Termination Of Trial Research Articles

Prostate cancer clinical trial completion: The role of geography

Background/aimsOne in five cancer clinical trials fails with another third failing to meet enrollment goals. Prior efforts to improve enrollment focus on patient facing interventions, but geographic factors such as regional cancer incidence may doom trials before they even begin. For these reasons, we examined associations of regional prostate cancer incidence with trial termination, and identified scientifically-underserved areas where future trials might thrive. MethodsWe merged US phase 2–3 prostate cancer clinical trial data from ClinicalTrials.gov with prostate cancer incidence data from statecancerprofiles.cancer.gov. We matched trial information from 293 closed and 560 active trials with incidence data for 2947 counties. Using multivariable logistic regression, we identified associations with trial termination. We identified ‘scientifically-underserved’ counties with the highest cancer incidence quintile (>61 annual cases) but lowest active trials quintile (0 or 1 trial). ResultsOf 293 closed trials, one in three was terminated (n = 96, 32.8%). On multivariable analysis, only lower regional prostate cancer incidence was associated with higher likelihood of premature trial termination (OR 0.98, 95% CI [0.96–0.99] for every 100 cases, p = 0.03). We identified 188 counties with >61 annual prostate cancer cases but 0 or 1 active trials, indicating potential scientifically-underserved areas. ConclusionsIn this novel study, we found prostate cancer trials in areas with low prostate cancer incidence were more likely to fail. We also identified scientifically-underserved areas where trials might thrive. Our findings provide a more nuanced understanding of clinical trial feasibility and upstream opportunities for improvement.

Ultrasonic particles: An approach for targeted gene delivery.

Gene therapy has been widely investigated for the treatment of genetic, acquired, and infectious diseases. Pioneering work utilized viral vectors; however, these are suspected of causing serious adverse events, resulting in the termination of several clinical trials. Non-viral vectors, such as lipid nanoparticles, have attracted significant interest, mainly due to their successful use in vaccines in the current COVID-19 pandemic. Although they allow safe delivery, they come with the disadvantage of off-target delivery. The application of ultrasound to ultrasound-sensitive particles allows for a direct, site-specific transfer of genetic materials into the organ/site of interest. This process, termed ultrasound-targeted gene delivery (UTGD), also increases cell membrane permeability and enhances gene uptake. This review focuses on the advances in ultrasound and the development of ultrasonic particles for UTGD across a range of diseases. Furthermore, we discuss the limitations and future perspectives of UTGD.

Cilostazol for Secondary Stroke Prevention: History, Evidence, Limitations, and Possibilities.

Cilostazol is a PDE3 (phosphodiesterase III) inhibitor with a long track record of safety that is Food and Drug Administration and European Medicines Agency approved for the treatment of claudication in patients with peripheral arterial disease. In addition, cilostazol has been approved for secondary stroke prevention in several Asian countries based on trials that have demonstrated a reduction in stroke recurrence among patients with noncardioembolic stroke. The onset of benefit appears after 60 to 90 days of treatment, which is consistent with cilostazol's pleiotropic effects on platelet aggregation, vascular remodeling, blood flow, and plasma lipids. Cilostazol appears safe and does not increase the risk of major bleeding when given alone or in combination with aspirin or clopidogrel. Adverse effects such as headache, gastrointestinal symptoms, and palpitations, however, contributed to a 6% increase in drug discontinuation among patients randomized to cilostazol in a large secondary stroke prevention trial (CSPS.com [Cilostazol Stroke Prevention Study for Antiplatelet Combination]). Due to limitations of prior trials, such as open-label design, premature trial termination, large loss to follow-up, lack of functional or cognitive outcome data, and exclusive enrollment in Asia, the existing trials have not led to a change in clinical practice or guidelines in Western countries. These limitations could be addressed by a double-blind placebo-controlled randomized trial conducted in a broader population. If positive, it would increase the evidence in support of long-term treatment with cilostazol for secondary prevention in the millions of patients worldwide who have experienced a noncardioembolic ischemic stroke.

