Impact of Prosigna test on adjuvant treatment decision in lymph node-negative early breast cancer-a prospective national multicentre study (EMIT-1).

BACKGROUND: EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions. PATIENTS AND METHODS: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians' treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed. RESULTS: Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94). CONCLUSION: The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals.

Evolution and development of the cetacean skull roof: a case study in novelty and homology.

Skulls of living whales and dolphins (cetaceans) are telescoped-bones of the skull roof are overlapped by expanded facial bones and/or anteriorly extended occipital bones. Evolution of the underlying skull roof (calvarium), which lies between the telescoped regions, is relatively unstudied. We explore the evolution and development of the calvarium of toothed whales (odontocetes) by integrating fetal data with Oligocene odontocete fossils from North America, including eight neonatal and juvenile skulls of Olympicetus†. We identified two potential synapomorphies of crown Cetacea: contact of interparietals with frontals, and a single anterior median interparietal (AMI) element. Within Odontoceti, loss of contact between the parietals diagnoses the clade including Delphinida, Ziphiidae and Platanistidae (=Synrhina). Delphinida is characterized by a greatly enlarged interparietal. New fetal series of delphinoids reveal a consistent developmental pattern with three elements: the AMI and bilateral posterior interparietals (PIs). The PIs most resemble the medial interparietal elements of terrestrial artiodactyls, suggesting that the AMI of cetaceans could be a unique ossification. More broadly, the paucity of conserved anatomical relationships of the interparietals, as well as the fact that the elements often do not coalesce into a single bone, demonstrates that assessing homology of the interparietals across mammals remains challenging. This article is part of the theme issue 'The mammalian skull: development, structure and function'.

Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial.

BACKGROUND: Recent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested. OBJECTIVE: To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction. METHODS: PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations. RESULTS: The study is ongoing. Results will be published when the study is completed. CONCLUSION: PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy. TRIAL REGISTRATION: The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588 ). Registered 30 November 2018.

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.

BRAF mutational status as a prognostic marker for survival in malignant melanoma: a systematic review and meta-analysis.

Background: The analysis of the BRAF mutational status has been established as a standard procedure during diagnosis of advanced malignant melanoma due to the fact that BRAF inhibitors constitute a cornerstone in the treatment of metastatic disease. However, the general impact of BRAF mutational status on survival remains unclear. Our study aimed to assess the underlying prognostic significance of BRAF mutant versus wild type (WT) malignant melanoma on overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS).Material and methods: A systematic literature search in EMBASE, Medline and Cochrane CENTRAL was performed. Studies were included if they reported survival outcomes for BRAF mutant versus WT patients as hazard ratios (HR) or in Kaplan-Meier (KM) curves. Random-effects meta-analysis models were used to pool HRs across the studies.Results: Data from 52 studies, representing 7519 patients, were pooled for analysis of OS. The presence of a BRAF mutation was statistically significantly associated with a reduced OS (HR [95% confidence interval (CI)]: 1.23 [1.09-1.38]), however, with substantial heterogeneity between the studies (I2: 58.0%). Meta-regression and sensitivity analyses showed that age, sex and BRAF mutation testing method did not have a significant effect on the OS HR. BRAF mutant melanoma showed comparable effect on DFS to non-BRAF mutant melanoma in stage I-III melanoma (combined HR: 1.16, 95% CI: 0.92-1.46), and on PFS in stage III-IV (HR: 0.98 (95% CI: 0.68-1.40)).Conclusion: Although there was substantial heterogeneity between the studies, the overall results demonstrated a poorer prognosis and OS in patients harbouring BRAF mutations. Future studies should take this into account when evaluating epidemiological data and treatment effects of new interventions in patients with malignant melanoma.

Patterns of genomic evolution in advanced melanoma.

