Three-phase 18F-fluorocholine PET/CT in the evaluation of prostate cancer recurrence.

AIM: Contribution of 3-phase 18F-fluorocholine PET/CT in suspected prostate cancer recurrence at early rise of PSA. PATIENTS, METHODS: Retrospective analysis was performed in 47 patients after initial treatment with radiotherapy (n=30) or surgery (n=17). Following CT, 10 minutes list-mode PET acquisition was done over the prostate bed after injection of 300 MBq of 18F-fluorocholine. Three timeframes of 3 minutes each were reconstructed for analysis. All patients underwent subsequent whole body PET/CT. Delayed pelvic PET/CT was obtained in 36 patients. PET/CT was interpreted visually by two observers and SUVmax determined for suspicious lesions. Biopsies were obtained from 13 patients. RESULTS: Biopsies confirmed the presence of cancer in 11 of 13 patients with positive PET for a total of 15 local recurrences in which average SUVmax increased during 14 minutes post injection and marginally decreased in delayed scanning. Conversely inguinal lymph nodes with mild to moderate metabolic activity on PET showed a clearly different pattern with decreasing SUVmax on dynamic images. Three-phase PET/CT contributed to the diagnostic assessment of 10 of 47 patients with biological evidence of recurrence of cancer. It notably allowed the discrimination of confounding blood pool or urinary activity from suspicious hyperactivities. PET/CT was positive in all patients with PSA>or=2 ng/ml (n=34) and in 4/13 patients presenting PSA values<2 ng/ml. CONCLUSION: 18F-fluorocholine 3-phase PET/CT showed a progressively increasing SUVmax in biopsy confirmed cancer lesions up to 14 minutes post injection while decreasing in inguinal lymph nodes interpreted as benign. Furthermore, it was very useful in differentiating local recurrences from confounding blood pool and urinary activity.

Selective toxicity of the general anesthetic propofol for GABAergic neurons in rat brain cell cultures.

The intravenous, short-acting general anesthetic propofol was applied to three-dimensional (aggregating) cell cultures of fetal rat telencephalon. Both the clinically used formulation (Disoprivan, ICI Pharmaceuticals, Cheshire, England) and the pure form (2,6-diisopropylphenol) were tested at two different periods of brain development: immature brain cell cultures prior to synaptogenesis and at the time of intense synapses and myelin formation. At both time periods and for clinically relevant concentrations and time of exposure (i.e., concentrations > or = 2.0 micrograms/ml for 8 hr), propofol caused a significant decrease of glutamic acid decarboxylase activity. This effect persisted after removal of the drug, suggesting irreversible structural changes in GABAergic neurons. The gamma-aminobutyric acid type A (GABAA) blocking agents bicuculline and picrotoxin partially attenuated the neurotoxic effect of propofol in cultures treated at the more mature phase of development. This protective effect was not observed in the immature brain cells. The present data suggest that propofol may cause irreversible lesions to GABAergic neurons when given at a critical phase of brain development. In contrast, glial cells and myelin appeared resistant even to high doses of propofol.

ECG interpretation during the acute phase of coronary syndromes: in need of improvement?

QUESTION UNDER STUDY: Emergency room (ER) interpretation of the ECG is critical to assessment of patients with acute coronary syndromes (ACS). Our aim was to assess its reliability in our institution, a tertiary teaching hospital. METHODS: Over a 6-month period all consecutive patients admitted for ACS were included in the study. ECG interpretation by emergency physicians (EPs) was recorded on a preformatted sheet and compared with the interpretation of two specialist physicians (SPs). Discrepancies between the 2 specialists were resolved by an ECG specialist. RESULTS: Over the 6-month period, 692 consecutive patients were admitted with suspected ACS. ECG interpretation was available in 641 cases (93%). Concordance between SPs was 87%. Interpretation of normality or abnormality of the ECG was concordant between EPs and SPs in 475 cases (74%, kappa = 0.51). Interpretation of ischaemic modifications was concordant in 69% of cases, and as many ST segment elevations were unrecognised as overdiagnosed (5% each). The same findings occurred for ST segment depressions and negative T waves (12% each). CONCLUSIONS: Interpretation of the ECG recorded during ACS by 2 SPs was discrepant in 13% of cases. Similarly, EP interpretation was discrepant from SP interpretation in 25% of cases, equally distributed between over- and underdiagnosing of ischaemic changes. The clinical implications and impact of medical education on ECG interpretation require further study.