Termination Based on Event Accrual in Per Protocol Versus Intention to Treat in the ROCKET AF Trial

BackgroundIn event‐driven clinical trials, study termination is based on accrual of a target number of primary efficacy events. For noninferiority trials in which superiority is conditionally examined, the ideal cohort in which to track event accrual is unclear. We used data from the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial to determine the effect of primary efficacy‐event tracking in the per‐protocol cohort during the on‐treatment period versus the intention‐to‐treat (ITT) cohort during the ITT period.Methods and ResultsROCKET AF was terminated after accruing 429 primary efficacy events (stroke or systemic embolism) in the per‐protocol cohort during the on‐treatment period for noninferiority. We identified the date on which 429 events occurred in the ITT cohort during the ITT period. We performed noninferiority and superiority analyses based on hypothetical study termination on this date. ROCKET AF would have terminated 226 days earlier if events were tracked during the ITT period. Similar to the main trial findings, rivaroxaban would have met noninferiority versus warfarin for the primary efficacy end point (hazard ratio [HR], 0.77; 95% CI, 0.62–0.96; P<0.001). In contrast to the main trial findings, rivaroxaban would have met superiority for the primary efficacy end point (HR, 0.82; 95% CI, 0.68–0.99; P=0.038). In both termination scenarios, rivaroxaban was associated with a lower risk of intracranial hemorrhage and similar risk of other safety end points.ConclusionsClinical trial termination based on event accrual in the ITT cohort versus the per‐protocol cohort may have important implications on trial results depending on rates of study drug discontinuation and event rates off treatment.

Influence of Dietary Replacement of Fish Meal with Crayfish Shell Meal on the Skin Coloration, Muscle Texture, and Amino Acid Composition of Oujiang Color Common Carp Cyprinus carpio var. color

AbstractAn 8‐week feeding trial was conducted to investigate the influence of dietary replacement of fish meal with crayfish shell meal (red swamp crayfish Procambarus clarkii) on the skin coloration, muscle texture, and amino acid composition of Oujiang color common carp Cyprinus carpio var. color. One‐hundred‐eighty fish with average initial weight of 3.0 ± 0.5 g were fed with two isonitrogenous and isolipidic diets (a control diet and a crayfish shell meal diet with 25% substitution of fish meal protein [CSM25]). At the termination of the feeding trial, there were no significant differences between the two groups in terms of lightness (L*), redness (a*), and yellowness (b*) values. Interestingly, one unexpected finding was the extent to which the highest value for total color difference (ΔE) was observed in caudal skin. The springiness, adhesiveness, cohesiveness, gumminess, and chewiness of the muscle were not affected by the CSM25 diet in this study. Muscle hardness was decreased by dietary supplementation with crayfish shell meal, although this decrease was not significant. Notably, there were significant increases in the levels of threonine, leucine, and lysine in the CSM25 group. The current results indicate that crayfish shell meal can alter some essential amino acid levels in muscle. These findings might help others to better understand the influence of dietary replacement of fish meal with crayfish shell meal on skin coloration, muscle texture, and amino acid composition.

Induction of colorectal carcinogenesis in the C57BL/6J and A/J mouse strains with a reduced DSS dose in the AOM/DSS model

BackgroundColorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide and thus mouse models of CRC are of significant value to study the pathogenesis. The Azoxymethane/Dextran sulfate sodium (AOM/DSS) model is a widely used, robust initiation-promotion model for chemical induction of colitis-associated CRC in rodents. However, the dosage of chemicals, treatment regimens and outcome measures vary greatly among studies employing this model. Thus, the aim of this study was to examine an AOM/DSS model involving a reduced (1%) dose of DSS for induction of carcinogenesis in A/J and C57BL/6J (B6) mice.ResultsWe show that colonic preneoplastic lesions can be reliably detected in A/J and B6 mice by use of a AOM/DSS model involving a single injection of 10 mg/kg AOM followed by three 7-day cycles of a low-dose (1%) DSS administration. Supporting existing evidence of A/J mice exhibiting higher susceptibility to AOM than B6 mice, our AOM/DSS-treated A/J mice developed the highest number of large colonic lesions. Clinical symptoms in both strains subjected to the AOM/DSS treatment did not persist in-between treatment cycles, demonstrating that the animals tolerated the treatment well.ConclusionsOur findings suggest that a reduced dose of DSS in the AOM/DSS model can be considered in future studies of early phase colorectal carcinogenesis in the A/J and B6 mouse strains using preneoplastic lesions as an outcome measure, and that such regimen may reduce the risk of early trial terminations to accommodate human endpoints. Overall, our data emphasize the importance of devoting attention towards choice of protocol, outcome measures and mouse strain in studies of CRC in mice according to the study purpose.

