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.

Fungal Planet description sheets: 1614-1696.

Novel species of fungi described in this study include those from various countries as follows: Australia, Baobabopsis sabindy in leaves of Eragrostis spartinoides, Cortinarius magentiguttatus among deep leaf litter, Laurobasidium azarandamiae from uredinium of Puccinia alyxiae on Alyxia buxifolia, Marasmius pseudoelegans on well-rotted twigs and litter in mixed wet sclerophyll and subtropical rainforest. Bolivia, Favolaschia luminosa on twigs of Byttneria hirsuta, Lecanora thorstenii on bark, in savannas with shrubs and trees. Brazil, Asterina costamaiae on leaves of Rourea bahiensis, Purimyces orchidacearum (incl. Purimyces gen. nov.) as root endophyte on Cattleya locatellii. Bulgaria, Monosporascus bulgaricus and Monosporascus europaeus isolated from surface-sterilised, asymptomatic roots of Microthlaspi perfoliatum. Finland, Inocybe undatolacera on a lawn, near Betula pendula. France, Inocybe querciphila in humus of mixed forest. Germany, Arrhenia oblongispora on bare soil attached to debris of herbaceous plants and grasses. Greece, Tuber aereum under Quercus coccifera and Acer sempervirens. India, Alfoldia lenyadriensis from the gut of a Platynotus sp. beetle, Fulvifomes subramanianii on living Albizzia amara, Inosperma pavithrum on soil, Phylloporia parvateya on living Lonicera sp., Tropicoporus maritimus on living Peltophorum pterocarpum. Indonesia, Elsinoe atypica on leaf of Eucalyptus pellita. Italy, Apiotrichum vineum from grape wine, Cuphopyllus praecox among grass. Madagascar, Pisolithus madagascariensis on soil under Intsia bijuga. Netherlands, Cytosporella calamagrostidis and Periconia calamagrostidicola on old leaves of Calamagrostis arenaria, Hyaloscypha caricicola on leaves of Carex sp., Neoniesslia phragmiticola (incl. Neoniesslia gen. nov.) on leaf sheaths of standing dead culms of Phragmites australis, Neptunomyces juncicola on culms of Juncus maritimus, Zenophaeosphaeria calamagrostidis (incl. Zenophaeosphaeria gen. nov.) on culms of Calamagrostis arenaria. Norway, Hausneria geniculata (incl. Hausneria gen. nov.) from a gallery of Dryocoetes alni on Alnus incana. Pakistan, Agrocybe auriolus on leaf litter of Eucalyptus camaldulensis, Rhodophana rubrodisca in nutrient-rich loamy soil with Morus alba. Poland, Cladosporium nubilum from hypersaline brine, Entomortierella ferrotolerans from soil at mines and postmining sites, Pseudopezicula epiphylla from sooty mould community on Quercus robur, Quixadomyces sanctacrucensis from resin of Pinus sylvestris, Szafranskia beskidensis (incl. Szafranskia gen. nov.) from resin of Abies alba. Portugal, Ascocoryne laurisilvae on degraded wood of Laurus nobilis, Hygrocybe madeirensis in laurel forests, Hygrocybula terracocta (incl. Hygrocybula gen. nov.) on mossy areas of laurel forests planted with Cryptomeria japonica. Republic of Kenya, Penicillium gorferi from a sterile chicken feather embedded in a soil sample. Slovakia, Cerinomyces tatrensis on bark of Pinus mugo, Metapochonia simonovicovae from soil. South Africa, Acremonium agapanthi on culms of Agapanthus praecox, Alfaria elegiae on culms of Elegia ebracteata, Beaucarneamyces stellenboschensis (incl. Beaucarneamyces gen. nov.) on dead leaves of Beaucarnea stricta, Gardeniomyces kirstenboschensis (incl. Gardeniomyces gen. nov.) rotting fruit of Gardenia thunbergia, Knufia dianellae on dead leaves of Dianella caerulea, Lomaantha quercina on twigs of Quercus suber. Melanina restionis on dead leaves of Restio duthieae, Microdochium buffelskloofinum on seeds of Eragrostis cf. racemosa, Thamnochortomyces kirstenboschensis (incl. Thamnochortomyces gen. nov.) on