Implications of the prostate cancer prevention trial: a decision analysis model of survival outcomes.

PURPOSE: To assess the estimated effect of finasteride prevention of prostate cancer on overall survival. METHODS: Data for our decision tree model came from men in the two arms (finasteride or placebo) of the Prostate Cancer Prevention Trial (PCPT) and from clinically localized prostate cancer patients studied for long-term survival outcomes. Our model compared survival outcomes for men treated with finasteride or placebo. Prostate cancer rates were based on the 7-year period prevalence of prostate cancer detected in the PCPT; survival probabilities were abstracted from the long-term outcome studies. We assessed variability in the PCPT and long-term survival studies to test the variability of our model. RESULTS: Survival advantages for a finasteride-treated (v those not treated with finasteride) population include gains of 1.7 months in 15-year cause-specific survival (assuming finasteride-altered Gleason scores and prostate cancer prevalence rates in the PCPT), of up to 3 months for cancers treated conservatively or surgically (assuming finasteride does not alter Gleason scores), and of 0.35 months (assuming the rate of cancers detected by for-cause biopsies in the PCPT), which increased to 1.7 months when assuming a 30% rate of biopsy-detected cancer in the PCPT placebo group. Model-variability analyses support several survival benefits associated with finasteride (eg, the uniform benefits assuming finasteride does not alter Gleason scores) but question certain others (eg, in 15-year recurrence-free survivals assuming finasteride does alter Gleason scores). CONCLUSION: Finasteride can impart survival benefits according to our model, especially when we assume that finasteride does not alter Gleason scores.     

Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor-related apoptosis-inducing ligand in chemoresistant Bcl-2-overexpressing cells.

PURPOSE: Bcl-2 overexpression is frequently detected in lymphoid malignancies, being associated with poor prognosis and reduced response to therapy. Here, we evaluated whether Bcl-2 overexpression affects the cytotoxic activity of proteasome inhibitors taken alone or in association with conventional anticancer drugs or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). EXPERIMENTAL DESIGN: Jurkat cells engineered to overexpress Bcl-2 were treated with proteasome inhibitors (MG132, epoxomicin, and bortezomib), anticancer drugs (etoposide and doxorubicin), TRAIL, or combinations of these compounds. Cell death and loss of mitochondrial transmembrane potential were detected by flow cytometry. Cytosolic relocalization of cytochrome c and SMAC/Diablo, caspase cleavage, and Bcl-2 and Mcl-1 levels were determined by immunoblotting. Nuclear factor-kappaB inhibition was done by retroviral transduction with a dominant-negative mutant of IkappaBalpha. RESULTS: Bcl-2 overexpression results in significant inhibition of apoptosis in response to proteasome inhibitors, antiblastics, and TRAIL. Addition of TRAIL to proteasome inhibitors results in a synergistic cytotoxic effect in Bcl-2-overexpressing cells, whereas this result is not reproduced by the combination of proteasome inhibitors with antiblastic drugs. Importantly, proteasome inhibitors plus TRAIL induce mitochondrial dysfunction irrespective of up-regulated Bcl-2. Bcl-2 cleavage to a fragment with putative proapoptotic activity and elimination of antiapoptotic Mcl-1 may both play a role in proteasome inhibitors-TRAIL cooperation. Conversely, nuclear factor-kappaB inhibition by proteasome inhibitors is per se insufficient to explain the observed synergy. CONCLUSIONS: Combined proteasome inhibitors and TRAIL overcome the apoptotic threshold raised by Bcl-2 and may prove useful in the treatment of chemoresistant malignancies with up-regulated Bcl-2.     

Bioreversible quaternary N-acyloxymethyl derivatives of the tertiary amines bupivacaine and lidocaine—synthesis, aqueous solubility and stability in buffer, human plasma and simulated intestinal fluid

Design of water-soluble prodrugs may constitute a means to improve the oral bioavailability of drugs suffering from dissolution rate-limited absorption. The model drug bupivacaine containing a tertiary amine function has been converted into bioreversible quaternary N-acyloxymethyl derivatives. The pH-independent solubility of the N-butanoyloxymethyl derivate exceeded 1000 mg ml⁻¹ corresponding approximately to a 10,000-fold increase in water solubility compared to that of bupivacaine base. The kinetics of hydrolysis of the prodrugs was studied in the pH range 0.1–9.8 (37 °C). Decomposition was found to follow first-order kinetics and U-shaped pH-rate profiles were constructed. The observed differences between the hydrolytic lability of the derivatives might most likely be ascribed to steric effects. In most cases, the prodrugs were quantitatively converted into bupivacaine. However, for the hydrolysis of the N-butanoyloxymethyl derivative at neutral to slightly alkaline pH parallel formation of bupivacaine (80%) and an unknown compound X (20%) was observed. LC–MS analysis of the latter compound suggests that an aromatic imide structure has been formed from an intramolecular acyl transfer reaction involving a nucleophilic attack of the amide nitrogen atom on the ester carbonyl carbon atom. Whereas the derivatives were poor substrates for plasma enzymes; they were hydrolyzed rapidly to parent bupivacaine in the presence of pancreatic enzymes (simulated intestinal fluid) at 37 °C. The data indicate that such prodrugs possess sufficient stability in the acidic environment of the stomach to reach the small intestine in intact form where they can be cleaved efficiently by action of pancreatic enzymes prior to drug absorption. Thus, the N-acyloxymethyl approach might be of potential utility to enhance oral bioavailability of tertiary amines exhibiting pK_a values below approximately 6 and intrinsic solubilities in the low μM range.     

