and formalin-fixed and paraffin-embedded (FFPE) tissue. We aimed to assess its prognostic performance in the biomarker cohort of the Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG-8) patient population, and to obtain a higher level of evidence with regard to its clinical validity after RNA extraction from FFPE biobank tissue. PATIENTS AND METHODS: A prespecified retrospective analysis to test the prognostic performance of the MammaPrint test to predict distant recurrence-free survival at 5 and 10 years as primary end point was carried out. MammaPrint risk, clinicopathological factors (after central pathological review), and clinical risk (using a modified version of Adjuvant! Online) were evaluated by Cox regression analyses. RESULTS: From 1347 available samples, 607 (45%) failed quality control after RNA extraction. In total, 658 (49%) patients were included in survival analyses: MammaPrint low risk versus high risk is a significant prognostic factor for distant recurrence-free survival at 5 years (94.0% versus 91.6%) with a significant risk reduction of 6.5% at 10 years (log-rank P value = 0.017, low risk 91.3% versus high risk 84.8%). The multivariable models suggest that hazard ratio (HR) is primarily driven by tumor stage (5-year HR 3.89; confidence interval 1.97-7.71) and nodal status (5-year HR 1.73; confidence interval 0.91-3.21). After adjustment for clinical risk groups, MammaPrint HRs remain stable with values just below 2.0 after the first 3 years. CONCLUSIONS: The MammaPrint test showed significant prognostic performance at 5 and 10 years of follow-up. In the particular cohort of ABCSG-8, the statistical independence from clinically assessed covariates remains unclear, and no conclusions concerning the clinical validity of the test can be drawn.

The genomic expression test EndoPredict is a prognostic tool for identifying risk of local recurrence in postmenopausal endocrine receptor-positive, her2neu-negative breast cancer patients randomised within the prospective ABCSG 8 trial.

BACKGROUND: The aim of this study was to examine whether EndoPredict (EP), a novel genomic expression test, is effective in predicting local recurrence (LR)-free survival (LRFS) following surgery for breast cancer in postmenopausal women. In addition, we examined whether EP may help tailor local therapy in these patients. METHODS: From January 1996 to June 2004, 3714 postmenopausal patients were randomly assigned to either tamoxifen or tamoxifen followed by anastrozole within the prospective ABCSG 8 trial. Using assay scores from EP, we classified breast tumour blocks as either low or high risk for recurrence. RESULTS: Data were gathered from 1324 patients. The median follow-up was 72.3 months and the cumulative incidence of LR was 2.6% (0.4% per year). The risk of LR over a 10-year period among patients with high-risk lesions (n=683) was significantly higher (LRFS=91%) when compared with patients with low-risk lesions (n=641) (10-year LRFS=97.5%) (HR: 1.31 (1.16-1.48) P<0.005). The groups that received breast conservation surgery (BCT) and mastectomy (MX) had similar LR rates (P=0.879). Radiotherapy (RT) after BCT significantly improved LRFS in the cohorts predicted by EP to be low-risk for LR (received RT: n=436, 10-year LRFS 99.8%; did not receive RT: n=63, 10-year LRFS 83.6%, P<0.005). CONCLUSIONS: EndoPredict is an effective prognostic tool for predicting LRFS. Among postmenopausal, low-risk patients, EP does not appear to be useful for tailoring local therapy.

Artelastocarpin and carpelastofuran, two new flavones, and cytotoxicities of prenyl flavonoids from Artocarpus elasticus against three cancer cell lines.

Further study of one of the fractions from the wood of Artocarpus elasticus furnished two new prenylated flavonoids artelastocarpin and carpelastofuran as well as ethyl 2,4-dihydroxybenzoate. The two flavonoids and the prenylated flavonoids artelastin, artelastochromene, artelasticin, artocarpesin, and cyclocommunin isolated earlier from this species were tested for cytotoxicity in vitro against three human cell lines. All seven flavonoids were active, the cytotoxic effect varying from strong to moderate and with artelastin showing the most potent activity.

New coumarins from Pterocaulon polystachyum.

Aerial parts of Pterocaulon polystachyum from Chaco province, Argentina, afforded the known coumarins ayapin, isoscopoletin, prenyletin, prenyletin methyl ether, virgatenol, obtusinin, 5-methoxy-6,7-methylenedioxycoumarin, 5-(3,3-dimethylallyloxy)-6,7-methylenedioxycoumarin, 5-(2',3'-dihydroxy-3-methylbutanoxy)-6,7-methylenedioxycoumarin, haplopinol methyl ether, 6-(1,1-dimethyl-2-propenyl)-7-hydroxycoumarin and demethylnieshoutin; the last two are new as natural products while the five new coumarins from the collection were isovirgatenol, 3'-deoxyobtusinin, 6-methoxy-7-(2'-hydroxyethoxy)-coumarin, 5-(2'-hydroxyethoxy)-6,7-methylenedioxycoumarin and a substance tentatively identified as 5-hydroxy-6,7-methylenedioxy-8-(3,3-dimethylallyl)-coumarin.

Tetillapyrone and nortetillapyrone, two unusual hydroxypyran-2-ones from the marine sponge Tetilla japonica.

Extraction of the marine sponge Tetilla japonica from the Bay of Thailand furnished tetillapyrone and nortetillapyrone, two unusual tetrahydrofurylhydroxypyran-2-ones, whose structures were established by NMR spectrometry and an X-ray analysis of tetillapyrone.

Sesquiterpene lactones from Centaurea tweediei.

