Late Endpoints Research Articles

Prognostic utility of MELD-XI in adult congenital heart disease patients undergoing cardiac transplantation.

Model of End-Stage Liver Disease eXcluding INR (MELD-XI) at cardiac transplant has demonstrated prognostic survival utility, but has not been specifically validated in adult congenital heart disease (ACHD) in a registry study. Adults undergoing first-time orthotopic heart transplant from 2005 to 2015 in the United Network for Organ Sharing (UNOS) registry were examined in parallel: ACHD (n=543), ischemic-dilated cardiomyopathy (IDCM, n=6954) and valvular heart disease (VHD, n=355). Our primary endpoint was a composite of death, graft failure, and retransplantation assessed at 3months (early), and those with freedom from early endpoint were reassessed at 5years (late). Interactions between hepatorenal indices and waitlist time were examined. Secondary outcomes relating to long-term morbidity were assessed at late endpoint. Freedom from endpoint analysis in ACHD at clinically relevant endpoints was also conducted. Model of End-Stage Liver Disease eXcluding INR score at transplant associated with an increased risk of early endpoint in all cohorts. At late endpoint, bilirubin level associated with increased risk uniquely in ACHD. Model of End-Stage Liver Disease eXcluding INR holds prognostic application to ACHD in early time points and demonstrates unique waitlist interactions. Transplant bilirubin level may hold significance in long-term risk stratification of the ACHD population. Time on waitlist is an important consideration to contextualize these values.

Nationwide cohort study of mitral valve repair versus replacement for infective endocarditis

ObjectivesThe feasibility and long-term outcomes of mitral valve (MV) repair in patients with infective endocarditis (IE) remain unclear. MethodsUsing Taiwan's National Health Insurance Research Database, we identified 1999 patients who underwent MV surgery for IE during 2000 to 2013. The patients were more likely to have undergone valve replacement (1575 patients; 78.8%) than valve repair (424 patients; 21.2%). After 1:1 propensity score matching, 352 patients in each group were included for analysis. Perioperative outcomes and late composite end points, comprising all-cause mortality, MV reoperation, any stroke, major bleeding, and readmission for heart failure, were compared. ResultsPatients who received MV repair had fewer perioperative complications, lower in-hospital mortality rates (6.3% vs 10.8%; P = .031), and lower risks of late mortality (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.44-0.80), and composite end point (HR, 0.67; 95% CI, 0.52-0.87) during a mean follow-up of 4.8 years. Subgroup analysis revealed a trend in which the beneficial effect of MV repair was not apparent when surgeries were performed in hospitals within the lowest volume quartile (P for interaction = .091). In patients who underwent surgery during active IE, MV repair was also related to a lower rate of late mortality (HR, 0.64; 95% CI, 0.48-0.85). ConclusionsMitral repair for IE has better perioperative and late outcomes than mitral replacement. Mitral repair performed by an experienced team is recommended for IE patients instead of MV replacement whenever possible, even with an active infection status.

Effectiveness and Safety of Rituximab in Recalcitrant Pemphigoid Diseases.

Rituximab (RTX) is a monoclonal antibody targeting CD20, a transmembrane protein expressed on B cells, causing B cell depletion. RTX has shown great efficacy in studies of pemphigus vulgaris, but data of pemphigoid diseases are limited. To assess the effectiveness and safety of RTX in pemphigoid diseases. The medical records of 28 patients with pemphigoid diseases that were treated with RTX were reviewed retrospectively. Early and late endpoints, defined according to international consensus, were disease control (DC), partial remission (PR), complete remission (CR), and relapses. Safety was measured by reported adverse events. Patients with bullous pemphigoid (n = 8), mucous membrane pemphigoid (n = 14), epidermolysis bullosa acquisita (n = 5), and linear IgA disease (n = 1) were included. Treatment with 500 mg RTX (n = 6) or 1,000 mg RTX (n = 22) was administered on days 1 and 15. Eight patients received additional 500 mg RTX at months 6 and 12. Overall, DC was achieved in 67.9%, PR in 57.1%, and CR in 21.4% of the cases. During follow-up, 66.7% patients relapsed. Repeated treatment with RTX led to remission (PR or CR) in 85.7% of the retreated cases. No significant difference in response between pemphigoid subtypes was found. IgA-dominant cases (n = 5) achieved less DC (20 vs. 81.3%; p = 0.007), less PR (20 vs. 62.5%; p = 0.149), and less CR (0 vs. 18.8%; p = 0.549) compared to IgG-dominant cases (n = 16). Five severe adverse events and three deaths were reported. One death was possibly related to RTX and one death was disease related. RTX can be effective in recalcitrant IgG-dominant pemphigoid diseases, however not in those where IgA is dominant.