Long-term, multilineage hematopoiesis occurs in the combined absence of beta-catenin and gamma-catenin

The canonical Wnt signaling pathway plays key roles in stem-cell maintenance, progenitor cell expansion, and lineage decisions. Transcriptional responses induced by Wnt depend on the association of either beta-catenin or gamma-catenin with lymphoid enhancer factor/T cell factor transcription factors. Here we show that hematopoiesis, including thymopoiesis, is normal in the combined absence of beta- and gamma-catenin. Double-deficient hematopoietic stem cells maintain long-term repopulation capacity and multilineage differentiation potential. Unexpectedly, 2 independent ex vivo reporter gene assays show that Wnt signal transmission is maintained in double-deficient hematopoietic stem cells, thymocytes, or peripheral T cells. In contrast, Wnt signaling is strongly reduced in thymocytes lacking TCF-1 or in nonhematopoietic cells devoid of beta-catenin. These data provide the first evidence that hematopoietic cells can transduce canonical Wnt signals in the combined absence of beta- and gamma-catenin

Gamma Knife radiosurgery in benign skull base tumors after planned subtotal resection: preliminary results in combined approaches

Aim: The management of large lesions of the skull base, such as vestibular schwanommas (VS), meningiomas (MEN) or pituitary adenomas (PA), is challenging, with microsurgery remaining the main treatment option. Planned subtotal resection is now being increasingly considered to reduce the risk of neurological deficits following complete resection. The residual part of the tumor can then be treated with Gamma Knife Radiosurgery (GKR) to achieve long-term growth control. Methods: This case series documents early results with planned subtotal resection followed by GKR in Lausanne University Hospital, between July 2010 and March 2012. There were 24 patients who underwent surgery, with 22 having already undergone GKR and 2 waiting for GKR. We analyzed clinical symptoms for all patients, as well as audiograms, ophthalmological and endocrinological tests, when indicated. Results: Nine patients had VS surgery (mean diameter 35 mm; range 30-44.5) through a retrosigmoid approach. There were no post-operative facial nerve deficits. Of the 3 patients whom had useful hearing pre-operatively, this improved in 2 and remained stable in 1. Four patients with clinoid MEN (mean diameter 26.5 mm; range 17-42) underwent subtotal resection of the tumor, and the component in the cavernous sinus was later treated with GKR. The visual status remained stable in 3 patients and one had complete visual recovery. 4 patients underwent subtotal resection of petro-clival MEN (mean diameter 36 mm; range 32-42): 3 had House-Brackmann (HB) grade 2 facial function that recovered completely; one continues to have HB grade 4 facial deficit following surgery. Of the 7 patients with PA (mean diameter 34.5 mm; range 20-54.5), 2 had acromegaly, the others were non functional PA. Six patients underwent trans-sphenoidal surgery, while one patient had a transcavernous sinus resection of the tumor (with prior staged trans-sphenoidal surgery). Visual status improved in 3 patients while the others remained stable. Two patients had transient diabetes insipidus following surgery. Up to now, no additional deficit or worsening has been reported after GKR. Conclusions: Our data suggest that planned subtotal resection has an excellent clinical outcome with respect to preservation of cranial nerves, and other neurological functions, and a good possibility of recovery of many of the pre-operative cranial nerve dysfunctions. The results in terms of tumor control following GKR need further long-term evaluation.

Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice.

