Prostate cancer treatment with Irreversible Electroporation (IRE): Safety, efficacy and clinical experience in 471 treatments.

BackgroundIrreversible Electroporation (IRE) is a novel image-guided tissue ablation technology that induces cell death via very short but strong pulsed electric fields. IRE has been shown to have preserving properties towards vessels and nerves and the extracellular matrix. This makes IRE an ideal candidate to treat prostate cancer (PCa) where other treatment modalities frequently unselectively destroy surrounding structures inducing severe side effects like incontinence or impotence. We report the retrospective assessment of 471 IRE treatments in 429 patients of all grades and stages of PCa with 6-year maximum follow-up time.Material and findingsThe patient cohort consisted of low (25), intermediate (88) and high-risk cancers (312). All had multi-parametric magnetic resonance imaging, and 199 men had additional 3D-mapping biopsy for diagnostic work-up prior to IRE. Patients were treated either focally (123), sub-whole-gland (154), whole-gland (134) or for recurrent disease (63) after previous radical prostatectomy, radiation therapy, etc. Adverse effects were mild (19.7%), moderate (3.7%) and severe (1.4%), never life-threatening. Urinary continence was preserved in all cases. IRE-induced erectile dysfunction persisted in 3% of the evaluated cases 12 months post treatment. Mean transient IIEF-5-Score reduction was 33% within 12-month post IRE follow-up and 15% after 12 months. Recurrences within the follow-up period occurred in 10% of the treated men, 23 in or adjacent to the treatment field and 18 outside the treatment field (residuals). Including residuals for worst case analysis, Kaplan Maier estimation on recurrence rate at 5 years resulted in 5.6% (CI95: 1.8-16.93) for Gleason 6, 14.6% (CI95: 8.8-23.7) for Gleason 7 and 39.5% (CI95: 23.5-61.4) for Gleason 8-10.ConclusionThe results indicate comparable efficacy of IRE to standard radical prostatectomy in terms of 5-year recurrence rates and better preservation of urogenital function, proving the safety and suitability of IRE for PCa treatment. The data also shows that IRE, besides focal therapy of early PCa, can also be used for whole-gland ablations, in patients with recurrent PCa, and as a problem-solver for local tumor control in T4-cancers not amenable to surgery and radiation therapy anymore

Informationally Robust Equlibria

Informationally Robust Equilibria (IRE) are introduced in Robson (1994) as a refinement of Nash equilibria for e.g. bimatrix games, i.e. mixed extensions of two person finite games.Similar to the concept of perfect equilibria, basically the idea is that an IRE is a limit of some sequence of equilibria of perturbed games.Here, the perturbation has to do with the hypothetical possibility that the action of one the players is revealed to his fellow player before the fellow player has to decide on his own action.Whereas Robson models these perturbations in extensive form and uses subgame perfection to solve these games, we model the perturbations in strategic form, thus remaining in the class of bimatrix games. Moreover, within the perturbations we impose two possible types of tie breaking rules, which leads to the notions optimistic and pessimistic IRE.The paper provides motivation on IRE and its definition.Several properties will be discussed.In particular, we have that IRE is a strict concept, and that IRE components are faces of Nash components.Specific results from potential gamesnash equilibria;game theory;information

Iron regulates mRNA translation initiation through RNA iron responsive element (IRE)

The non-coding IRE-RNA structure, a 30 nt stem loop structure, regulates synthesis of proteins in iron trafficking, cell cycling, and nervous system function. IRE-RNA binding with iron regulatory protein (IRP) proteins inhibits ribosome accessing mRNA. Increasing iron concentration decreases IRP binding with IRE-RNA. Previous models of IRE-mRNA translation regulation concentrate on Fe-S binding to IRP and IRP degradation after release from IRE-RNA. These models lack information on the details of decreasing IRE-RNA/IRP protein binding with iron concentration elevation. This research shows 1. Eukaryotic initiation factor 4F (eIF4F) binds to IRE-RNA with high affinity and works as a positive control element in mRNA translation. 2. eIF4F, IRP competitively bind to IRE-RNA. 3. Fe2+ increases eIF4F/IRE-RNA binding affinity, which outcompetes IRP binding. 4. Fe2+ induces an IRE-RNA conformation change leading to changes in binding affinity with eIF4F and IRP. 5. M7GTP cap doesn\u27t affect eIF4F or IPR1 binding with 73 nt of the 5\u27 noncoding region mRNA which includes the IRE 6. eIF4F/IRE-RNA has a much longer life time than IRP1/IRE-RNA which suggests both kinetics and stability of the complexes are important. 7. eIF4G, a subunit of eIF4F, binds to IRE-RNA without other subunits. A novel regulatory mechanism is proposed where metabolic iron (Fe2+) induces IRE-RNA conformation change to decrease inhibitor protein (IRP) binding and increase activator protein (eIF4F) binding, indicating IRE-RNA act as a riboregulator

Falling birth rates and world population decline: A quantitative discussion (1950-2040)

The UN data (1950-2010) and projections (both medium and low-fertility variants for 2015- 2040) show that fertility rates are already below replacement level in all continents except Africa. In this paper we develop a simple new approach for population projections based on a Improved Rate Equations (IRE) model. Population projections under the (1) Malthusian assumption, (2) an (IRE) model fitting and extrapolating from actual UN population data up to 2040, and (3) UN projections (low-fertility variant), are compared. The model fits quite well actual data and suggests a world population decline in the 21st Century. The economic, social and political consequences of this new and global circumstance would be far reachin