culms of Thamnochortus fraternus, Tubeufia hagahagana on leaves of Hypoxis angustifolia, Wingfieldomyces cypericola on dead leaves of Cyperus papyrus. Spain, Geastrum federeri in soil under Quercus suber and Q. canariensis, Geastrum nadalii in calcareous soil under Juniperus, Quercus, Cupressus, Pinus and Robinia, Hygrocybe garajonayensis in laurel forests, Inocybe cistophila on acidic soil under Cistus ladanifer, Inocybe sabuligena in a mixed Quercus ilex subsp. ballota/Juniperus thurifera open forest, Mycena calongei on mossy bark base of Juniperus oxycedrus, Rhodophana ulmaria on soil in Ulmus minor forest, Tuber arriacaense in soil under Populus pyramidalis, Volvariella latispora on grassy soils in a Quercus ilex ssp. rotundifolia stand. Sweden, Inocybe iota in alpine heath on calcareous soil. Thailand, Craterellus maerimensis and Craterellus sanbuakwaiensis on laterite and sandy soil, Helicocollum samlanense on scale insects, Leptosporella cassiae on dead twigs of Cassia fistula, Oxydothis coperniciae on dead leaf of Copernicia alba, Russula mukdahanensis on soil, Trechispora sangria on soil, Trechispora sanpatongensis on soil. Türkiye, Amanita corylophila in a plantation of Corylus avellana. Ukraine, Pararthrophiala adonis (incl. Pararthrophiala gen. nov.) on dead stems of Adonis vernalis. USA, Cladorrhinum carnegieae from Carnegiea gigantea, Dematipyriformia americana on swab from basement wall, Dothiora americana from outside air, Dwiroopa aeria from bedroom air, Lithohypha cladosporioides from hospital swab, Macroconia verruculosa on twig of Ilex montana, associated with black destroyed ascomycetous fungus and Biatora sp., Periconia floridana from outside air, Phytophthora fagacearum from necrotic leaves and shoots of Fagus grandifolia, Queenslandipenidiella californica on wood in crawlspace. Morphological and culture characteristics are supported by DNA barcodes. Citation: Crous PW, Jurjevic Z, Balashov S, De la Peña-Lastra S, Mateos A, Pinruan U, Rigueiro-Rodríguez A, Osieck ER, Altés A, Czachura P, Esteve-Raventós F, Gunaseelan S, Kaliyaperumal M, Larsson E, Luangsa-ard JJ, Moreno G, Pancorbo F, Piatek M, Sommai S, Somrithipol S, Asif M, Delgado G, Flakus A, Illescas T, Kezo K, Khamsuntorn P, Kubátová A, Labuda R, Lavoise C, Lebel T, Lueangjaroenkit P, Maciá-Vicente JG, Paz A, Saba M, Shivas RG, Tan YP, Wingfield MJ, Aas T, Abramczyk B, Ainsworth AM, Akulov A, Alvarado P, Armada F, Assyov B, Avchar R, Avesani M, Bezerra JL, Bhat JD, Bilanski P, Bily DS, Boccardo F, Bozok F, Campos JC, Chaimongkol S, Chellappan N, Costa MM, Dalecká M, Darmostuk V, Daskalopoulos V, Dearnaley J, Dentinger BTM, De Silva NI, Dhotre D, Carlavilla JR, Doungsa-ard C, Dovana F, Erhard A, Ferro LO, Gallegos SC, Giles CE, Gore G, Gorfer M, Guard FE, Hanson S-A, Haridev P, Jankowiak R, Jeffers SN, Kandemir H, Karich A, Kislo K, Kiss L, Krisai-Greilhuber I, Latha KPD, Lorenzini M, Lumyong S, Manimohan P, Manjón JL, Maula F, Mazur E, Mesquita NLS, Mlynek K, Mongkolsamrit S, Morán P, Murugadoss R, Nagarajan M, Nalumpang S, Noisripoom W, Nosalj S, Novaes QS, Nowak M, Pawlowska J, Peiger M, Pereira OL, Pinto A, Plaza M, Polemis E, Polhorský A, Ramos DO, Raza M, Rivas-Ferreiro M, Rodriguez-Flakus P, Ruszkiewicz-Michalska M, Sánchez A, Santos A, Schüller A, Scott PA, Sen I, Shelke D, Sliwa L, Solheim H, Sonawane H, Strasiftáková D, Stryjak-Bogacka M, Sudsanguan M, Suwannarach N, Suz LM, Syme K, Taskin H, Tennakoon DS, Tomka P, Vaghefi N, Vasan V, Vauras J, Wiktorowicz D, Villarreal M, Vizzini A, Wrzosek M, Yang X, Yingkunchao W, Zapparoli G, Zervakis GI, Groenewald JZ (2024). Fungal Planet description sheets: 1614-1696. Fungal Systematics and Evolution 13: 183-440. doi: 10.3114/fuse.2024.13.11.