This study demonstrates that endogenously produced interferon gamma (IFN-gamma) forms the basis of a tumor surveillance system that controls development of both chemically induced and spontaneously arising tumors in mice. Compared with wild-type mice, mice lacking sensitivity to either IFN-gamma (i.e., IFN-gamma receptor-deficient mice) or all IFN family members (i.e., Stat1-deficient mice) developed tumors more rapidly and with greater frequency when challenged with different doses of the chemical carcinogen methylcholanthrene. In addition, IFN-gamma-insensitive mice developed tumors more rapidly than wild-type mice when bred onto a background deficient in the p53 tumor-suppressor gene. IFN-gamma-insensitive p53(-/-) mice also developed a broader spectrum of tumors compared with mice lacking p53 alone. Using tumor cells derived from methylcholanthrene-treated IFN-gamma-insensitive mice, we found IFN-gamma's actions to be mediated at least partly through its direct effects on the tumor cell leading to enhanced tumor cell immunogenicity. The importance and generality of this system is evidenced by the finding that certain types of human tumors become selectively unresponsive to IFN-gamma. Thus, IFN-gamma forms the basis of an extrinsic tumor-suppressor mechanism in immunocompetent hosts.

Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.

PURPOSE: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS: Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.

EuroCMR (European Cardiovascular Magnetic Resonance) registry: results of the German pilot phase.

OBJECTIVES: During its German pilot phase, the EuroCMR (European Cardiovascular Magnetic Resonance) registry sought to evaluate indications, image quality, safety, and impact on patient management of routine CMR. BACKGROUND: CMR has a broad range of applications and is increasingly used in clinical practice. METHODS: This was a multicenter registry with consecutive enrollment of patients in 20 German centers. RESULTS: A total of 11,040 consecutive patients were enrolled. Eighty-eight percent of patients received gadolinium-based contrast agents. Twenty-one percent underwent adenosine perfusion, and 11% high-dose dobutamine-stress CMR. The most important indications were workup of myocarditis/cardiomyopathies (32%), risk stratification in suspected coronary artery disease/ischemia (31%), as well as assessment of viability (15%). Image quality was good in 90.1%, moderate in 8.1%, and inadequate in 1.8% of cases. Severe complications occurred in 0.05%, and were all associated with stress testing. No patient died during or due to CMR. In nearly two-thirds of patients, CMR findings impacted patient management. Importantly, in 16% of cases the final diagnosis based on CMR was different from the diagnosis before CMR, leading to a complete change in management. In more than 86% of cases, CMR was capable of satisfying all imaging needs so that no further imaging was required. CONCLUSIONS: CMR is frequently performed in clinical practice in many participating centers. The most important indications are workup of myocarditis/cardiomyopathies, risk stratification in suspected coronary artery disease/ischemia, and assessment of viability. CMR imaging as used in the centers of the pilot registry is a safe procedure, has diagnostic image quality in 98% of cases, and its results have strong impact on patient management.

Peroxisome-proliferator-activated receptor (PPAR)-gamma activation stimulates keratinocyte differentiation.

Previous studies demonstrated that peroxisome-proliferator-activated receptor (PPAR)-alpha or PPAR-delta activation stimulates keratinocyte differentiation, is anti-inflammatory, and improves barrier homeostasis. Here we demonstrate that treatment of cultured human keratinocytes with ciglitazone, a PPAR-gamma activator, increases involucrin and transglutaminase 1 mRNA levels. Moreover, topical treatment of hairless mice with ciglitazone or troglitazone increases loricrin, involucrin, and filaggrin expression without altering epidermal morphology. These results indicate that PPAR-gamma activation stimulates keratinocyte differentiation. Additionally, PPAR-gamma activators accelerated barrier recovery following acute disruption by either tape stripping or acetone treatment, indicating an improvement in permeability barrier homeostasis. Treatment with PPAR-gamma activators also reduced the cutaneous inflammatory response that is induced by phorbol 12-myristate-13-acetate, a model of irritant contact dermatitis and oxazolone, a model of allergic contact dermatitis. To determine whether the effects of PPAR-gamma activators are mediated by PPAR-gamma, we next examined animals deficient in PPAR-gamma. Mice with a deficiency of PPAR-gamma specifically localized to the epidermis did not display any cutaneous abnormalites on inspection, but on light microscopy there was a modest increase in epidermal thickness associated with an increase in proliferating cell nuclear antigen (PCNA) staining. Key functions of the skin including permeability barrier homeostasis, stratum corneum surface pH, and water-holding capacity, and response to inflammatory stimuli were not altered in PPAR-gamma-deficient epidermis. Although PPAR-gamma activators stimulated loricrin and filaggrin expression in wild-type animals, however, in PPAR-gamma-deficient mice no effect was observed indicating that the stimulation of differentiation by PPAR-gamma activators is mediated by PPAR-gamma. In contrast, PPAR-gamma activators inhibited inflammation in both PPAR-gamma-deficient and wild-type mouse skin, indicating that the inhibition of cutaneous inflammation by these PPAR-gamma activators does not require PPAR-gamma in keratinocytes. These observations suggest that thiazolidindiones and perhaps other PPAR-gamma activators maybe useful in the treatment of cutaneous disorders.