Systematic review of irreversible electroporation role in management of locally advanced pancreatic cancer

Background: Ablative techniques provide in patients with locally advanced pancreatic cancer (LAPC) symptomatic relief, survival benefit and potential downsizing. Irreversible Electroporation (IRE) represents potentially an ideal solution as no thermal tissue damage occurs. The purpose of this review is to present an overview on safety, feasibility, oncological results, survival and quality of life improvement obtained by IRE. Methods: A systematic search was performed in PubMed, regarding the use of IRE on PC in humans for studies published in English up to March 2019. Results: 15 original studies embodying 691 patients with unresectable LAPC who underwent IRE were included. As emerged, IRE works better on tumour sizes between 3–4 cm. Oncological results are promising: median OS from diagnosis or treatment up to 27 months. Two groups investigated borderline resectable tumours treated with IRE before resection with margin attenuation, whereas IRE has proved to be effective in pain control. Conclusions: Electroporation is bringing new hopes in LAPC management. The first aim of IRE is to offer a palliative treatment. Further efforts are needed for patient selection, as well as the use of IRE for ‘margin accentuation’ during surgical resection. Even if promising, IRE needs to be validated in large, randomized, prospective series

Irreversible Electroporation (IRE) in Locally Advanced Pancreatic Cancer: A Review of Current Clinical Outcomes, Mechanism of Action and Opportunities for Synergistic Therapy

Locally advanced pancreatic cancer (LAPC) accounts for 30% of patients with pancreatic cancer. Irreversible electroporation (IRE) is a novel cancer treatment that may improve survival and quality of life in LAPC. This narrative review will provide a perspective on the clinical experience of pancreas IRE therapy, explore the evidence for the mode of action, assess treatment complications, and propose strategies for augmenting IRE response. A systematic search was performed using PubMed regarding the clinical use and safety profile of IRE on pancreatic cancer, post-IRE sequential histological changes, associated immune response, and synergistic therapies. Animal data demonstrate that IRE induces both apoptosis and necrosis followed by fibrosis. Major complications may result from IRE; procedure related mortality is up to 2%, with an average morbidity as high as 36%. Nevertheless, prospective and retrospective studies suggest that IRE treatment may increase median overall survival of LAPC to as much as 30 months and provide preliminary data justifying the well-designed trials currently underway, comparing IRE to the standard of care treatment. The mechanism of action of IRE remains unknown, and there is a lack of data on treatment variables and efficiency in humans. There is emerging data suggesting that IRE can be augmented with synergistic therapies such as immunotherapy

Molecular cloning and preliminary function study of iron responsive element binding protein 1 gene from cypermethrin-resistant Culex pipiens pallens

<p>Abstract</p> <p>Background</p> <p>Insecticide resistance jeopardizes the control of mosquito populations and mosquito-borne disease control, which creates a major public health concern. Two-dimensional electrophoresis identified one protein segment with high sequence homology to part of <it>Aedes aegypti </it>iron-responsive element binding protein (IRE-BP).</p> <p>Method</p> <p>RT-PCR and RACE (rapid amplification of cDNA end) were used to clone a cDNA encoding full length IRE-BP 1. Real-time quantitative RT-PCR was used to evaluate the transcriptional level changes in the Cr-IRE strain <it>Aedes aegypti </it>compared to the susceptible strain of <it>Cx. pipiens pallens</it>. The expression profile of the gene was established in the mosquito life cycle. Methyl tritiated thymidine (³H-TdR) was used to observe the cypermethrin resistance changes in C6/36 cells containing the stably transfected IRE-BP 1 gene of <it>Cx. pipiens pallens</it>.</p> <p>Results</p> <p>The complete sequence of iron responsive element binding protein 1 (IRE-BP 1) has been cloned from the cypermethrin-resistant strain of <it>Culex pipiens pallens </it>(Cr-IRE strain). Quantitative RT-PCR analysis indicated that the IRE-BP 1 transcription level was 6.7 times higher in the Cr-IRE strain than in the susceptible strain of 4th instar larvae. The IRE-BP 1 expression was also found to be consistently higher throughout the life cycle of the Cr-IRE strain. A protein of predicted size 109.4 kDa has been detected by Western blotting in IRE-BP 1-transfected mosquito C6/36 cells. These IRE-BP 1-transfected cells also showed enhanced cypermethrin resistance compared to null-transfected or plasmid vector-transfected cells as determined by ³H-TdR incorporation.</p> <p>Conclusion</p> <p>IRE-BP 1 is expressed at higher levels in the Cr-IRE strain, and may confer some insecticide resistance in <it>Cx. pipiens pallens</it>.</p

Short sales and price discovery in real estate markets

Indirect real estate (IRE) returns are often shown to lead direct real estate (DRE) returns. Apart from differences in liquidity, transaction costs, and management skills, the DRE market is also less complete than the IRE market – when negative shocks arrive, one can only short IRE (e.g. real estate stocks or REITs), but not DRE. This study investigates if short sales in the IRE market convey any information to the DRE market. Based on high-frequency (weekly) property price data in Hong Kong from 1999 to 2011, we found that short sales in the IRE market led DRE returns, even after controlling for the lagged IRE returns in a VAR model. This suggests that short sales contain private information on the real estate market that is not fully reflected in IRE returns. The spillover effect of short sales, however, weakened after the 2007 global financial crisis because increased uncertainty over the credibility of individual firms made short sales carry more firm-specific information than market-wide news.postprin