Glomeruloid microvascular proliferation is associated with lack of response to chemotherapy in breast cancer.

BACKGROUND: Glomeruloid microvascular proliferation (GMP), a novel histology-based angiogenesis marker, has been associated with decreased survival in several human cancers. METHODS: In this study, we evaluated the ability of GMP to predict clinical response to neoadjuvant chemotherapy in a series of locally advanced breast cancers (n=112). RESULTS: Presence of GMP (21% of the cases) was significantly associated with high-grade tumours and TP53 mutations in addition to the basal-like and HER2 subtypes of breast cancer as defined by gene expression data. GMP was correlated to a gene expression signature for tumour hypoxia response. The GMP pattern was also significantly associated with lack of treatment response and progressive disease (P=0.004). INTERPRETATION: The findings suggest that GMP might be able to predict the lack of response to neoadjuvant chemotherapy in locally advanced breast cancer. Whether GMP may be an independent predictor compared with other factors including TP53 mutation status and tumour grade needs confirmation in larger studies.

Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients.

The mechanisms causing resistance to chemotherapeutic drugs in cancer patients are poorly understood. Recent evidence suggests that different forms of chemotherapy may exert their cytotoxic effects by inducing apoptosis. The tumor suppressor gene P53 has a pivotal role inducing apoptosis in response to cellular damage. In vitro investigations have shown intact p53 to play a critical role executing cell death in response to treatment with cytotoxic drugs like 5-fluorouracil, etoposide and doxorubicin. Recently, mutations in the P53 gene were found to confer resistance to anthracyclines in a mouse sarcoma tumor model, and overexpression of the p53 protein (which, in most cases, is due to a mutated gene) was found to be associated with lack of response to cisplatin-based chemotherapy in non-small cell lung cancer. Previous studies have shown mutations in the P53 gene or overexpression of the p53 protein to predict a poor prognosis, but also a beneficial effect of adjuvant radiotherapy or chemotherapy in breast cancer. In this study we present data linking specific mutations in the P53 gene to primary resistance to doxorubicin therapy and early relapse in breast cancer patients.

Modelling the propagation of effects of chronic exposure to ionising radiation from individuals to populations.

