Activity of raltitrexed and gemcitabine in advanced pancreatic cancer

Background: Gemcitabine has evolved as standard therapy in advanced pancreatic cancer since the demonstration of a significant clinical benefit. Phase II trials have shown that gemcitabine can be successfully combined with thymidylate synthase (TS) inhibitors such as continuous-infusion 5-fluorouracil (5-FU). However, continuous-infusion 5-FU is inconvenient because of the need for a central venous access. The aim of this study was to assess the efficacy and safety of gemcitabine in combination with raltitrexed (Tomudex), a novel and selective TS inhibitor that has the advantage of a 3-weekly treatment interval and manageable toxicity. Patients and methods: Chemotherapy-naïve patients with measurable advanced pancreatic cancer were treated with raltitrexed 3 mg/m2 as a 15-min infusion on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days. Results: Twenty-five eligible patients (17 male, eight female) with metastatic (21 patients) or locally advanced (four patients) disease entered the study. The median number of courses per patient was four (range 1-14). One patient was not evaluable for response. There were three partial remissions [12%; 95% confidence interval (CI) 2.6% to 31.2%] and nine stable disease situations (36%; 95% CI 18.0% to 57.5%), while the tumours of 12 patients (48%; 95% CI 27.8% to 68.7%) showed progressive disease after three treatment cycles. WHO grade 3/4 toxicity was rare and symptomatic in only one patient, who experienced grade 4 diarrhoea and grade 3 nausea and vomiting. Symptomatic benefit was seen in 12 patients. Median survival was 185 days (95% CI 129-241) with six patients still alive. Conclusions: The efficacy of raltitrexed plus gemcitabine is limited, but compares well with other chemotherapy treatment options in advanced pancreatic cancer. However, this combination is convenient and symptomatic toxicity is rare. Thus, raltitrexed and gemcitabine should be investigated further in combination with drugs interfering with specific molecular target

Magnetic resonance imaging of parotid gland tumors: a pictorial essay.

Imaging of parotid gland tumors is challenging due to the wide variety of differential diagnoses. Malignant parotid tumors can have very similar features to benign ones, such as slow growth and displacement instead of infiltration of neighboring structures. Malignant and benign tumors may therefore not be clinically distinguishable. Correct characterization of parotid tumors (i.e., benign or malignant) determines preoperative treatment planning and is important in optimizing the individualized surgical plan. Magnetic resonance imaging (MRI) is the imaging modality of choice for evaluation of suspected parotid gland lesions and differentiation between benign and malignant lesions. Certain conventional MRI features can suggest whether a mass is more likely to be a benign or low-grade malignancy or a high-grade malignancy and adding diffusion-weighted imaging or advanced MRI techniques like perfusion can aid in this distinction. Morphological features seen on MRI, such as low signal on T2-w, infiltrative changes or ill-defined margins, change over time and diffusion restriction can point to the malignant nature of the lesion. MRI is useful for detection and localization of the lesion(s), and associated findings like perineural spread of tumor, lymph node involvement and infiltrative changes of the surrounding tissues. In this pictorial essay, we present selected images of a variety of benign and malignant parotid tumors and emphasize the MRI features that may be useful in their characterization

Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer recurrence: definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation

Background: Adjuvant systemic treatment for patients with isolated locoregional recurrence (ILRR) of breast cancer is based on a single reported randomized trial. The trial, conducted by the Swiss Group for Clinical Cancer Research, compared tamoxifen (TAM) with observation after complete excision of the ILRR and proper radiotherapy. We performed a definitive analysis of treatment outcome at >11 years of follow-up, after the majority of the patients had a subsequent event of interest. Patient and methods One hundred and sixty-seven patients with ‘good-risk' characteristics of disease were randomized. ‘Good-risk' was defined as estrogen receptor expression in the ILRR, or having a disease-free interval of >12 months and a recurrence consisting of three or less tumor nodules, each ≤3 cm in diameter. Seventy-nine percent of the patients were postmenopausal at randomization. Results: The median follow-up time of the surviving patients was 11.6 years. The median post ILRR disease-free survival (DFS) was 6.5 years with TAM and 2.7 years with observation (P = 0.053). The difference was mainly due to reduction of further local relapses (P = 0.011). In postmenopausal patients, TAM led to an increase of DFS from 33% to 61% (P = 0.006). In premenopausal women, 5-year DFS was 60%, independent of TAM medication. For the whole study population, the median post-recurrence overall survival (OS) was 11.2 and 11.5 years in the observation and the TAM group, respectively; premenopausal patients experienced a 5-year OS of 90% for observation compared with 67% for TAM (P = 0.175), while the respective figures for postmenopausal patients were both 75%. Conclusions: These definitive results confirmed that TAM significantly improves the post-recurrence DFS of patients after local treatment for ILRR. This beneficial effect does not translate into a detectable OS advantag