Parallel imaging with phase scrambling.

PURPOSE: Most existing methods for accelerated parallel imaging in MRI require additional data, which are used to derive information about the sensitivity profile of each radiofrequency (RF) channel. In this work, a method is presented to avoid the acquisition of separate coil calibration data for accelerated Cartesian trajectories. METHODS: Quadratic phase is imparted to the image to spread the signals in k-space (aka phase scrambling). By rewriting the Fourier transform as a convolution operation, a window can be introduced to the convolved chirp function, allowing a low-resolution image to be reconstructed from phase-scrambled data without prominent aliasing. This image (for each RF channel) can be used to derive coil sensitivities to drive existing parallel imaging techniques. As a proof of concept, the quadratic phase was applied by introducing an offset to the x(2) - y(2) shim and the data were reconstructed using adapted versions of the image space-based sensitivity encoding and GeneRalized Autocalibrating Partially Parallel Acquisitions algorithms. RESULTS: The method is demonstrated in a phantom (1 × 2, 1 × 3, and 2 × 2 acceleration) and in vivo (2 × 2 acceleration) using a 3D gradient echo acquisition. CONCLUSION: Phase scrambling can be used to perform parallel imaging acceleration without acquisition of separate coil calibration data, demonstrated here for a 3D-Cartesian trajectory. Further research is required to prove the applicability to other 2D and 3D sampling schemes. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

Interferon-gamma impacts at multiple points during the progression of autoimmune diabetes.

The role of interferon-gamma in autoimmune diabetes was assessed by breeding a null mutation of the interferon-gamma receptor alpha chain into the nonobese diabetic mouse strain, as well as into a simplified T cell receptor transgenic model of diabetes. In contrast to a previous report on abrogation of the interferon-gamma gene, mutation of the gene encoding its receptor led to drastic effects on disease in both mouse lines. Nonobese diabetic mice showed a marked inhibition of insulitis-both the kinetics and penetrance-and no signs of diabetes; the transgenic model exhibited near-normal insulitis, but this never evolved into diabetes, either spontaneously or after experimental provocation. This failure could not be explained by perturbations in the ratio of T helper cell phenotypes; rather, it reflected a defect in antigen-presenting cells or in the islet beta cell targets.

Monoclonal antibodies against carcinoembryonic antigen (CEA) used in a solid-phase enzyme immunoassay. First clinical results.

A solid-phase enzyme immunoassay using both mouse monoclonal and goat polyclonal antibodies against carcinoembryonic antigen (CEA) was developed. The assay detects 0.6 to 1.2 ng of CEA per ml of serum and has 3 incubation steps which can be performed in 1 day. Polystyrene balls coated with polyclonal goat anti-CEA antibodies are first incubated with heat-extracted serum samples. Bound CEA is then detected by addition of mouse monoclonal antibodies, followed by goat IgG anti-mouse IgG1 coupled to alkaline phosphatase. Results with this enzyme immunoassay using monoclonal antibodies (M-EIA) have been compared with those obtained by the conventional inhibition radioimmunoassay (RIA) using goat antiserum. Three hundred and eighty serum samples from 167 patients with malignant or non-malignant diseases and from 134 normal individuals with or without heavy smoking habits were analyzed by the 2 assays. Excellent correlation between the results of the 2 assays was obtained, but the M-EIA, using monoclonal antibodies from a single hybridoma, did not discriminate better than the conventional RIA between CEA produced by different types of carcinoma and between CEA associated with malignant or non-malignant diseases. Follow-up studies of several patients by sequential CEA determinations with the 2 assays showed that the M-EIA was as accurate as the RIA for the detection of tumor recurrences.