The adenosine A2A receptor agonist T1–11 ameliorates neurovisceral symptoms and extends the lifespan of a mouse model of Niemann-Pick type C disease

Niemann-Pick C is a fatal neurovisceral disorder caused, in 95% of cases, by mutation of NPC1 gene. Therapeutic options are extremely limited and new “druggable” targets are highly warranted. We previously demonstrated that the stimulation of the adenosine A2A receptor (A2AR) normalized the pathological phenotype of cellular models of NPC1. Since the validation of A2ARs as a therapeutic target for NPC1 can be obtained only conducting studies in in vivo models of the disease, in the present paper, the effects of two agonists of A2ARs were evaluated in the mouse model Balb/c Npc1nih, hereafter indicated as NPC1−/−. The agonists CGS21680 (2.5 and 5mg/kg/day by intraperitoneal injection) and T1–11 (50mg/kg/day in drinking water) were administered at a presymptomatic stage of the disease of NPC1−/− mice (PN28 and PN30, respectively); the experimental groups were the following: vehicle-treated WT mice (N=16 for both CGS and T1–11 treatments); vehicle-treated NPC1−/− mice (N=14 for CGS and 12 for T1–11 treatment); CGS-treated NPC1−/− mice (N=7) and T1–11-treated NPC1−/− mice (N=11). The efficacy of the treatments was evaluated by comparing vehicle-treated and CGS or T1–11-treated NPC1−/− mice for their motor deficits (analyzed by both rotarod and footprint tests), hippocampal cognitive impairment (by Novel Object Recognition (NOR) test), cerebellar neurodegeneration (Purkinje neurons counting), and cholesterol and sphingomyelin accumulation in spleen and liver. Finally, the effect of both agonists on survival was evaluated by applying a humane late endpoint (weight loss >30% of peak weight, punched posture and reduced activity in the cage). The results demonstrated that, while CGS21680 only slightly attenuated cognitive deficits, T1–11 ameliorated motor coordination, significantly improved cognitive impairments, increased the survival of Purkinje neurons and reduced sphingomyelin accumulation in the liver. More importantly, it significantly prolonged the lifespan of NPC1−/− mice. In vitro experiments conducted in a neuronal model of NPC1 demonstrated that the ability of T1–11 to normalize cell phenotype was mediated by the selective activation of A2ARs and modulation of intracellular calcium levels.In conclusion, our results fully confirm the validity of A2ARs as a new target for NPC1 treatment. As soon as new ligands with improved pharmacokinetic characteristics (i.e. orally active, with brain bioavailability and metabolic stability) will be obtained, A2AR agonists could represent a breakthrough in the treatment of NPC.

Why RBE must be a variable and not a constant in proton therapy.