Genomic alterations occurring during melanoma progression and the resulting genomic heterogeneity between metastatic deposits remain incompletely understood. Analyzing 86 metastatic melanoma deposits from 53 patients with whole-exome sequencing (WES), we show a low branch to trunk mutation ratio and little intermetastatic heterogeneity, with driver mutations almost completely shared between lesions. Branch mutations consistent with UV damage indicate that metastases may arise from different subclones in the primary tumor. Selective gain of mutated BRAF alleles occurs as an early event, contrasting whole-genome duplication (WGD) occurring as a late truncal event in about 40% of cases. One patient revealed elevated mutational diversity, probably related to previous chemotherapy and DNA repair defects. In another patient having received radiotherapy toward a lymph node metastasis, we detected a radiotherapy-related mutational signature in two subsequent distant relapses, consistent with secondary metastatic seeding. Our findings add to the understanding of genomic evolution in metastatic melanomas.

An economic analysis of cisplatin alone versus cisplatin doublets in the treatment of women with advanced or recurrent cervical cancer.

PURPOSE OF INVESTIGATION: Randomized trials have demonstrated improvements in overall survival when using platinum doublets com- pared to single agent platinum in the treatment of women with advanced or recurrent cervical cancer. The authors sought to evaluate the cost effectiveness of these regimens. METHODS: A decision model was developed based on Gynecologic Oncology Group (GOG) protocols 179 and 204. Cisplatin alone was compared to cisplatin/paclitaxel (CP), cisplatin/topotecan (CT), cisplatin/gemcitabine (GC), cisplatin/vinorelbine (CV), and a hypothetical novel agent. Parameters included overall survival (OS), cost, and complications. One way sensitivity analyses were performed. In further sensitivity analysis, a hypothetical agent that added 3.7 months survival to CP's survival was studied. RESULTS: The chemotherapy drug costs for six cycles of cisplatin was 89 USD while for cisplatin/paclitaxel it was 489 USD. The highest chemotherapy cost was for GC at 18,306 USD. The average total cost of six cycles CP was 13,250 USD while the average cost of cisplatin alone was 14,573 USD. The highest average cost for six cycles was for GC at 33,559 USD. With cisplatin/paclitaxel being the most effective, the cost effectiveness analysis showed that cisplatin, CT, GC, and VC were all dominated by CP. Because of the regimens being dominated, no baseline ICERs compared to CP were calculable. Sensitivity analyses demonstrate that even all of the chemotherapies were given for free, CP would still be the regimen of choice. CONCLUSIONS: In this model, CP is the most cost effective regimen for the treatment of these patients with an average cost of 13,250 USD. With the fact that GOG 204 also showed statistically significantly improved survival for CP, CP should be considered the regimen of choice.

Vascular endothelial growth factor (VEGF) and cyclooxygenase 2 (COX 2) immunostaining in ovarian cancer.

PURPOSE OF INVESTIGATION: Vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX 2) are markers of angiogenesis and potential therapeutic targets. Previous studies demonstrate that VEGF is upregulated in some ovarian cancers. The purpose of this study was to determine the correlation of VEGF and COX 2 staining with survival in ovarian cancer patients. MATERIALS AND METHODS: One hundred forty-three consecutive patients with ovarian carcinoma underwent primary staging or cytoreduction prior to platinum-based chemotherapy. Their tumors were immunohistochemically stained for expression of VEGF and COX 2. FIGO stage, grade, cytoreduction status, and histology were also analyzed as prognostic factors. RESULTS: Twenty-seven patients had Stage I tumors, three Stage II, 87 Stage III, and 26 Stage IV. Median follow-up was 74 months (mean 79 months). One hundred nineteen patients (83.2%) had tumors that were positive for VEGF and 110 patients (76.9%) had tumors that were positive for COX 2. Patients with tumors staining positive for both VEGF and COX 2 (68.5%) had a significantly increased risk of dying from their ovarian cancer (Chi-square p = 0.011, Log rank p = 0.037). Multivariate logistic regression analysis revealed FIGO stage, grade, cytoreduction status, and VEGF/COX 2 expression to be independent prognostic indicators of survival. Conclusion: VEGF and COX 2 staining are frequently positive in ovarian cancer. Patients whose tumors are positive for both VEGF and COX 2 have a decreased survival. These patients may benefit from anti-angiogenesis targeted therapy.

Cyclin E is overexpressed by clear cell carcinomas of the endometrium and is a prognostic indicator of survival.