Comprehensive cardiac rehabilitation for patients following infective endocarditis: results of the randomized CopenHeartIE trial.

Infective endocarditis is a complex and highly mortal disease requiring lengthy treatment. Physical and mental deconditioning is common. Nonetheless, rehabilitation is virtually unexplored in this population. The aim of this trial was therefore to investigate the effects of cardiac rehabilitation in patients following endocarditis. In a randomized trial, adults with left-sided or cardiac device endocarditis were randomized 1:1 to 12 weeks of physical exercise training and five psycho-educational consultations (cardiac rehabilitation) vs. usual care without rehabilitation (control). Primary outcome was mental health measured by SF-36 Mental Component Summary (MCS) at 6 months. Secondary outcome was physical capacity measured by peak oxygen uptake (VO2) at 4 months. Exploratory outcomes were investigated. Low inclusion rate resulted in trial termination before reaching the target sample size. A total of 117 participants (mean age: 60 years, 81% male) were randomized to cardiac rehabilitation (n = 58) or to control (n = 59). Mental health and physical capacity at baseline were generally poor (MCS: 38.9-42.2 points, VO2 peak: 16.1-16.6 mL/kg/min). Cardiac rehabilitation compared with control showed no effect on mental health (MCS: 44.6 points vs. 48.8 points, P = 0.41) or physical capacity (VO2 peak: 19.9 mL/kg/min vs. 18.0 mL/kg/min, P = 0.09). Effects favouring the intervention were identified in exploratory outcomes including general fatigue (P = 0.005), and physical capacity as maximal power (W) (P = 0.005). Adherence to the intervention was 28%. Results indicate no effect of cardiac rehabilitation in patients following endocarditis; however, lack of statistical power and poor adherence render findings inconclusive. Valuable insight into patients' capabilities and safety was gained, and further investigations into rehabilitation needs and modes of delivery in this high-need population should be a future priority. The trial is registered at ClinicalTrials.gov, NCT01512615.

Evaluation by simulation of clinical trial designs for evaluation of treatment during a viral haemorrhagic fever outbreak

Viral haemorrhagic fevers are characterized by irregular outbreaks with high mortality rate. Difficulties arise when implementing therapeutic trials in this context. The outbreak duration is hard to predict and can be short compared to delays of trial launch and number of subject needed (NSN) recruitment. Our objectives were to compare, using clinical trial simulation, different trial designs for experimental treatment evaluation in various outbreak scenarios. Four type of designs were compared: fixed or group-sequential, each being single- or two-arm. The primary outcome was 14-day survival rate. For single-arm designs, results were compared to a pre-trial historical survival rate pH. Treatments efficacy was evaluated by one-sided tests of proportion (fixed designs) and Whitehead triangular tests (group-sequential designs) with type-I-error = 0.025. Both survival rates in the control arm pC and survival rate differences Δ (including 0) varied. Three specific cases were considered: “standard” (fixed pC, reaching NSN for fixed designs and maximum sample size NMax for group-sequential designs); “changing with time” (increased pC over time); “stopping of recruitment” (epidemic ends). We calculated the proportion of simulated trials showing treatment efficacy, with K = 93,639 simulated trials to get a type-I-error PI95% of [0.024; 0.026]. Under H0 (Δ=0), for the “standard” case, the type-I-error was maintained regardless of trial designs. For “changing with time” case, when pC > pH, type-I-error was inflated, and when pC < pH it decreased. Wrong conclusions were more often observed for single-arm designs due to an increase of Δ over time. Under H1 (Δ=+0.2), for the “standard” case, the power was similar between single- and two-arm designs when pC = pH. For “stopping of recruitment” case, single-arm performed better than two-arm designs, and fixed designs reported higher power than group-sequential designs. A web R-Shiny dashboard was developed: https://pmn-bch.shinyapps.io/simu-vhf/. At an outbreak beginning, group-sequential two-arm trials should be preferred, as the infected cases number increases allowing to conduct a strong randomized control trial. Group-sequential designs allow early termination of trials in cases of harmful experimental treatment. After the epidemic peak, fixed single-arm design should be preferred, as the cases number decreases but this assumes a high level of confidence on the pre-trial historical survival rate.