This article considered why the proton therapy (PT) relative biological effect (RBE) should be a variable rather than a constant. The reasons for a variable proton RBE are enumerated, with qualitative and quantitative arguments. The heterogeneous data sets collated by Paganetti et al (2002) and the more homogeneous data of Britten et al (2013) are further analyzed using linear regression fitting and RBE-inclusive adaptations of the linear-quadratic (LQ) radiation model. The in vitro data show RBE increasing as dose per fraction is lowered. In the Paganetti et al (2002) data sets, the differences between observed and expected effects are smaller when the LQ model is used, but with such data heterogeneity, firm statistical conclusions cannot be obtained. The more homogeneous data set shows an unequivocal variation in RBE with dose per faction. The in vivo data are inappropriate for assessments of late normal tissue effects in radiotherapy. Also, if there is the same degree of uncertainty in an RBE of 1.1 or in an RBE of 2-3 for C ions, the fractional and biological effective doses can vary considerably and be greater in the proton case. So, errors in RBE assignment are important for protons, just as with C ions. Further experimental programmes are proposed, including late normal tissue end points. Better RBE allocations might further improve PT outcomes. This study provides a rigorous critique of the 1.1 RBE used for protons, from theoretical and practical standpoints. Data analysis shows that the LQ model is more appropriate than simple linear regression. Comprehensive research programmes are suggested.

Clinical and immunological outcomes of high- and low-dose rituximab treatments in patients with pemphigus: a randomized, comparative, observer-blinded study

Rituximab is a promising therapy in pemphigus. However, there is no consensus on optimum dose. To compare the efficacy, in terms of clinical and immunological outcomes in patients with pemphigus, of a high (2×1000mg) vs. a low dose (2×500mg) of rituximab. This was a randomized, observer-blinded trial wherein 22 patients with pemphigus were randomized into two treatment groups. Patients received either two doses (day 0 and day 15) of 1000mg rituximab or 500mg rituximab, and were followed up for 48weeks. Clinical activity was assessed by a blinded investigator. Indices of enzyme-linked immunosorbent assays (ELISAs) for desmoglein (Dsg)1 and Dsg3, and CD19 cell count were examined at regular intervals. There was no statistically significant difference in early and late clinical end points, and total cumulative dose of corticosteroids between the two groups. At week 40, the fall in Ikeda severity score was significantly more in the 2×1000mg group than in 2×500mg group (P=0·049). Patients in the 2×500mg group received a significantly higher cumulative dose of azathioprine (P=0·018). The ELISA indices of Dsg1 and Dsg3 showed a statistically significant decline in the 2×1000mg group only. B cell repopulation occurred earlier in the 2×500mg group by 8weeks. A few clinical and immunological study parameters have suggested improved outcomes in patients receiving high-dose (2×1000mg) rituximab.

Designing quantitative structure activity relationships to predict specific toxic endpoints for polybrominated diphenyl ethers in mammalian cells

Polybrominated diphenyl ethers (PBDEs) are known as effective flame retardants and have vast industrial application in products like plastics, building materials and textiles. They are found to be structurally similar to thyroid hormones that are responsible for regulating metabolism in the body. Structural similarity with the hormones poses a threat to human health because, once in the system, PBDEs have the potential to affect thyroid hormone transport and metabolism. This study was aimed at designing quantitative structure–activity relationship (QSAR) models for predicting toxic endpoints, namely cell viability and apoptosis, elicited by PBDEs in mammalian cells. Cell viability was evaluated quantitatively using a general cytotoxicity bioassay using Janus Green dye and apoptosis was evaluated using a caspase assay. This study has thus modelled the overall cytotoxic influence of PBDEs at an early and a late endpoint by the Genetic Function Approximation method. This research was a twofold process including running in vitro bioassays to collect data on the toxic endpoints and modeling the evaluated endpoints using QSARs. Cell viability and apoptosis responses for Hep G2 cells exposed to PBDEs were successfully modelled with an r2 of 0.97 and 0.94, respectively.

Biomarkers and chemopreventives in oral carcinogenesis and its prevention.

Squamous cell carcinoma is the predominant type of oral malignancy and is a result of oral carcinogenesis. Oral carcinogenesis is a mutifactorial and complex process related to the sequential occurrence of alterations in genetic structures, promoting inhibitory or excitatory effects of the tumor oncogenes and gene suppressors, compromising the histophysiology of the division, differentiation and cell death; and therefore, methods to prevent, detect, or treat it in the best way is constantly being searched for. Biomarkers reveal the genetic and molecular changes related to early, intermediate and late endpoints in the process of oral carcinogenesis. Thereby, they are likely to not only refine our ability to predict the biologic course of oral cancer and distinguish individuals at high and/or low risk of oral cancer development; but, also they will also reveal the genetic and molecular changes related to various endpoints of oral carcinogenesis. Chemopreventives are chemicals of natural or synthetic origin, which reduce the incidence of fatal diseases such as cancer before clinical symptoms occur. Chemopreventives are agents whose curative capacity is defined with help of biomarkers, as the later determine the effectiveness and safety of chemopreventives.