OBJECTIVE: Upregulation of cyclin E and cyclin D1-6 accelerates the transition from G1 to S phase. The objective of this study was to determine if cyclin D1 and E are prognostic indicators in endometrial cancer. MATERIALS AND METHODS: Surgically-treated patients with endometrial carcinoma had their tumors stained for nuclear expression of cyclin D1 and E. Quantification of staining and measurement of growth phase fraction were performed using image analysis. FIGO stage, grade, and histology were also analyzed. RESULTS: Cyclin D1 and E expression was unrelated to DNA index (p = 0.93). While cyclin D1 expression did not correlate with S+G2M phase fraction (p = 0.69), increased cyclin E expression was directly correlated with increased S+G2M phase fraction (p = 0.002). Cyclin E expression was highest in clear cell carcinomas (p = 0.042) while cyclin D1 expression was highest in adenosquamous carcinomas (p = 0.028). Patients dying from cancer had significantly higher expression of cyclin D1 (p = 0.042) and E (p = 0.02) as compared to patients surviving their disease. Multivariate logistic regression revealed FIGO stage, grade, and lack of cyclin E overexpression to be independent prognostic indicators of survival. CONCLUSION: Cyclin E expression is related to increased growth fraction, clear cell histology, and decreased survival in patients with endometrial cancer.

Total colectomy in primary ovarian cytoreduction.

OBJECTIVE: To review the indications, procedure, and complications associated with total colectomy with ileorectal anastamosis in women undergoing primary debulking of ovarian cancer. METHODS: Charts were reviewed to determine all patients undergoing total colectomy with ileorectal anastamosis during primary debulking of ovarian, peritoneal, or fallopian tube cancer. Charts were also reviewed for perioperative morbidity and mortality, as well as rates of fecal incontinence. RESULTS: Nine patients underwent the above procedures during primary debulking of ovarian cancer. The mean age was 61 years with a mean BMI of 31 kg/m2. The average postoperative hospital stay was 11 days with an average estimated blood loss of 700 ml. There was no perioperative mortality. Although all patients had greatly increased frequency of stools, no patients had incontinence of stool after eight weeks. CONCLUSIONS: Radical surgery, including total colectomy, can be performed in select patients with primary ovarian cancer. Acceptable morbidity, mortality, and rectal continence can be obtained.

Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole--of clinical importance?

Aromatase inhibition is the gold standard for treatment of early and advanced breast cancer in postmenopausal women suffering from an estrogen receptor-positive disease. The currently established group of anti-aromatase compounds comprises two reversible aromatase inhibitors (anastrozole and letrozole) and on the other hand, the irreversible aromatase inactivator exemestane. Although exemestane is the only widely used aromatase inactivator at this stage, physicians very often have to choose between either anastrozole or letrozole in general practice. These third-generation aromatase inhibitors (letrozole/Femara (Novartis Pharmaceuticals, Basel, Switzerland) and anastrozole/Arimidex (AstraZeneca, Pharmaceuticals, Macclesfield, Cheshire, UK)), have recently demonstrated superior efficacy compared with tamoxifen as initial therapy for early breast cancer improving disease-free survival. However, although anastrozole and letrozole belong to the same pharmacological class of agents (triazoles), an increasing body of evidence suggests that these aromatase inhibitors are not equipotent when given in the clinically established doses. Preclinical and clinical evidence indicates distinct pharmacological profiles. Thus, this review focuses on the differences between the non-steroidal aromatase inhibitors allowing physicians to choose between these compounds based on scientific evidence. Although we are waiting for the important results of a still ongoing head-to-head comparison in patients with early breast cancer at high risk for relapse (Femara Anastrozole Clinical Evaluation trial; 'FACE-trial'), clinicians have to make their choices today. On the basis of available evidence summarised here and until FACE-data become available, letrozole seems to be the best choice for the majority of breast cancer patients whenever a non-steroidal aromatase inhibitor has to be chosen in a clinical setting. The background for this recommendation is discussed in the following chapters.

Hot spots in dynamic (18)FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas.

Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI-based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine ((18)FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p < 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4-44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of (18)FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning.

Targeting energy expenditure via fuel switching and beyond.

Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an over-nutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'.

Robotically-assisted laparoscopic radical parametrectomy and radical vaginectomy.