Aerial parts of Centaurea tweediei from Argentina afforded as the main constituent the sesquiterpene lactone onopordopicrin and minor amounts of a new heliangolide, a new guaianolide, a new eudesmanolide, a new eudesmane acid and the lignans arctigenin and matairesinol.

Sesquiterpene lactones and other constituents of Disynaphia multicrenulata from Argentina.

Flowers and leaves of Disynaphia multicrenulata from Argentina afforded a large number of known germacradienolides and heliangolides, a new germacradienolide, a known melampolide, a new parthenolide derivative, one known and seven new cronquistiolides, a new 4Z-melampolide, three known and five new eudesmanolides, a new elemadienolide, a known grazielolide, an isoguaiagrazielolide, two diepoxygermacran-8,12-olides, three common kauranoic acids, pinoresinol, jaceosidin and the sesquiterpene oplopanone. Structures were elucidated by high-field 1H NMR spectrometry. The relationship to the known chemistry of other members of the Disynaphiinae is discussed.

11,17-dideoxyagelorin A and B, new bromotyrosine derivatives and analogs from the marine sponge Suberea aff. praetensa.

A collection of the marine sponge Suberea aff. praetensa from the Gulf of Thailand furnished the bromotyrosine derivatives fistularin-3, agelorins A and B and the new desoxyagelorins A and B.

Xanthones from Calophyllum teysmannii var. inophylloide.

Further study of the wood of Calophyllum teysmannii Miq. var. inophylloide from Thailand yielded the xanthones 1,2,8-trimethoxyxanthone, 6-hydroxy-1,2,5,7-tetramethoxyxanthone and 3-(3'-carboxybutyl)-4-methoxyxanthone (teysmannic acid) in addition to scriblitifolic acid, 1,7-dihydroxyxanthone and the benzoic acid derivative leiocarpic acid.

First clinical experience with the automatic positioning system and Leksell gamma knife Model C. Technical note.

In May of 1999, the first Leksell Model C gamma knife was installed at the Gamma Knife Zentrum in Krefeld, Germany. The authors recount their experience with this latest technical gamma knife development. Until the end of 1999, extensive physical and technical tests were performed and the system's hardware and software were continuously improved and adapted to the user's needs. By the end of 1999, 163 GKSs had been performed using the new functionality of the Model C in manual or "trunnion" mode. The trunnions, the two parts of the system that fix the patient headframe to the gamma knife when the isocenter positions, are checked manually. During the same period the new automatic positioning system (APS) was extensively tested and refined so that the first APS treatment could be performed in January 2000. Fifty GKSs have been performed with the APS capability of the Model C. It was possible to use APS alone in 74% of surgeries whereas in 14% some shots were given with APS and some with trunnions. In 12%, GKS was scheduled and planned for APS, but due to unexpected technical (6%) or mechanical (6%) reasons the treatment had to be performed manually. At present there are some spatial restrictions with Model C in APS mode when compared with the Model B. The most significant restriction is the narrow space for the patient's shoulders, especially when deep-seated lesions are treated. Through mechanical changes of the APS motor housing and some modifications of and to the motor driven couch adjustment, these limitations will be reduced in the future. The APS treatment runs smoothly and fast. In no case did any relevant safety error occur during GKS. The more stringent mechanical limitations of the APS compared with the Model B means that frame placement on the head is more critical than before.

Xanthones from Calophyllum teysmannii var. inophylloide.

Further study of the wood of Calophyllum teysmannii Miq. var. inophylloide yielded xanthones 7-hydroxy-1,2,8-trimethoxyxanthone, 6-hydroxy-1,2,5-trimethoxyxanthone, and 2-carbomethoxy-6-methoxyxanthone in addition to 3,8-dihydroxy-1,2,4-trimethoxyxanthone, 3-hydroxy-2,4-dimethoxyxanthone, 1,7-dihydroxy-3-methoxyanthone (gentisin) and 2-hydroxyxanthone.

Immunomodulatory Activity of Xanthones from Calophyllum teysmannii var. inuphylloide.

Nine xanthones, including 3-(4-hydroxy-3-metnylbutyl)-4,8-dihydroxyxanthone, were isolated from the wood of a Thai collection of CALOPHYLLUM TEYSMANNII Miq. var. INUPHYLLOIDE (King) P. Stephen. Immunomodulatory activities of eight of these have been investigated.

Sesquiterpene lactones and other constituents of Centaurea napifolia.

Aerial parts of Centaurea napifolia furnished the sesquiterpene lactones cnicin, 4'-acetoxycnicin, melitensin, dehydromelitensin, two known esters of dehydromelitensin, lappaol and a lappaol isomer, and a 1,2-diacylated glucose.

Constituents of Knema laurina and Knema tenuinervia ssp. setosa.

Extraction of the stem bark of KNEMA LAURINA Warb. and KNEMA TENUINERVIA W. J. J. O. de Wilde ssp. SETOSA de Wilde furnished 3-(12-phenyl-8 Z-dodecenyl)-phenol and 3-(8 Z-pentadecenyl)-phenol together with 8-hydroxy-6-methoxy-3- N-pentylisocoumarin, respectively. 2-Carboxy-3-(12-phenyldodecyl)-phenol) and 2,4-dihydroxy-6-(10-phenyldecyl)-acetophenone were common to both extracts.

Lignans and Other Constituents of Centaurea sphaerocephala ssp. polyacantha.

Extraction of the aerial parts of CENTAUREA SPHAEROCEPHALA L. ssp. POLYACANTHA (Willd.) Dostal furnished the lignans (-)-matairesinol, (-)-arctigenin, and (-)-arctiin, two sesquilignans lappaol A and a stereo- or structural isomer of lappaol A, and a new dithienylacetylene.