Evaluation by simulation of clinical trial designs for evaluation of treatment during a viral haemorrhagic fever outbreak

BackgroundViral haemorrhagic fevers are characterized by irregular outbreaks with high mortality rate. Difficulties arise when implementing therapeutic trials in this context. The outbreak duration is hard to predict and can be short compared to delays of trial launch and number of subject needed (NSN) recruitment. Our objectives were to compare, using clinical trial simulation, different trial designs for experimental treatment evaluation in various outbreak scenarios.MethodsFour type of designs were compared: fixed or group-sequential, each being single- or two-arm. The primary outcome was 14-day survival rate. For single-arm designs, results were compared to a pre-trial historical survival rate pH. Treatments efficacy was evaluated by one-sided tests of proportion (fixed designs) and Whitehead triangular tests (group-sequential designs) with type-I-error = 0.025. Both survival rates in the control arm pC and survival rate differences Δ (including 0) varied. Three specific cases were considered: “standard” (fixed pC, reaching NSN for fixed designs and maximum sample size NMax for group-sequential designs); “changing with time” (increased pC over time); “stopping of recruitment” (epidemic ends). We calculated the proportion of simulated trials showing treatment efficacy, with K = 93,639 simulated trials to get a type-I-error PI95% of [0.024;0.026].ResultsUnder H0 (Δ = 0), for the “standard” case, the type-I-error was maintained regardless of trial designs. For “changing with time” case, when pC > pH, type-I-error was inflated, and when pC < pH it decreased. Wrong conclusions were more often observed for single-arm designs due to an increase of Δ over time. Under H1 (Δ = + 0.2), for the “standard” case, the power was similar between single- and two-arm designs when pC = pH. For “stopping of recruitment” case, single-arm performed better than two-arm designs, and fixed designs reported higher power than group-sequential designs. A web R-Shiny application was developed.ConclusionsAt an outbreak beginning, group-sequential two-arm trials should be preferred, as the infected cases number increases allowing to conduct a strong randomized control trial. Group-sequential designs allow early termination of trials in cases of harmful experimental treatment. After the epidemic peak, fixed single-arm design should be preferred, as the cases number decreases but this assumes a high level of confidence on the pre-trial historical survival rate.

Field-scale performance of biochar-amended soil covers for landfill methane oxidation

A field validation of three biochar-amended soil covers (2%, 10%, and 100% biochar-amended soils) along with a soil control cover was conducted within the intermediate cover of an active municipal solid waste (MSW) landfill in conjunction with laboratory studies evaluating the effect of biochar in enhancing methane (CH4) oxidation in cover soils. Baseline CH4 emissions and pre-existing site conditions were characterized prior to installation of test plots simulating three cover designs evaluated in related laboratory studies. Static chamber measurements of surface CH4 fluxes and sampling of soil pore gas at different depths were conducted across the 8-month monitoring period to assess cover performance. Surface fluxes from the test plots exhibited wide spatial variability, with one location emitting fluxes > 1100 g CH4 m−2 day−1 in one survey. Potential rates of CH4 oxidation were determined in batch assays of exhumed soil core subsamples following termination of the field trial and ranged from ~1 to 350 μg CH4 g−1 day−1. The heterogeneity of the waste led to nonuniform CH4 loads in the test plots. The soil control test plot was exposed to higher CH4 loads and biochar-amended test plots were exposed to significantly lower CH4 loads. As a result, the soil control test plot showed higher CH4 oxidation rates (257–289 μg CH4 g−1 day−1) than the biochar-amended test plots. Similarly, the soil control plot also showed higher relative abundance of methanotrophs which was positively correlated with the CH4 oxidation rates. The test plot with 10% biochar-amended soil experienced CH4 loads nearly 25% of that in soil control and still showed CH4 oxidation rates (260 μg CH4 g−1 day−1) comparable to that of soil control which showed the efficacy of biochar amendment in enhancing CH4 oxidation rates. The environmental and CH4 exposure conditions affected the microbial community composition in the test plots and showed the dominance of type I methanotrophic genus such as Methylomonas and Crenothrix spp. Overall, the waste heterogeneity led to nonuniform CH4 exposure conditions at each test plot making it hard to distinctly quantify the effect of biochar amendment on CH4 oxidation rates.