This study evaluated the potential effect of ionising radiation on population growth using simple population models and parameter values derived from chronic exposure experiments in two invertebrate species with contrasting life-history strategies. In the earthworm Eisenia fetida, models predicted increasing delay in population growth with increasing gamma dose rate (up to 0.6 generation times at 11 mGy h(-1)). Population extinction was predicted at 43 mGy h(-1). In the microcrustacean Daphnia magna, models predicted increasing delay in population growth with increasing alpha dose rate (up to 0.8 generation times at 15.0 mGy h(-1)), only after two successive generations were exposed. The study examined population effects of changes in different individual endpoints (including survival, number of offspring produced and time to first reproduction). Models showed that the two species did not respond equally to equivalent levels of change, the fast growing daphnids being more susceptible to reduction in fecundity or delay in reproduction than the slow growing earthworms. This suggested that susceptibility of a population to ionising radiation cannot be considered independent of the species' life history.

Radiosensitivity and transgenerational effects in non-human species.

The ALLIANCE working group on effects of ionising radiation on wildlife brings together European researchers to work on the topics of radiosensitivity and transgenerational effects in non-human biota. Differences in radiation sensitivity across species and phyla are poorly understood, but have important implications for understanding the overall effects of radiation and for radiation protection; for example, sensitive species may require special attention in monitoring and radiation protection, and differences in sensitivity between species also lead to overall effects at higher levels (community, ecosystem), since interactions between species can be altered. Hence, understanding the mechanisms of interspecies radiation sensitivity differences may help to clarify mechanisms underpinning intraspecies variation. Differences in sensitivity may only be revealed when organisms are exposed to ionising radiation over several generations. This issue of potential long-term or hereditary effects for both humans and wildlife exposed to low doses of ionising radiation is a major concern. Animal and plant studies suggest that gamma irradiation can lead to observable effects in the F1 generation that are not attributable to inheritance of a rare stable DNA mutation. Several studies have provided evidence of an increase in genomic instability detected in germ or somatic cells of F1 organisms from exposed F0 organisms. This can lead to induced radiosensitivity, and can result in phenotypic effects or lead to reproductive effects and teratogenesis. In particular, studies have been conducted to understand the possible role of epigenetic modifications, such as DNA methylation, histone modifications, or expression of non-coding RNAs in radiosensitivity, as well as in adaptation effects. As such, research using biological models in which the relative contribution of genetic and epigenetic processes can be elucidated is highly valuable.

Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer.

TP53 status [mutations, immunostaining, and loss of heterozygosity (LOH)], expression of c-erbB-2, bcl-2, and histological grading were correlated to the response to doxorubicin monotherapy (14 mg/m2) administered weekly to 90 patients with locally advanced breast cancer. Mutations in the TP53 gene, in particular those affecting or disrupting the loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (P = 0.063 for all mutations and P = 0.008 for mutations affecting L2/L3, respectively). Similarly, expression of c-erbB-2 (P = 0.041), a high histological grade (P = 0.023), and lack of expression of bcl-2 (P = 0.018) all predicted chemoresistance. No statistically significant association between either p53 immunostaining or TP53 LOH and response to therapy was recorded, despite the finding that both were associated with TP53 mutation status (p53 immunostaining, P < 0.001; LOH, P = 0.021). Lack of immunostaining for p53 despite mutation of the TP53 gene was particularly seen in tumors harboring nonsense mutations or deletions/splices (7 of 10 negative for staining compared with 4 of 16 with missense mutations). TP53 mutations (total/affecting L2/L3 domains) were associated with expression of c-erbB-2 (P < 0.001 for both), high histological grade (P = 0.001 and P = 0.025), and bcl-2 negativity (P = 0.003 and P = 0.002). TP53 mutations, histological grade, and expression of bcl-2 (but not LOH or c-erbB-2 expression) all predicted for relapse-free as well as breast cancer-specific survival in univariate analysis (Ps between <0.0001 and 0.0155), but only tumor grade was found to be predictive in multivariate analysis (P = 0.01 and P = 0.0007, respectively). Our data are consistent with the hypothesis that certain TP53 mutations predict for resistance to doxorubicin in breast cancer patients. However, the observation that the majority of patients with TP53 mutations affecting or disrupting the L2/L3 domains with LOH in addition (n = 12) obtained a partial response (n = 4) or stabilization of disease (n = 5) during chemotherapy suggests redundant mechanisms to compensate for loss of p53 function. Our findings are consistent with the hypothesis that other defects may act in concert with loss of p53 function, causing resistance to doxorubicin in breast cancers.