Prostaglandins Are Essential for Cervical Ripening in LPS-Mediated Preterm Birth But Not Term or Antiprogestin-Driven Preterm Ripening

Globally, an estimated 13 million preterm babies are born each year. These babies are at increased risk of infant mortality and life-long health complications. Interventions to prevent preterm birth (PTB) require an understanding of processes driving parturition. Prostaglandins (PGs) have diverse functions in parturition, including regulation of uterine contractility and tissue remodeling. Our studies on cervical remodeling in mice suggest that although local synthesis of PGs are not increased in term ripening, transcripts encoding PG-endoperoxide synthase 2 (Ptgs2) are induced in lipopolysaccharide (LPS)-mediated premature ripening. This study provides evidence for two distinct pathways of cervical ripening: one dependent on PGs derived from paracrine or endocrine sources and the other independent of PG actions. Cervical PG levels are increased in LPS-treated mice, a model of infection-mediated PTB, consistent with increases in PG synthesizing enzymes and reduction in PG-metabolizing enzymes. Administration of SC-236, a PTGS2 inhibitor, along with LPS attenuated cervical softening, consistent with the essential role of PGs in LPS-induced ripening. In contrast, during term and preterm ripening mediated by the antiprogestin, mifepristone, cervical PG levels, and expression of PG synthetic and catabolic enzymes did not change in a manner that supports a role for PGs. These findings in mice, supported by correlative studies in women, suggest PGs do not regulate all aspects of the parturition process. Additionally, it suggests a need to refocus current strategies toward developing therapies for the prevention of PTB that target early, pathway-specific processes rather than focusing on common late end point mediators of PTB.

Results Of The Randomised Phase II NCRI Arctic (Attenuated dose Rituximab with ChemoTherapy In CLL) Trial Of Low Dose Rituximab In Previously Untreated CLL