Preliminary study on the toxicological impacts of Pinus roxburghii and Nauplius graveolens extracts on albino mice

The objective of this study was to evaluate the potential toxicity of methanolic extracts of Pinus roxburghii branch (P. roxburghii) and Nauplius graveolens (N. graveolens). Single oral dosage was administered to male mice at increasing concentrations of 100, 250,500,1000 and 2000 mg/kg body weight to assess the median LD50, which causes the death of 50% (one half) of the mice. Blood samples were collected at the end of the 14 day toxicological trial for the liver and kidney function tests. The results showed that the LD50 of P. roxburghii was 1708.3 mg/ kg body weight and of N. graveolens 1562.5 mg/kg body weight. The acute toxicity had detrimental effects on the liver and kidney function. Based on this finding, a second trial was designed, and the mice were administered day after day intragastrically one tenth (1/10) the LD50 of each plant extract for a whole month. At the termination of the 30-day trial, blood samples and organs were collected for liver and kidney function tests. The long-term administration of 1/10 the LD50 dosages had no significant adverse effects neither on the liver and kidney functions nor on the histopathological examination. In conclusion, further studies are warranted to determine the potential application of these plant as natural therapeutic products.

LSD1 as a Biomarker and the Outcome of Its Inhibitors in the Clinical Trial: The Therapy Opportunity in Tumor.

Tumors are the foremost cause of death worldwide. As a result of that, there has been a significant enhancement in the investigation, treatment methods, and good maintenance practices on cancer. However, the sensitivity and specificity of a lot of tumor biomarkers are not adequate. Hence, it is of inordinate significance to ascertain novel biomarkers to forecast the prognosis and therapy targets for tumors. This review characterized LSD1 as a biomarker in different tumors. LSD1 inhibitors in clinical trials were also discussed. The recent pattern advocates that LSD1 is engaged at sauce chromatin zones linking with complexes of multi-protein having an exact DNA-binding transcription factor, establishing LSD1 as a favorable epigenetic target, and also gives a large selection of therapeutic targets to treat different tumors. This review sturdily backing the oncogenic probable of LSD1 in different tumors indicated that LSD1 levels can be used to monitor and identify different tumors and can be a useful biomarker of progression and fair diagnosis in tumor patients. The clinical trials showed that inhibitors of LSD1 have growing evidence of clinical efficacy which is very encouraging and promising. However, for some of the inhibitors such as GSK2879552, though selective, potent, and effective, its disease control was poor as the rate of adverse events (AEs) was high in tumor patients causing clinical trial termination, and continuation could not be supported by the risk-benefit profile. Therefore, we propose that, to attain excellent clinical results of inhibitors of LSD1, much attention is required in designing appropriate dosing regimens, developing in-depth in vitro/in vivo mechanistic works of LSD1 inhibitors, and developing inhibitors of LSD1 that are reversible, safe, potent, and selective which may offer safer profiles.