BACKGROUND: Radical parametrectomy is a technically challenging operation used for women found to have occult cervix cancer after a hysterectomy for benign reasons. A similar operation, radical vaginectomy, is rarely performed because of the its technical difficulty in getting adequate margins without an attached uterus. CASE REPORTS: A 41-year-old woman was found to have a presumed surgical Stage IB1 squamous cell carcinoma of the cervix at time of surgery for uterine prolapse. The patient was offered multiple options of surgery and chemoradiation. A second case, a 55-year-old woman, was found to have 1 cm vaginal cancer nine years after a total vaginal hysterectomy for carcinoma in situ of the cervix. She was also offered chemoradiation versus surgery. For the robotically-assisted laparoscopic radical parametrectomy operating time was 186 minutes with an estimated blood loss of 250 ml. For the robotically-assisted laparoscopic radical vaginectomy operating time was 154 minutes with an estimated blood loss of 150 ml. Neither patient had a hospitalization over 24 hours. There were no intraoperative or postoperative complications. CONCLUSIONS: Robotically-assisted laparoscopic radical paremetrectomy and vaginectomy are both technically feasible procedures.

[Angiographic moyamoya in a female with glycogenosis type IA - a case report focusing therapeutic management: bilateral encephalo-duro-arterio-myo-synangiosis (EDAMS)]. / Angiografisches Moyamoya bei Glykogenose Typ IA - Management bei einer erwachsenen Patientin: Fallbericht mit Schwerpunkt auf der Behandlung: beidseitige Encephalo-Duro-Arterio-Myo-Synangiose (EDAMS).

Angiographic Moyamoya is a rare cerebrovascular disease most frequent in asia. Its characateristics are recurrent ischemic attacks due to progressive occlusion of ICA branches. Angiography reveals fine arterial collateralisation reminding of ascending smoke ("moyamoya" in japanese). Neurosurgical treatment strategies include direct and indirect reanastomosation procedures. Randomised trials for comparison of clinical outcome and long term survival remain missing. A 23 years old female with glycogenosis type IA was first diagnosed bilateral angiographic moyamoya with bilateral proximal stenosis of ICA after transient ischemic attack (TIA). Coincidence of both rare diseases moyamoya and glycogenosis has previously been reported in three cases, so that this metabolic dysfunction presumably is a true risk factor for moyamoya. In our case, excellent angiographic and functional results were achieved by bilateral, consecutive Enzephalo-Duro-Arterio-Myo-Synangiosis (EDAMS).

Evaluation of plasma and tissue estrogen suppression with third-generation aromatase inhibitors: of relevance to clinical understanding?

Development of aromatase inhibition and aromatase inhibitors as a therapeutic strategy was initiated through two different pathways. The one pathway went through systematic exploration of aromatase substrate analogues for enzyme inhibitions, subsequently leading to the development of steroidal agents for clinical use. The second involved clinical observation with an unsuccessful anti-epileptic compound named aminoglutethimide, attempting to achieve a "medical adrenalectomy". Endocrine studies on patients treated with aminoglutethimide lead to direct assessment of in vivo aromatase inhibition in patients on treatment, thus identifying a novel therapeutic strategy. As such, both research programs represent different examples of pioneering translational work leading towards a successful therapeutic strategy. Subsequent studies with respect to total aromatase inhibition have led to successful development of more potent strategies. Most importantly, these studies have revealed a correlation between aromatase inhibition and clinical outcome. Ongoing studies exploring tissue estrogen levels as well as gene expression profiles on therapy may further improve this important therapeutic area.

Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors.