Women treated with breast conserving surgery do better than those with mastectomy independent of detection mode, prognostic and predictive tumor characteristics.

BACKGROUND: Primary breast conserving treatment (BCT) is well known to have similar long-term survival as mastectomy in breast cancer patients. However, recent studies are suggesting better survival among women treated with BCT compared with mastectomy. More knowledge is needed to understand how disease specific survival is influenced by detection mode, prognostic and predictive tumor characteristics. We aimed to investigate this issue among women targeted by the Norwegian Breast Cancer Screening Program. METHOD: Information about 9547 women aged 50-69 years diagnosed with primary invasive breast cancer without distant metastasis, who underwent either BCT or mastectomy, 2005-2011, were included in the study. Kaplan-Meier plots were used to estimate six years survival, while Cox proportional hazards models were used to estimate the hazard ratio (HR) of breast cancer death associated with surgical treatment. Information about molecular subtype, detection mode, age at diagnosis, tumor size, lymph node involvement, and histologic grade, in addition to radiation treatment, chemotherapy and endocrine therapy were included in adjusted analyses. RESULTS: BCT was performed among 61.9% of the women included in the study. Women treated with BCT had prognostic and predictive favorable tumor characteristics compared to women treated with mastectomy. Adjusted analyses revealed a 1.7 (95% CI: 1.3-2.4) higher risk of breast cancer death among women who underwent mastectomy compared with BCT. CONCLUSION: Women treated with BCT have significantly better breast cancer-specific survival and a lower risk of dying from breast cancer compared to women treated with mastectomy, independent of detection mode, prognostic and predictive tumor characteristic.

Predictive value of tumour cell proliferation in locally advanced breast cancer treated with neoadjuvant chemotherapy.

We previously reported that defects in apoptotic pathways (mutations in the TP53 gene) predicted resistance to doxorubicin monotherapy. The aim of this study was to evaluate whether cell proliferation, as assessed by mitotic frequency and Ki-67 levels, may provide additional predictive information in the same tumours and to assess any potential correlations between these markers and mutations in the TP53 gene and erbB-2 overexpression. Surgical specimens were obtained from ninety locally advanced breast cancers before commencing primary chemotherapy consisting of weekly doxorubicin (14 mg/m2) for 16 weeks. 38% of the patients had a partial response (PR) to therapy, 52% had stable disease (SD) while 10% had progressive disease (PD). Univariate analysis showed a significant association between a high cell proliferation rate (expressed as a high mitotic frequency) and resistance to doxorubicin (P = 0.001). Further analyses revealed this association to be limited to the subgroup of tumour expressing wild-type TP53 (P = 0.016), and TP53 mutation status was the only factor predicting drug resistance in the multivariate analyses. The finding that a high mitotic frequency, as well as a high Ki-67 staining, correlated to TP53 mutations (P = 0.001 for both), suggests TP53 mutations are the key predictor of drug resistance, although cell proliferation may play an additional role in tumours harbouring wild-type TP53. Regarding overall (OS) and relapse-free survival (RFS), multivariate analyses (Cox' proportional hazards regression) revealed a high histological grade and negative oestrogen receptor (ER) status to be the variables that were most strongly related to breast cancer death (P = 0.001 and P = 0.001, respectively). A key reason for this difference with respect to the factors predicting chemotherapy resistance could be due to the adjuvant use of tamoxifen in all patients harbouring ER-positive tumours.

Proton magnetic resonance spectroscopy of brain biopsies from patients with intractable epilepsy.