EFFECT OF NIGELLA SATIVA ON SERUM TESTOSTERONE LEVELS IN LETROZOLE INDUCED POLYCYSTIC OVARIAN SYNDROME IN MICE

Objective: Monitor the ameliorative impact of Nigella sativa on fasting blood glucose and serum testosteronelevels in polycystic ovarian syndrome caused by letrozole in mice.&#x0D; Study Design: Laboratory based randomized control trial.&#x0D; Place and Duration of Study: Anatomy department, Army Medical College in teamwork with National Instituteof Health. Time span is Dec 2014 Dec 2015.&#x0D; Methodology: Total 40 mature female BALB/c mice were chosen and distributed in four groups (ten mice in each one). Group 1 was given normal diet. Rests of three groups were treated with Letrozole at dose of 1 mg/kg body weight once daily for eight weeks. Group 3 was also given Nigella sativa seeds powder at dose of 10 g/kg body weight once daily starting at 22 day and continued up to eight weeks. Group 4 was treated with Nigella sativa oil at a dose of 4 ml/kg body weight once daily starting at 22 day and continued up to eight weeks. At termination of trial, fasting blood glucose level (FBG) was recorded by taking blood sample by glucometer from mouse lateral tail vein after 12 hours fasting. Mice with blood glucose level 250-464 mg/dl were marked hyperglycemic. Final blood sample was taken through cardiac puncture for serum testosterone evaluation.&#x0D; Results: Fasting blood glucose and Serum testosterone levels were raised in group 2 animals in comparison togroup 1 while they were reduced remarkably in group 3 and 4 in comparison of group 2.&#x0D; Conclusion: Nigella sativa seeds in both solid and liquid state leave..................

Partial Versus Complete Bacillus Calmette-Guérin Intravesical Therapy and Bladder Cancer Outcomes in High-risk Non–muscle-invasive Bladder Cancer: Is NIMBUS the Full Story?

BackgroundIt is important to understand the implications of reduced bacillus Calmette-Guérin (BCG) treatment intensity, given global shortages and early termination of the NIMBUS trial. ObjectiveTo assess the association of partial versus complete BCG induction with outcomes. Design, setting, and participantsThis is a retrospective cohort study of veterans diagnosed with high-risk non–muscle-invasive bladder cancer (NMIBC; high grade [HG] Ta, T1, or carcinoma in situ) between 2005 and 2011 with follow-up through 2014. InterventionPatients were categorized into partial versus complete BCG induction (one to five vs five or more instillations). Partial BCG induction subgroups were defined for comparison with the NIMBUS trial. Outcome measurements and statistical analysisPropensity score–adjusted regression models were used to assess the association of partial BCG induction with risk of recurrence and bladder cancer death. Results and limitationsAmong 540 patients, 114 (21.1%) underwent partial BCG induction. Partial versus complete BCG induction was not significantly associated with the risk of recurrence in HG Ta (cumulative incidence [CIn] 46.6% vs 53.9% at 5 yr, p = 0.38) or T1 (CIn 47.1% vs 56.7 at 5 yr, p = 0.19) disease. Similarly, we found no increased risk of bladder cancer death (HG Ta: CIn 4.7%7vs 5.4% at 5 yr, p = 0.87; T1: CIn 10.0% vs 11.4% at 5 yr, p = 0.77). NIMBUS-like induction was associated with an increased risk of recurrence in patients with HG Ta disease, although not statistically significant. Unmeasured confounding is a limitation. ConclusionsCancer outcomes were similar among high-risk NMIBC patients who underwent partial versus complete BCG induction, suggesting that future research is needed to determine how to optimize BCG delivery for the greatest number of patients, especially during global shortages. Patient summaryOutcomes were similar between patients receiving partial and complete courses of bacillus Calmette-Guérin (BCG) therapy. Future research is needed to determine how to best deliver BCG to the greatest number of patients, particularly during medication shortages.

Predictive modeling of clinical trial terminations using feature engineering and embedding learning

In this study, we propose to use machine learning to understand terminated clinical trials. Our goal is to answer two fundamental questions: (1) what are common factors/markers associated to terminated clinical trials? and (2) how to accurately predict whether a clinical trial may be terminated or not? The answer to the first question provides effective ways to understand characteristics of terminated trials for stakeholders to better plan their trials; and the answer to the second question can direct estimate the chance of success of a clinical trial in order to minimize costs. By using 311,260 trials to build a testbed with 68,999 samples, we use feature engineering to create 640 features, reflecting clinical trial administration, eligibility, study information, criteria etc. Using feature ranking, a handful of features, such as trial eligibility, trial inclusion/exclusion criteria, sponsor types etc., are found to be related to the clinical trial termination. By using sampling and ensemble learning, we achieve over 67% Balanced Accuracy and over 0.73 AUC (Area Under the Curve) scores to correctly predict clinical trial termination, indicating that machine learning can help achieve satisfactory prediction results for clinical trial study.