BACKGROUND: Acquired resistance to endocrine therapy in breast cancer is poorly understood. Characterisation of the molecular response to aromatase inhibitors in breast cancer tissue may provide important information regarding development of oestrogen hypersensitivity. METHODS: We examined the expression levels of nuclear receptor co-regulators, the orphan nuclear receptor liver receptor homologue-1 and HER-2/neu growth factor receptor using real-time RT-PCR before and after 13-16 weeks of primary medical treatment with the aromatase inhibitors anastrozole or letrozole. RESULTS: mRNA expression of the steroid receptor co-activator 1 (SRC-1) and peroxisome-proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) was correlated (P=0.002), and both co-activators increased during treatment in the patient group as a whole (P=0.008 and P=0.032, respectively), as well as in the subgroup of patients achieving an objective treatment response (P=0.002 and P=0.006). Although we recorded no significant change in SRC-3/amplified in breast cancer 1 level, the expression correlated positively to the change of SRC-1 (P=0.002). Notably, we recorded an increase in HER-2/neu levels during therapy in the total patient group (18 out of 26; P=0.016), but in particular among responders (15 out of 21; P=0.008). CONCLUSION: Our results show an upregulation of co-activator mRNA and HER-2/neu during treatment with aromatase inhibitors. These mechanisms may represent an early adaption of the breast cancer cells to oestrogen deprivation in vivo.

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.

PET and SPECT in epilepsy: a critical review.

Molecular imaging with ictal and interictal single-photon emission computed tomography (SPECT) as well as positron emission tomography (PET) rank among the established functional imaging tests for the presurgical evaluation of epileptic onset zone in patients with intractable partial epilepsy. In temporal lobe epilepsy the sensitivity of these methods was shown to be excellent, in particular if a multimodal platform is used, which combines the functional imaging with the additional morphological information of magnetic resonance imaging (MRI), but was lower in extra temporal lobe epilepsy. Functional imaging with SPECT and PET reflects seizure related changes of cerebral perfusion, glucose-metabolism and neuroreceptor status. In this review the usefulness of SPECT and PET imaging in clinical routine in epilepsy as well as the role of different neuroreceptor PET-tracer, which were used in epilepsy are discussed. The use of perfusion SPECT tracer allows the investigation of ictal activations, but the low temporal resolution of ictal perfusion SPECT often results in the detection of both the ictal onset zone as well as the propagation pathways, an area that has not always need to be resected in order to render a patient seizure free. The additional use of interictal PET with fluorine-18 fluorodeoxyglucose which measures regional cerebral metabolism or interictal perfusion SPECT enhance the informational value of ictal SPECT and were shown to be important tools to better define the ictal onset and surround inhibition zones. In recent years PET imaging of different cerebral neuroreceptor-systems inter alia GABA(A) receptors, serotonin receptors (5-HT(1A)), opioid receptors as well as dopamine receptors was used to investigate the neurochemical basis of epilepsy, the role of these neurotransmitters for the epileptogenesis as well as the spread of epileptic activity during seizures and partially entered in clinical routine. Currently some of these radioligands are also used to investigate new treatment approaches.

Estrogen receptor alpha and beta expression in a case matched series of serous and endometrioid adenocarcinomas of the ovary.

OBJECTIVE: The purpose of this study was to analyze estrogen receptor alpha and beta (ERalpha, ERbeta) expression in a stage and grade matched cohort of patients with serous and endometrioid adenocarcinoma of the ovary. METHODS: Forty-two patients from 1991 to the present were found to have the diagnosis of endometrioid adenocarcinoma of the ovary and have tissue available for analysis. Of these 42, ten were selected for analysis. These were stage and grade matched with ten patients having serous adenocarcinoma of the ovary during the same time period. ERalpha and ERbeta mRNA was detected by a multiplex RT-PCR and amplification of random hexamer generated cDNA using a housekeeping gene (G3PD) as a control for mRNA quality and quantity. Methylation specific PCR (MS-PCR) was used to correlate methylation of the ERalpha and ERbeta CpG islands with mRNA expression status. RESULTS: ERalpha expression was present in ten of ten endometrioid adenocarcinomas but in only five of ten serous carcinomas (chi2, p = 0.01). ERbeta expression was present in six of ten endometrioid adenocarcinomas and in four of ten serous caricinomas (chi2, p = 0.65). Methylation of the ERalpha and ERbeta CpG islands was found in tumors without mRNA expression but not in the tumors with mRNA expression (p = 0.005). CONCLUSIONS: ERalpha expression, but not ERbeta expression, is significantly more common in endometrioid than serous adenocarcinomas of the ovary when controlled for stage and grade. The role of methylation in ER silencing may lead to potential therapeutic interventions.