In the present study metabolite concentrations were determined by proton magnetic resonance spectroscopy (MRS) in biopsies obtained from patients suffering intractable epilepsy from several different causes. Seven patients had gliosis, four had mild cortical dysplasia, three had tuberous sclerosis, two had astrocytomas, and one had a cavernous angioma. No significant differences were found in gliotic tissue in comparison with controls except for an increase in lactate. However, in the subgroup with tuberous sclerosis an increase was found in GABA and a dramatic decrease in N-acetyl aspartate (NAA). The most marked changes were found in the group with mild cortical dysplasia. There was a considerable decrease in NAA as well as large increases in GABA, alanine, tyrosine, acetate, inositol, glucose and lactate. The GABA content did not appear to correlate with antiepileptic therapy. Moreover, since all these patients required surgery, an elevated GABA level does not necessarily provide protection from seizures. The results indicate that use of proton MRS could become a useful presurgical predictor of underlying pathology.

Increase of endo-peptidases and exo-peptidases in thyroid-tumors.

Production of proteolytic enzymes is important for the invasive properties of malignant tumours. In this series of 43 cases of various non-neoplastic and neoplastic thyroid lesions, the activity of dipeptidyl peptidase I and dipeptidyl peptidase IV was increased in papillary carcinomas. In addition, cathepsin B and cathepsin L were markedly elevated in 2 of 3 follicular carcinomas, and tryptase, which is a marker of mast cells, was also significantly elevated in follicular carcinomas. Our results indicate that proteolytic proteins are important in thyroid carcinomas, and in addition there seem to be some differences between papillary and follicular tumours. Larger studies are needed to confirm these findings.

Lack of diagnostic-value of DNA content and p53 immunostaining in normal, hyperplastic and neoplastic parathyroid tissue.

The aim of this project was to study the diagnostic value of DNA content and p53 protein expression in normal, hyperplastic and neoplastic parathyroid lesions. Tissue samples of 74 parathyroid glands from 34 patients with primary hyperparathyroidism were studied by DNA flow cytometry and p53 immunostaining. In 9 of 23 patients (39%) with parathyroid adenoma, a nondiploid cell population was present. Some normal looking glands removed from the same patients also had a nondiploid DNA index. Multiglandular hyperplasia was found in 11 patients, and in 5 of these (45%) the histograms showed nondiploid cells. The proliferative activity was generally low and S-phase fraction did not differ in glands with hyperplasia or adenoma, when compared with normal looking glands. One single case of hyperplasia showed a weak p53 positivity in scattered nuclei, probably representing wild type p53 protein. Thus, our present results suggest that DNA content and p53 protein staining are of no value in the routine work up of parathyroid glands removed from patients with primary hyperparathyroidism.

Progesterone binding cyst protein in hormone receptor positive breast cancer; a predictive factor for effect of adjuvant tamoxifen treatment.

Progesterone binding cyst protein (PBCP) was measured in breast cancer cytosols from 128 pre- and post-menopausal women with operable node positive (pN+) breast cancer Stage II. All patients were included in a national multicenter study on the effect of adjuvant tamoxifen treatment in hormone sensitive breast cancer, i.e. estrogen receptor content of at least 10 pmol/g cytosol protein. Patients were randomised to receive adjuvant tamoxifen 20 mg once daily for two years or no endocrine treatment. At a median follow-up of 60 months, we found PBCP content in the primary tumor to be an important factor with regard to the effect of adjuvant tamoxifen treatment. The benefit of adjuvant tamoxifen treatment on relapse-free survival and overall survival was confined to the subpopulation of patients with PBCP negative tumors. PBCP should be further evaluated as a predictive factor for the effect of tamoxifen treatment.

Systemic heparinization of uremic patients and its effects on blood lipids and on in vitro toxicity of the plasma.