Overcoming the impact of the COVID‐19 pandemic on oncology early phase trials and drug development in Asia—Experiences and perspectives of the Asian Oncology Early Phase 1 Consortium

AimThe significance and prioritization of early phase oncology trial continuation during a global pandemic is unknown. This study reported the outcomes, multiple challenges, and broad recommendations associated with the impact of the novel coronavirus disease 2019 (COVID‐19) on oncology early phase 1 trials—and on drug development in Asia—based on the experiences and perspectives of Asian oncology phase 1 centers.MethodsBetween March and April 2020 during the initial period of outbreak, the impact of COVID‐19 across oncology phase 1 sites in five Asian countries—China (Hong Kong), Japan, South Korea, Taiwan, and Singapore—was retrospectively analyzed.ResultsThere was no trial termination or treatment discontinuation in all five countries. Although the most common impact was new patient enrollment being placed on hold, which was based on pharmaceutical sponsors’ decision‐making, the situation varied per site. Most sites had no restrictions in place that would limit their ability to fully comply with the requirements of conducting the early phase studies. The number of protocol deviations during the pandemic was largely dependent on domestic transportation status during the outbreak rather than the ability of the clinical trial centers.ConclusionDetermining the risk to benefits ratio of patients with cancer who are enrolled in early phase 1 clinical trials under the unusual circumstances of a global pandemic is important. Specific guidance or guidelines on the conduct of early phase 1 clinical trials during public health emergencies that are based on the recent lessons learned is urgently required.

Tailored 70S30C Bioactive glass induces severe inflammation as pulpotomy agent in primary teeth: an interim analysis of a randomised controlled trial.

This study compared clinical, histologic, and inflammatory outcomes of Biodentine and Bioactive glass (70S30C-BAG) as pulpotomy agents in primary teeth. A randomised, clinical trial was performed recruiting 70 children, 5-9years old, having ≥ 1 tooth indicated for vital pulpotomy. Participants were randomised to Biodentine or 70S30C-BAG groups. Clinical evaluation was scheduled at 1, 3, 6, 9, and 12months. Additional 16 teeth were extracted after 6weeks to assess histologic and inflammatory response (IL-8/IL-10 ratio) using ELISA. Fisher exact, Mann Whitney U test, and t test were used to compare clinical, histologic outcomes and IL-8/IL-10 ratio. After 3months, 10 teeth treated with Biodentine were clinically successful, while 9 teeth treated with 70S30C-BAG failed (P < 0.001) necessitating trial termination. Causes of failure were analysed by assessing the pH and ionic release of 70S30C-BAG. Biodentine-treated teeth showed minor inflammation, normal pulp, and hard tissue formation.70S30C-BAG-treated teeth showed severe inflammation, abscesses, root resorption without hard tissue formation. There was a significantly greater percent reduction of IL-8/IL-10 ratio in Biodentine than 70S30C-BAG (mean ± SD = 66.39 ± 18.56 and 40.66 ± 0.86, P = 0.02). Biodentine showed favourable clinical, histologic, and anti-inflammatory outcomes, promoting pulp healing and regeneration. 70S30C-BAG resulted in pulp necrosis-through persistent inflammation-causing clinical failure. Biodentine is a promising pulpotomy agent in primary teeth; it promoted healing and regeneration of the dentine-pulp complex. In its current form, 70S30C-BAG is not a suitable pulpotomy agent; it induced persistent inflammation, negating the pulp ability to heal and regenerate. TRN: NCT03786302, 12/19/2018.