IntroductionFCR improves PFS and OS in CLL. Previous non-randomised Phase II trials suggest adding mitoxantrone to FCR (FCM-R) improves outcomes. The rituximab dose in CLL was inferred from lymphoma but in CLL even low doses of rituximab lead to the loss of CD20 expression (“shaving”) suggesting that low dose rituximab with chemotherapy may be effective. AimsThe primary objective was to assess whether the CR rate to FCM-miniR was not inferior to FCR. Secondary objectives were MRD eradication, overall response rates and safety. Late endpoints (not reported) were PFS, OS and MRD relapse. MethodsARCTIC was a phase IIB, randomised, controlled, parallel group trial in previously untreated CLL performed in 34 UK centres. 206 patients were to be randomised to FCR or FCM-miniR with an 80% power to show that FCM-miniR did not lead to 10% worse CR rates compared to FCR. A formal interim analysis on the primary endpoint was planned after 103 patients. The schedule for oral FCR was equivalent to iv FCR with iv rituximab given on Day 1 (375mg/m2 Cycle 1; 500mg/m2 Cycles 2-6), oral fludarabine (24mg/m2/day for 5 days; Days 1-5) and oral cyclophosphamide (150mg/m2/day for 5 days; Days 1-5). FCM-miniR included intravenous mitoxantrone (6mg/m2/day) and 100mg rituximab on Day 1 of 6 cycles given 28 days apart. Patients with neutropenia delaying therapy received G-CSF (lenograstim 263mcg/day; Days 7-13) on all remaining cycles. Prophylaxis with co-trimoxazole and acyclovir was used. Results200 patients were recruited, 100 to each arm. The interim analysis after 103 patients indicated that although the CR rate to FCM-miniR was similar to predicted it was inferior to FCR. The independent DMC advised that the trial would not show non-inferiority for FCM-miniR and recruitment was stopped. A further 97 patients were recruited up to the interim analysis. 21 patients still receiving FCM-miniR were advised to cross-over to FCR. 100 patients received FCR, 79 FCM-miniR and 21 patients randomised to FCM-miniR crossed over to FCR.The treatment arms were well balanced for the following: median age 63 (36-80) and 20% (n=40) over 70; 67.5% male; 17% prog. stage A, 47% stage B and 35.5% stage C. 33.5% had a creatinine clearance under 70ml/min. 60% (87/146) had unmutated Ig genes; 4% (6/164) 17p deletion; and 15% (26/168) 11q deletion. More 11q del patients were randomised to FCM-miniR (15 vs 7). 29.5% (59/200) discontinued therapy early including 30% (n=30) FCR and 35.4% (n=28) FCM-miniR. 141 (70.5%) completed 6 cycles. 93 (49%) of 189 received G-CSF - more with FCM-miniR compared with FCR (54% vs 44%). 117 (58.5%) patients experienced a dose modification; 57% for FCR and 62% for FCM-miniR; the most common being dose delay in 47% of patients. 181 SAE's were reported from 104 patients; 79 events from 49% (49/100) receiving FCR, 80 from 58% (46/79) receiving FCM-miniR and 47% (9/22) cross-over patients. 62.5% of related SAE's were infectious. 3 patients died due to an SAE, 1 FCR and 2 FCM-miniR.We report only the 179 intention-to-treat patients who did not cross-over. To date 146 of 179 patients (82%) have undergone independent central review. 70% (102/146) achieved a CR or CRi; 78% (62/79) FCR and 60% (40/67) FCM-miniR. 13/22 (59%) patients with a baseline creatinine clearance of <60ml/min (received 50% fludarabine dose) achieved a CR or CRi. ORR was 94% (145/154) in evaluable patients, 96% (81/84) FCR and 91% (64/70) FCM-miniR. MRD by flow cytometry (sensitivity <10-4) was assessed in the marrow 3 months post-therapy; of assessable patients to date 51% (78/152) had undetectable MRD, 55% (47/85) FCR and 46% (31/67) FCM-miniR. ConclusionARCTIC was stopped prematurely as it was clear that the arm containing mitoxantrone and low dose rituximab would not be non-inferior to FCR. However both FCR and FCM-miniR performed well with CR rates of 78% and 60% respectively. This compares favourably to CR rates of 38% for FC in LRF CLL4 Trial and 44% for FCR in the GCLLSG CLL8 Trial. MRD was undetectable in 55% of patients receiving FCR and 46% for FCM-miniR. Oral FCR in front-line CLL results in extremely high CR rates and the eradication of detectable MRD in the majority. Low dose rituximab (100mg per cycle; 600mg total dose compared to 2875mg/m2 for standard FCR) in combination with FCM appears to be effective although FCM-miniR is inferior to full dose FCR. However there is more toxicity associated with the addition of mitoxantrone confounding the comparison of rituximab doses. Disclosures:Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria. Off Label Use: The use of ofatumumab in combination with chlorambucil in previously untreated CLL. The reported trial will support the extension of the ofatumumab licence. Schuh:GSK: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria.

Clinical experiences of different dosing schedules of rituximab in pemphigus with various disease severities