A Multi-Center Phase II Study (SAKK 36/06) of Single Agent Everolimus (RAD001) In Patients with Relapsed or Refractory Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) accounts for 6% of all B-cell lymphomas and remains incurable for most patients. Those who relapse after first line therapy or hematopoietic stem cell transplantation have a dismal prognosis with short response duration after salvage therapy. On a molecular level, MCL is characterised by the translocation t[11;14] leading to Cyclin D1 overexpression. Cyclin D1 is downstream of the mammalian target of rapamycin (mTOR) kinase and can be effectively blocked by mTOR inhibitors such as temsirolimus. We set out to define the single agent activity of the orally available mTOR inhibitor everolimus (RAD001) in a prospective, multi-centre trial in patients with relapsed or refractory MCL (NCT00516412). The study was performed in collaboration with the EU-MCL network. Methods: Eligible patients with histologically/cytologically confirmed relapsed (not more than 3 prior lines of systemic treatment) or refractory MCL received everolimus 10 mg orally daily on day 1 - 28 of each cycle (4 weeks) for 6 cycles or until disease progression. The primary endpoint was the best objective response with adverse reactions, time to progression (TTP), time to treatment failure, response duration and molecular response as secondary endpoints. A response rate of ≤ 10% was considered uninteresting and, conversely, promising if ≥ 30%. The required sample size was 35 pts using the Simon's optimal two-stage design with 90% power and 5% significance. Results: A total of 36 patients with 35 evaluable patients from 19 centers were enrolled between August 2007 and January 2010. The median age was 69.4 years (range 40.1 to 84.9 years), with 22 males and 13 females. Thirty patients presented with relapsed and 5 with refractory MCL with a median of two prior therapies. Treatment was generally well tolerated with anemia (11%), thrombocytopenia (11%), neutropenia (8%), diarrhea (3%) and fatigue (3%) being the most frequent complications of CTC grade III or higher. Eighteen patients received 6 or more cycles of everolimus treatment. The objective response rate was 20% (95% CI: 8-37%) with 2 CR, 5 PR, 17 SD, and 11 PD. At a median follow-up of 6 months, TTP was 5.45 months (95% CI: 2.8-8.2 months) for the entire population and 10.6 months for the 18 patients receiving 6 or more cycles of treatment. Conclusion: This study demonstrates that single agent everolimus 10 mg once daily orally is well tolerated. The null hypothesis of inactivity could be rejected indicating a moderate anti-lymphoma activity in relapsed/refractory MCL. Further studies of either everolimus in combination with chemotherapy or as single agent for maintenance treatment are warranted in MCL.

Source inference of exogenous gamma-hydroxybutyric acid (GHB) administered to humans by means of carbon isotopic ratio analysis: novel perspectives regarding forensic investigation and intelligence issues.

γ-Hydroxybutyric acid (GHB) is an endogenous short-chain fatty acid popular as a recreational drug due to sedative and euphoric effects, but also often implicated in drug-facilitated sexual assaults owing to disinhibition and amnesic properties. Whilst discrimination between endogenous and exogenous GHB as required in intoxication cases may be achieved by the determination of the carbon isotope content, such information has not yet been exploited to answer source inference questions of forensic investigation and intelligence interests. However, potential isotopic fractionation effects occurring through the whole metabolism of GHB may be a major concern in this regard. Thus, urine specimens from six healthy male volunteers who ingested prescription GHB sodium salt, marketed as Xyrem(®), were analysed by means of gas chromatography/combustion/isotope ratio mass spectrometry to assess this particular topic. A very narrow range of δ(13)C values, spreading from -24.810/00 to -25.060/00, was observed, whilst mean δ(13)C value of Xyrem(®) corresponded to -24.990/00. Since urine samples and prescription drug could not be distinguished by means of statistical analysis, carbon isotopic effects and subsequent influence on δ(13)C values through GHB metabolism as a whole could be ruled out. Thus, a link between GHB as a raw matrix and found in a biological fluid may be established, bringing relevant information regarding source inference evaluation. Therefore, this study supports a diversified scope of exploitation for stable isotopes characterized in biological matrices from investigations on intoxication cases to drug intelligence programmes.