The effect of heparin on plasma lipids was investigated in uremic patients prior to and during hemodialysis, and in healthy individuals receiving equal heparin doses. The effects of heparin on plasma lipids were correlated with the effects of plasma on phytohemagglutinin (PHA)-stimulated lymphocytes, and on the function of human mononuclear phagocytes cultured in vitro. The plasma concentrations of high density lipoproteins, cholesterol and albumin were not influenced by systemic heparinization or hemodialysis. Plasma triglycerides showed a significant fall in both groups tested, and remained almost unchanged during hemodialysis. The ratio between the molar concentration of free fatty acids and albumin increased in both groups following systemic heparinization and was significantly correlated with a rise in plasma toxicity.

Microvessel proliferation by co-expression of endothelial nestin and Ki-67 is associated with a basal-like phenotype and aggressive features in breast cancer.

BACKGROUND: To quantify tumour angiogenesis, microvessel density (MVD) has been widely used. We here present a novel angiogenesis marker, microvessel proliferation (MVP), based on dual immunohistochemical staining of nestin and Ki-67. Immature endothelial cells express nestin, and when co-expressed with the proliferation marker Ki-67, the number of proliferating immature blood vessels can be measured. MATERIALS AND METHODS: Microvessel proliferation was evaluated in 178 breast cancer samples and estimated by vascular proliferation index (VPI), the ratio between the number of vessels containing proliferating endothelial cells and the total number of immature vessels. RESULTS: High VPI was strongly associated with several markers of aggressive breast cancer, such as negative oestrogen receptor (ER) status (p = 0.003), high tumour cell proliferation by Ki-67 (p = 0.004), high p53 expression (p = 0.001), and five profiles for the basal-like phenotype (odds ratios (OR); range 3.4-6.3). Also, high VPI was significantly associated with interval detected breast cancer compared with screening detected lesions (p < 0.0005), and adverse outcome in univariate and multivariate survival analysis (p = 0.034 and p = 0.022, respectively). CONCLUSION: Microvessel proliferation is a novel marker of ongoing angiogenesis and was associated with aggressive tumour features, basal-like phenotypes, interval presentation, and prognosis in this series of breast cancer.

An invitation to contribute to a strategic research agenda in radioecology.

With intentions of integrating a portion of their respective research efforts into a trans-national programme that will enhance radioecology, eight European organisations recently formed the European Radioecology ALLIANCE (www.er-alliance.org). The ALLIANCE is an Association open to other organisations throughout the world with similar interests in promoting radioecology. The ALLIANCE members recognised that their shared radioecological research could be enhanced by efficiently pooling resources among its partner organizations and prioritising group efforts along common themes of mutual interest. A major step in this prioritisation process was to develop a Strategic Research Agenda (SRA). An EC-funded Network of Excellence in Radioecology, called STAR (Strategy for Allied Radioecology), was formed, in part, to develop the SRA. This document is the first published draft of the SRA. The SRA outlines a suggested prioritisation of research topics in radioecology, with the goal of improving research efficiency and more rapidly advancing the science. It responds to the question: "What topics, if critically addressed over the next 20 years, would significantly advance radioecology?" The three Scientific Challenges presented within the SRA, with their 15 associated research lines, are a strategic vision of what radioecology can achieve in the future. Meeting these challenges will require a directed effort and collaboration with many organisations the world over. Addressing these challenges is important to the advancement of radioecology and in providing scientific knowledge to decision makers. Although the development of the draft SRA has largely been a European effort, the hope is that it will initiate an open dialogue within the international radioecology community and its stakeholders. This is an abbreviated document with the intention of introducing the SRA and inviting contributions from interested stakeholders. Critique and input for improving the SRA are welcomed via a link on the STAR website (www.star-radioecology.org).

Tissue estradiol is selectively elevated in receptor positive breast cancers while tumour estrone is reduced independent of receptor status.