Rituximab, a monoclonal antibody directed against B lymphocytes, has been found to be a therapeutic agent for severe, refractory autoimmune bullous diseases. However, a dosing schedule or treatment indication of rituximab has not yet been established. We investigated the efficacy of rituximab and different dosing schedules for different disease severities, retrospectively. A total of 23 patients with pemphigus who received rituximab were evaluated by a review of medical records. Group 1 patients (n=10) with severe pemphigus were treated with three or four infusions of rituximab at a dose of 375mg/m(2) at 1-week intervals. Group 2 (n=13) patients with mild to moderate pemphigus were treated with two infusions of rituximab at the same dose. Late end points, occurrence of relapse and adverse events and numbers of B cells were evaluated. The mean follow-up period was 25.6months in group 1 and 17.8months in group 2. In group 1, six patients (60.0%) achieved complete remission (CR), including two patients off therapy (CR OFF) and four patients on therapy (CR ON). The other four patients (40.0%) achieved partial remission on therapy (PR ON). In group 2, nine patients (69.2%) achieved CR (4 CR OFF, 5 CR ON) and four patients (30.8%) achieved PR ON. During the follow-up period, relapse occurred in five patients of group 1 and three patients of group 2. No serious adverse events were observed in any patients. We concluded that rituximab is an effective and safe treatment method not only in severe, recalcitrant pemphigus but also in mild to moderate pemphigus. Low dose of rituximab seemed to be sufficient to treat mild to moderate pemphigus.

1576 Effect of Dexamethasone Therapy on the Expression of Macrophage Migration Inhibitory Factor in Critically ill Children with Septic Shock

Background and objectivesMacrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a major role in the pathogenesis of sepsis. The goal of this study was to determine the...

Prevalence and peak incidence of acute and late normal tissue morbidity in the DAHANCA 6&7 randomised trial with accelerated radiotherapy for head and neck cancer

Background and purposeThe aim of this report was to describe the incidence and prevalence of acute and late morbidity in the DAHANCA 6&7 multicentre randomised trial with accelerated radiotherapy for squamous cell carcinoma of the head and neck. Materials and methodsThe DAHANCA 6&7 study included 1476 patients eligible for primary radiotherapy alone. Patients were randomised between five or six weekly fractions of conventional radiotherapy. The prescribed dose was 66–68Gy in 33–34 fractions. All patients were seen weekly during treatment and at regular intervals after completion where detailed morbidity recording was done. Reports from 1468 patients were available for analysis of treatment related morbidity. ResultsAccelerated radiotherapy caused a significant (p<0.05) increase in the peak incidence of: use of analgesics (53% vs. 65%), dysphagia (35% vs. 45%), mucosal oedema (52% vs. 59%), and mucositis (33% vs. 53%). All acute reactions were reversible and healed within three months after radiotherapy. Loss of taste, xerostomia, and acute skin reaction was not different between the two groups. For all late endpoints except fibrosis and atrophy a decline in prevalence was observed in the years after radiotherapy, there was no significant difference between randomisation arms in any of the late endpoints. ConclusionsSix fractions per week, resulting in a one-week reduction in overall treatment time relative to conventional radiotherapy increased acute but not late morbidity. Since acceleration improves loco-regional tumour control, the schedule represents a significant improvement of the therapeutic ratio for head and neck radiotherapy and might be close to the maximal gain possible with accelerated fractionation alone.

Low-dose rituximab is effective in pemphigus

Rituximab, an anti-CD20 antibody, was shown in open series studies to be effective in treating pemphigus at a dose of 4 × 375 mgm(-2) as approved for B-cell malignancies. We investigated whether a lower dose of rituximab is also effective for pemphigus. Patients with pemphigus were treated with a single course of two infusions of rituximab (500 mg each) at an interval of 2 weeks. Clinical consensus late end points, B-cell number, desmoglein 1 and desmoglein 3 indices were monitored. We enrolled 15 patients in the study: three with pemphigus foliaceus (PF) and 12 with pemphigus vulgaris (PV). The follow-up was 32-152 weeks (median 94). All 15 patients responded to therapy. Eight patients achieved complete remission in a median period of 5 weeks (four on minimal therapy, four off therapy). Seven patients achieved partial remission in a median period of 34·5 weeks (five on minimal therapy, two off therapy). Relapses (40%) were seen between 53 and 103 weeks (median 97) after start of therapy. B-cell numbers dropped to <1% after first infusion, and remained undetectable in patients with sustained remission. The antidesmoglein 1 index correlated well with the clinical severity in PF, but this was less obvious in PV. A low dose of rituximab is an effective and safe treatment for pemphigus. Relapses may occur, mostly at the end of the second year. Cost-effectiveness studies with a long follow-up are required to determine the proper dosage of this expensive drug in pemphigus.