Comparing single‐target and multitarget approaches for postoperative circulating tumour DNA detection in stage II–III colorectal cancer patients

Circulating tumour DNA (ctDNA) detection for postoperative risk stratification in cancer patients has great clinical potential. However, low ctDNA abundances complicates detection. Multitarget (MT) detection strategies have been developed to increase sensitivity. Yet, empirical evidence supporting performance gains of MT vs. single‐target (ST) strategies in a postoperative setting is limited. We compared ctDNA detection in 379 paired plasma samples from 112 stage II–III colorectal cancer patients by ST digital PCR and MT sequencing of 16 patient‐specific variants. The strategies exhibited good concordance (90%, Cohen''s Kappa 0.79), with highly correlated ctDNA quantifications (Pearson r = 0.985). A difference was observed in ctDNA detection preoperatively (ST 72/92, MT 88/92). However, no difference was observed immediately after surgery in recurrence (ST 11/22, MT 10/22) or nonrecurrence (both 2/34) patients. In serial samples, detection was similar within recurrence (ST 13/16, MT 14/16) and nonrecurrence (ST 3/49, MT 1/49) patients. Both approaches yielded similar lead times to standard‐of‐care radiology (ST 4.0 months, MT 4.1 months). Our findings do not support significant performance gains of the MT strategy over the ST strategy for postoperative ctDNA detection.     

Early effect of thrombolysis on structural brain network organisation after anterior‐circulation stroke in the randomized WAKE‐UP trial

The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE‐UP trial, comparing 127 imaging‐selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio‐topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network‐informed imaging biomarkers and improved prognostication in ischemic stroke.     

Isolation, structural elucidation and in vitro activity of 2-acetyl-2-decarboxamido-oxytetracycline against environmental relevant bacteria, including tetracycline-resistant bacteria

2-Acetyl-2-decarboxamido-oxytetracycline (ADOTC) is a major impurity of oxytetracycline (OTC) produced as a side product during fermentation. ADOTC was isolated from OTC and other impurities using preparative HPLC. The preparative column was an Xterra MS, C18 chromatographic column (100 mm x 19 mm i.d., 5 microm), and the mobile phase contained methanol-water (27:73 (v/v)) with 0.08 M formic acid added. The flow rate was 9.0 ml/min. It was possible to isolate few milligram ADOTC in a day. The compound was unambiguously identified using NMR and MS-MS. The anti-microbial activity against activated sludge bacteria was determined giving a potency of only 3% of that of OTC. With tetracycline-resistant bacteria, no anti-microbial activity was observed, indicating a mode of action similar to that of OTC.     

Experimental assessment of a new research tool for the estimation of two-dimensional myocardial strain

One-dimensional strain imaging has been shown to be angle dependent. To address this problem, a new methodology, 2D-strain, has become available. The aim of this study was to validate this methodology in an in vivo set-up against sonomicrometry. In five open chest sheep, ultrasound gray-scale images were acquired of the inferolateral wall from two different angles. The longitudinal and radial strain components were simultaneously extracted using the novel 2D-strain methodology. The extracted values were compared with sonomicrometry using Bland-Altman statistics and correlation coefficients. A good agreement was found for the longitudinal strain component, while, for the radial strain estimates, the accuracy was less. 2D-strain is a fast and accurate tool to assess longitudinal strain from apical views. Further improvements are needed for the method to be sufficiently accurate in estimating the deformation perpendicular or close to perpendicular to the ultrasound beam.     

Diagnostic performance of contrast-enhanced computed tomography in the immediate assessment of radiofrequency ablation success in colorectal liver metastases

Background  To determine the accuracy of contrast-enhanced multislice computed tomography (CT) in the assessment of treatment success immediately after CT-guided radiofrequency (RF) ablation. Methods  26 patients with 38 Colorectal liver metastasis (CRM) were treated by CT-guided RF ablation. Pre-contrast and portal phase CT features before and immediately after ablation were retrospectively evaluated quantitatively and qualitatively: Influence of attenuation characteristics, safety margin, congruency between tumor and coagulation, and morphological criteria (shape, margin distinction, margin configuration, and margin continuity) were investigated. Findings were statistically analyzed with regard to local tumor progression. Results  Mean observation period for follow-up scans was 6.4 months (range: 3–40 months). Attenuation characteristics, safety margin, and congruency had no significant effect on the probability of local tumor progression. Coagulations whose margin was categorized as “discontinuous” were significantly more often associated with local recurrence (p = 0.038). No significant influence on local recurrence could be detected regarding coagulation shape, margin distinction, and configuration. Conclusion  Computed tomography imaging immediately after RF ablation allows for morphological characterization of the coagulation and provides a valid baseline status for follow-up imaging. However, in CRM, morphological image criteria and attenuation characteristics have limited predictive value for immediate detection of persistent tumor.