Previous studies have suggested elevated estrogen production in tumour-bearing breast quadrants as well as in breast cancers versus benign tissue. Using highly sensitive assays, we determined breast cancer tissue estrogen concentrations together with plasma and benign tissue estrogen concentrations in each quadrant obtained from mastectomy specimens (34 postmenopausal and 13 premenopausal women). We detected similar concentrations of each of the three major estrogens estradiol (E(2)), estrone (E(1)) and E(1)S in tumour-bearing versus non-tumour-bearing quadrants. Considering malignant tumours, intratumour E(1) levels were reduced in cancer tissue obtained from pre- as well as postmenopausal women independent of tumour ER status (average ratio E(1) cancer: benign tissue of 0.2 and 0.3, respectively; p<0.001 for both groups), suggesting intratumour aromatization to be of minor importance. The most striking finding was a significant (4.1-8.6-fold) increased E(2) concentration in ER positive tumours versus normal tissue (p<0.05 and <0.001 for pre- and postmenopausal patients, respectively), contrasting low E(2) concentrations in ER- tumours (p<0.01 and <0.001 comparing E(2) levels between ER+ and ER- tumours in pre- and postmenopausals, respectively). A possible explanation to our finding is increased ligand receptor binding capacity for E(2) in receptor positive tumours but alternative factors influencing intratumour estrogen disposition cannot be excluded.

The effect of uraemic serum and plasma on proliferating cells in vitro.

Phytohaemagglutinin (PHA)-stimulated lymphocytes from healthy individuals and a malignant cell-line (K-562 cells) were cultured in a growth medium of 75 per cent RPMI 1640 (Gibco) supplemented with 25 per cent of uraemic serum or plasma obtained after systemic heparinization. Pooled human A Rh+ serum from 3 different donors served as controls. There was a depression of the DNA synthesis in both cell systems measured as uptake of methyl-3H-thymidine when the cells were cultured in uraemic milieu. Systemic heparinization markedly increased the depressive effect of uraemic plasma compared with controls. Heparin added to the growth media in concentrations much higher than those usually present in plasma after systemic heparinization had little effect on the cell proliferation. Systemic heparinization thus appears to induce production of toxic substances in plasma acting on proliferating cells.

The effect of serum and plasma from haemodialysis patients on human mononuclear phagocytes cultured in vitro.

Human mononuclear phagocytes from healthy individuals were cultured in plasma and sera from normal persons and patients with chronic renal failure receiving haemodialysis. There was a marked detachment of macrophages from the glass coverslips when the cells were grown for 4 days in uraemic serum or plasma compared to normal serum. The ability of the macrophages to adhere to the glass coverslips was reduced when the cells were cultured in plasma from normal persons and uraemics subjected to systemic heparinization. However, the toxic effect of in vivo heparinization was much higher in the uraemics than in normal persons. Heparin added to normal and uraemic blood samples in vitro far in excess of in vivo heparinization did not influence the macrophage function to the same extent. Cell toxic substances seem to be produced as a consequence of systemic heparinization. These substances were not removed during 100 minutes of haemodialysis. Heparin added to pooled A Rh+ serum in concentrations far above those present in plasma following in vivo heparinization had little adverse effect on the macrophage function.

[Breast conserving surgery in breast cancer. Experiences from the Haukeland Hospital 1983-88]. / Brystbevarende kirurgi ved cancer mammae. Erfaringer fra Haukeland sykehus 1983-88.

From 1983-88, 97 breast cancers in 94 women were treated with breast conserving surgery at Haukeland University Hospital. 71% of the tumours were less than 2 cm in diameter and 94% less than 3 cm. 65% had negative axillary nodal status. 90 patients had ductal carcinoma, three of whom also had extensive intraductal carcinoma. Pathological findings in the resection margins (invasive carcinoma, intraductal carcinoma or atypical epithelial hyperplasia) were reasons for reoperation in 14 patients, eight of them by mastectomy. Thus, after completion of initial treatment the breast was preserved in 89 patients. Postoperative irradiation to the breast was given as a routine. Three elderly patients were excepted. Two patients developed ipsilateral breast recurrences after six and 24 months respectively. The first was treated by re-resection and the second by mastectomy. Neither of these showed evidence of distant metastases. Distant metastases were discovered in five patients, two of these have since died.