The Impact of Clinical Factors on the Development of Late Radiation Toxicity: Results from the Medical Research Council RT01 Trial (ISRCTN47772397)

Aims A variety of dosimetric parameters have been shown to influence the incidence of late radiation toxicity. The effect of other treatment- and patient-related factors is less well established. The aim of this study was to elucidate the influence of such factors in the development of late symptoms after radical radiotherapy to the prostate. Materials and methods Patient- and treatment-related factors that are thought to influence the development of late toxicity were analysed in 788 patients who had received radical radiotherapy to the prostate in the Medical Research Council RT01 trial. Late toxicity data were recorded using the Radiation Therapy Oncology Group, Late Effects of Normal Tissues/Subjective, Objective, Management, Analytic, Royal Marsden Hospital and the University of California, Los Angeles, Prostate Cancer Index. Acute toxicity was measured using the Radiation Therapy Oncology Group grading system. Results On multivariate analysis, acute bowel toxicity was statistically significantly associated with increased proctitis (hazard ratio = 1.63, 95% confidence interval 1.18, 2.24; P = 0.003) and increased stool frequency (hazard ratio = 1.77, 95% confidence interval 1.27, 2.46; P = 0.001). Hypertension was strongly associated with a decreased risk of poor urinary stream (hazard ratio = 0.25, 95% confidence interval 0.09, 0.71; P = 0.009). There was an increased risk of rectal bleeding with increased age (hazard ratio = 1.04 per year of age, 95% confidence interval 1.01, 1.08; P = 0.009). As expected, a higher prescribed dose increased the risk of several late toxicity end points. Although acute bladder toxicity was associated with the presence of bladder symptoms at 5 years, the effect disappeared for all symptoms except increased urinary frequency and haematuria when a change in bladder function from baseline was calculated. Patients with any pretreatment bladder symptoms were more likely to report increased urinary frequency (hazard ratio = 2.09, 95% confidence interval 1.48, 2.95; P < 0.0005), increased urinary incontinence (hazard ratio = 4.22, 95% confidence interval 2.13, 8.35; P < 0.0005) and decreased stream (hazard ratio = 2.64, 95% confidence interval 1.62, 4.31; P < 0.0005), after treatment and before the most recent follow-up assessment. Conclusions In this study, increased acute gastrointestinal and bladder symptoms and prescribed dose were associated with increased late radiation toxicity. The presence of hypertension seemed to be protective for the development of late effects. Baseline symptoms should be taken into account when radiation toxicity is analysed.

What is the possible role of PSA doubling time (PSADT) and PSA velocity (PSAV ) in the decision-making process to initiate salvage radiotherapy following radical prostatectomy in patients with prostate cancer?

This article is an attempt to present a contemporary view on the role of the kinetics of PSA levels as defined by PSA doubling time (PSADT) and PSA velocity (PSAV) in the decision-making process to initiate salvage radiotherapy in patients with prostate cancer after radical prostatectomy (RP).The dynamics of the rise of PSA levels may be an early endpoint parameter, preceding the diagnosis of distant metastasis or death due to prostate cancer based on a single PSA determination. Thus, it seems reasonable to include the kinetics of PSA levels, apart from single PSA determination, in the decision-making algorithm.In a group of patients after RP, PSADT might be an early endpoint that could replace cause-specific survival rate as a late endpoint. PSADT allows distinguishing subgroups of patients at high risk of distant metastases and death, which in turn may lead to a change in the further treatment strategy. Therefore, patients with short PSA doubling time should become a subgroup, in which hormonal therapy should be considered. To date, there is no unanimous consent to accept the criteria of assessment of the dynamics of PSA levels as determinants of treatment in case of recurrences following RP. However, a number of non-randomized clinical trials in patients after RP suggest it would be useful to include these parameters in the decision-making process. For instance, a relationship was found between increased PSA velocity (>2 ng/mL/year) before initiation of oncological treatment and increased (12-fold) risk of death. A number of well-documented retrospective analyses show that PSADT is one of the most important parameters to describe the disease aggressiveness. It has to be stressed that single determination of PSA levels is much less precise in terms of describing the biological aggressiveness of prostate cancer than PSADT. Of course, the question regarding the need to include the PSA levels kinetic parameters as crucial elements of patient management algorithms can be answered in a definitive manner only by randomized clinical trials.