DECEPTION OFFENCE. ACQUITTAL SOLUTION. PRESCRIPTION TERM OF THE CRIMINAL LIABILITY

The Ploiesti Court of appeal changes the legal classification of the crime of deception, provided by art. 244 paragraph 1 of the Criminal Code with applic. art.5 of the Criminal Code, for which the defendants were sent to trial, in the crime provided by art.84 point 2 of Law no.59 / 1934 and orders the termination of the criminal trial against the defendants for the crime provided by art.84 point 2 of Law no.59 / 1934, as a result of fulfillment of the prescription term of criminal liability. Dismisses as inadmissible the civil action of the civil party SC H. P. SRL. It has not been proved the existence of certain, decisive malicious maneuvers, with a decisive role in determining the representatives of the civil party in the moment of concluding the sale-purchase contract, but, on the contrary, reveals that the parties had previously, for a period of almost 5 years, a good collaboration, in which they developed the same type of commercial relations. The representatives of the civil party knew that it was no money available in the debtor's account at the time of issuing the cheques by the defendants, and on the other hand, the payment of the goods was not made exclusively by cheques, as stipulated in the contract. The Court of Appeal also correctly held that the limitation period for criminal liability for the two defendants had expired. With regard to the civil action, in relation to the Decision no. 43/2008 of the High Court of Cassation and Justice- the United Sections, the Court of appeal did not solve the civil, rejecting it as inadmissible.

Hypertension in Chronic Kidney Disease (CKD): Diagnosis, Classification, and Therapeutic Targets

Blood pressure (BP) in the office is often recorded without standardization of the technique of measurement. When office BP measurement is performed with a research-grade methodology, it can inform better therapeutic decisions. The reference-standard method of ambulatory BP monitoring (ABPM) together with the assessment of BP in the office enables the identification of white-coat and masked hypertension, facilitating the stratification of cardiorenal risk. Compared with general population, the prevalence of resistant hypertension is 2- to 3-fold higher among patients with chronic kidney disease (CKD). The use of ABPM is mandatory in order to exclude the white-coat effect, a common cause of pseudoresistance, and confirm the diagnosis of true-resistant hypertension. After the premature termination of Systolic Blood Pressure Intervention Trial due to an impressive cardioprotective benefit of intensive BP-lowering, the 2017 American Heart Association/American College of Cardiology guideline reappraised the definition of hypertension and recommended a tighter BP target of <130/80 mm Hg for the majority of adults with a high cardiovascular risk profile, inclusive of patients with CKD. However, the benefit/risk ratio of intensive BP-lowering in particular subsets of patients with CKD (i.e., those with diabetes or more advanced CKD) continues to be debated. We explore the controversial issue of BP targets in CKD, providing a critical evaluation of the available clinical-trial evidence and guideline recommendations. We argue that the systolic BP target in CKD, if BP is measured correctly, should be <120 mm Hg.

Valproic acid combined with cisplatin-based chemoradiation in locally advanced head and neck squamous cell carcinoma patients and associated biomarkers.

BackgroundCisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, however, relapses are frequent. Our goal was to evaluate if association of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, with CCRT improved response rate (RR) and associated biomarkers.MethodsThis phase II trial included patients with unresectable locally advanced (LA) oropharynx (OP) squamous cell carcinoma. CCRT began after 2 weeks of VPA (P1). Primary goal was RR at 8 weeks after chemoradiation (CRT)+VPA (P2). Biomarkers included microRNA (miR) polymerase chain reaction (PCR)-array profiling in plasma compared to healthy controls by two-sample t-test. Distribution of p-values was analysed by beta-uniform mixture. Findings were validated by real-time PCR quantitative polymerase chain reaction (qPCR) for selected miRs in plasma and saliva. p16, HDAC2 and RAD23 Homolog B, Nucleotide Excision Repair Protein (HR23B) tumour immunohistochemistry were evaluated.ResultsGiven significant toxicities, accrual was interrupted after inclusion of ten LA p16 negative OP patients. All were male, smokers/ex-smokers, aged 41–65 and with previous moderate/high alcohol intake. Nine evaluable patients yielded a RR of 88%. At false discovery rate of 5%, 169 miRs were differentially expressed between patients and controls, including lower expression of tumour suppressors (TSs) such as miR-31, -222, -let-7a/b/e and -145. miR-let-7a/e expression was validated by qPCR using saliva. A HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease-free survival.ConclusionsVPA and CRT offered high RR; however, with prohibitive toxicities, which led to early trial termination. Patients and controls had a distinct pattern of miR expression, mainly with low levels of TS miRs targeting Tumor protein P53 (TP53). miR-let-7a/e levels were lower in patients compared to controls, which reinforces the aggressive nature of such tumours (NCT01695122).