Effects related to spacetime foam in particle physics

It is found that the existence of spacetime foam leads to a situation in which the number of fundamental quantum bosonic fields is a variable quantity. The general aspects of an exact theory that allows for a variable number of fields are discussed, and the simplest observable effects generated by the foam are estimated. It is shown that in the absence of processes related to variations in the topology of space, the concept of an effective field can be reintroduced and standard field theory can be restored. However, in the complete theory the ground state is characterized by a nonvanishing particle number density. From the effective-field standpoint, such particles are "dark". It is assumed that they comprise dark matter of the universe. The properties of this dark matter are discussed, and so is the possibility of measuring the quantum fluctuation in the field potentials.Comment: 18 pages, minor corrections added to the published varian

De Sitter space and perpetuum mobile

We give general arguments that any interacting non--conformal {\it classical} field theory in de Sitter space leads to the possibility of constructing a perpetuum mobile. The arguments are based on the observation that massive free falling particles can radiate other massive particles on the classical level as seen by the free falling observer. The intensity of the radiation process is non-zero even for particles with any finite mass, i.e. with a wavelength which is within the causal domain. Hence, we conclude that either de Sitter space can not exist eternally or that one can build a perpetuum mobile.Comment: 11 pages revtex, no figures. Added discussion to strengthen conclusio

Scaling properties of the redshift power spectrum: theoretical models

We report the results of an analysis of the redshift power spectrum $P^S(k,\mu)$ in three typical Cold Dark Matter (CDM) cosmological models, where $\mu$ is the cosine of the angle between the wave vector and the line-of-sight. Two distinct biased tracers derived from the primordial density peaks of Bardeen et al. and the cluster-underweight model of Jing, Mo, & B\"orner are considered in addition to the pure dark matter models. Based on a large set of high resolution simulations, we have measured the redshift power spectrum for the three tracers from the linear to the nonlinear regime. We investigate the validity of the relation - guessed from linear theory - in the nonlinear regime $$P^S(k,\mu)=P^R(k)[1+\beta\mu^2]^2D(k,\mu,\sigma_{12}(k)),$$ where $P^R(k)$ is the real space power spectrum, and $\beta$ equals $\Omega_0^{0.6}/b_l$. The damping function $D$ which should generally depend on $k$, $\mu$, and $\sigma_{12}(k)$, is found to be a function of only one variable $k\mu\sigma_{12}(k)$. This scaling behavior extends into the nonlinear regime, while $D$ can be accurately expressed as a Lorentz function - well known from linear theory - for values $D > 0.1$. The difference between $\sigma_{12}(k)$ and the pairwise velocity dispersion defined by the 3-D peculiar velocity of the simulations (taking $r=1/k$) is about 15%. Therefore $\sigma_{12}(k)$ is a good indicator of the pairwise velocity dispersion. The exact functional form of $D$ depends on the cosmological model and on the bias scheme. We have given an accurate fitting formula for the functional form of $D$ for the models studied.Comment: accepted for publication in ApJ;24 pages with 7 figures include

Does Quantum Mechanics Clash with the Equivalence Principle - and Does it Matter?

With an eye on developing a quantum theory of gravity, many physicists have recently searched for quantum challenges to the equivalence principle of general relativity. However, as historians and philosophers of science are well aware, the principle of equivalence is not so clear. When clarified, we think quantum tests of the equivalence principle won't yield much. The problem is that the clash/not-clash is either already evident or guaranteed not to exist. Nonetheless, this work does help teach us what it means for a theory to be geometric.Comment: 12 page

AP-4-mediated axonal transport controls endocannabinoid production in neurons

Davies et al. identify a putative mechanism underlying the childhood neurological disorder AP-4 deficiency syndrome. In the absence of AP-4, an enzyme that makes 2-AG is not transported to the axon, leading to axonal growth defects, which can be rescued by inhibition of 2-AG breakdown. The adaptor protein complex AP-4 mediates anterograde axonal transport and is essential for axon health. AP-4-deficient patients suffer from a severe neurodevelopmental and neurodegenerative disorder. Here we identify DAGLB (diacylglycerol lipase-beta), a key enzyme for generation of the endocannabinoid 2-AG (2-arachidonoylglycerol), as a cargo of AP-4 vesicles. During normal development, DAGLB is targeted to the axon, where 2-AG signalling drives axonal growth. We show that DAGLB accumulates at the trans-Golgi network of AP-4-deficient cells, that axonal DAGLB levels are reduced in neurons from a patient with AP-4 deficiency, and that 2-AG levels are reduced in the brains of AP-4 knockout mice. Importantly, we demonstrate that neurite growth defects of AP-4-deficient neurons are rescued by inhibition of MGLL (monoacylglycerol lipase), the enzyme responsible for 2-AG hydrolysis. Our study supports a new model for AP-4 deficiency syndrome in which axon growth defects arise through spatial dysregulation of endocannabinoid signalling.Special thanks to the MPIB Imaging Facility for outstanding technical support, in particular to Giovanni Cardone for his advice and assistance with the implementation of image analysis pipelines, as well as feedback on the manuscript, and to Martin Spitaler for his expert technical advice for imaging experiments