MicroRNAome changes in bystander three-dimensional human tissue models suggest priming of apoptotic pathways

The radiation-induced bystander effect (RIBE) is a phenomenon whereby unexposed cells exhibit molecular symptoms of stress exposure when adjacent or nearby cells are traversed by ionizing radiation (IR). Recent data suggest that RIBE may be epigenetically mediated by microRNAs (miRNAs), which are small regulatory molecules that target messenger RNA transcripts for translational inhibition. Here, we analyzed microRNAome changes in bystander tissues after α-particle microbeam irradiation of three-dimensional artificial human tissues using miRNA microarrays. Our results indicate that IR leads to a deregulation of miRNA expression in bystander tissues. We report that major bystander end points, including apoptosis, cell cycle deregulation and DNA hypomethylation, may be mediated by altered expression of miRNAs. Specifically, c-MYC-mediated upregulation of the miR-17 family was associated with decreased levels of E2F1 and RB1, suggesting a switch to a proliferative state in bystander tissues, while priming these cells for impending death signals. Upregulation of the miR-29 family resulted in decreased levels of its targets DNMT3a and MCL1, consequently affecting DNA methylation and apoptosis. Altered expression of miR-16 led to changes in expression of BCL2, suggesting modulation of apoptosis. Thus, our data clearly show that miRNAs play a profound role in the manifestation of late RIBE end points. In summary, this study creates a roadmap for understanding the role of microRNAome in RIBE and for developing novel RIBE biomarkers.

Science, Anaesthesia and animal studies: what is ‘evidence’?

Science, <i>Anaesthesia</i> and animal studies: what is ‘evidence’?

Usefulness of Delayed Enhancement by Magnetic Resonance Imaging in Hypertrophic Cardiomyopathy as a Marker of Disease and Its Severity

The aim of the present study was to evaluate, in patients with hypertrophic cardiomyopathy (HC), the association between late gadolinium enhancement and clinical end points, such as nonsustained ventricular tachycardia, arrhythmic risk factors, New York Heart Association class, symptoms, and left ventricular functional parameters. A total of 20 normal subjects (mean age 38 years, 16 men) and 100 patients with HC (mean age 46 years, 70 men) were enrolled in the present study. In the late gadolinium enhancement images, the extent of unenhanced, mildly enhanced, and higher enhanced myocardium was measured. Higher enhancement was present in 80% of the HC population and was significantly greater in patients with a New York Heart Association class >1. Mild enhancement was present in all the patients with HC. Receiver operating characteristic analysis revealed that a cutoff of >4.9% of mild enhancement had 100% sensitivity and 86% specificity to predict the occurrence of nonsustained ventricular tachycardia, and a cutoff of >2.4% of hyperenhancement had 77% sensitivity and 96% specificity. In conclusion, late gadolinium enhancement was associated with nonsustained ventricular tachycardia, arrhythmic risk factors, and worse New York Heart Association class.

A proposal for studying off-shell stability of vacuum geometries in string theoryThis paper was presented at the Theory CANADA 4 conference, held at Centre de recherches mathématiques, Montréal, Québec, Canada on 4–7 June 2008.

We briefly review studies of off-shell stability of vacuum geometries in semiclassical gravity. We propose a study of off-shell stability of vacua in string theory by a distinct, though somewhat related approach, by studying their stability under suitable world-sheet sigma model renormalization group (RG) flows. Stability under RG flow is a mathematically well-posed and tractable problem in many cases, as we illustrate through examples. The advantage is that we can make definite predictions about late time behaviour and endpoints of off-shell processes in string theory.