Dissymmetrical Chiral Peropyrenes: Synthesis via Iridium-Catalyzed C-H Activation/Alkyne Benzannulation and Study of Their Properties.

Dissymmetrical chiral peropyrenes with electron-rich and electron-deficient aryl substituents in the bay regions were synthesized via iridium-catalyzed C-H activation and alkyne benzannulation. The electronic properties were studied using cyclic and differential pulse voltammetry. The enantiomers were separated and exhibited high glum and gabs values in circularly polarized luminescence (CPL) and circular dichroism (CD), respectively. Variable-temperature NMR experiments were conducted on symmetrical and dissymmetrical chiral peropyrenes to compare the barrier to rotation of the aryl groups in the bay region.

Liquid biopsy in head neck cancer: ready for clinical routine diagnostics?

PURPOSE OF REVIEW: The bodily fluids of patients with solid cancers representing a minimally-invasive source of clinically exploitable biomarkers have attracted an increasing amount of attention in recent years. In patients with head and neck squamous cell carcinoma (HNSCC), cell-free tumour DNA (ctDNA) belongs to the most promising liquid biomarkers for monitoring disease burden and identifying patients at high risk of recurrence. In this review, we highlight recent studies, evaluating the analytical validity and clinical utility of ctDNA as a dynamic biomarker in HNSCC, especially as it relates to risk stratification and contrasting human papilloma virus (HPV+ and HPV-) and carcinomas. RECENT FINDINGS: The clinical potential of minimal residual disease monitoring through viral ctDNA in identifying HPV+ oropharyngeal carcinoma patients at higher risk of recurrence has recently been demonstrated. Furthermore, accumulating evidence supports a potential diagnostic value of ctDNA dynamics in HPV-negative HNSCC. Altogether, recent data suggest that ctDNA analysis may be a valuable tool in guiding (de)escalation of surgical interventions as well as adaptation in radiotherapy dosage, both in the definitive and adjuvant settings. SUMMARY: Rigorous clinical trials with patient-relevant endpoints are critical in order to demonstrate that treatment decisions based on ctDNA dynamics result in better outcomes in HNSCC.

Futility monitoring for randomized clinical trials with non-proportional hazards: An optimal conditional power approach.

BACKGROUND: Standard futility analyses designed for a proportional hazards setting may have serious drawbacks when non-proportional hazards are present. One important type of non-proportional hazards occurs when the treatment effect is delayed. That is, there is little or no early treatment effect but a substantial later effect. METHODS: We define optimality criteria for futility analyses in this setting and propose simple search procedures for deriving such rules in practice. RESULTS: We demonstrate the advantages of the optimal rules over commonly used rules in reducing the average number of events, the average sample size, or the average study duration under the null hypothesis with minimal power loss under the alternative hypothesis. CONCLUSION: Optimal futility rules can be derived for a non-proportional hazards setting that control the loss of power under the alternative hypothesis while maximizing the gain in early stopping under the null hypothesis.

Safe and effective performance of pediatric spinal deformity surgery in patients unwilling to accept blood transfusion: a clinical study and review of literature.

BACKGROUND: Pediatric deformity surgery traditionally involves major blood loss. Patients refusing blood transfusion add extra clinical and medicolegal challenges; specifically the Jehovah's witnesses population. The objective of this study is to review the safety and effectiveness of blood conservation techniques in patients undergoing pediatric spine deformity surgery who refuse blood transfusion. METHODS: After obtaining institutional review board approval, we retrospectively reviewed 20 consecutive patients who underwent spinal deformity surgery and refused blood transfusion at a single institution between 2014 and 2018. We collected pertinent preoperative, intraoperative and most recent clinical and radiological data with latest follow-up (minimum two-year follow-up). RESULTS: Twenty patients (13 females) with a mean age of 14.1 years were identified. The type of scoliotic deformities were adolescent idiopathic (14), juvenile idiopathic (1), neuromuscular (3) and congenital (2). The major coronal Cobb angle was corrected from 55.4° to 11.2° (80% correction, p <  0.001) at the latest follow-up. A mean of 11.4 levels were fused and 5.6 levels of Pontes osteotomies were performed. One patient underwent L1 hemivertebra resection and three patients had fusion to pelvis. Estimated blood loss, percent estimated blood volume loss, and cell saver returned averaged 307.9 mL, 8.5%, and 80 mL, respectively. Average operative time was 214 min. The average drop in hemoglobin after surgery was 2.9 g/dL. The length of hospital stay averaged 5.1 days. There were no intraoperative complications. Three postoperative complications were identified, none related to their refusal of transfusion. One patient had in-hospital respiratory complication, one patient developed a late infection, and one patient developed asymptomatic radiographic distal junctional kyphosis. CONCLUSIONS: Blood conservation techniques allow for safe and effective spine deformity surgery in pediatric patients refusing blood transfusion without major anesthetic or medical complications, when performed by an experienced multidisciplinary team. LEVEL OF EVIDENCE: Level IV.

Design and analysis of biomarker-integrated clinical trials with adaptive threshold detection and flexible patient enrichment.

We propose a new adaptive threshold detection and enrichment design in which the biomarker threshold is adaptively estimated and updated by optimizing a trade-off between the size of the biomarker positive population and the magnitude of the treatment effect in that population. Enrichment is based on an enrollment criterion that accounts for the uncertainty in estimation of the threshold. Early termination for futility is allowed based on predictive success probability. Valid testing and estimation techniques for the treatment effect overall and inpatient subgroups are studied. Simulations and an example demonstrate advantages of the proposed design over existing designs.

Bias-adjusted Kaplan-Meier survival curves for marginal treatment effect in observational studies.

For time-to-event outcomes, the Kaplan-Meier estimator is commonly used to estimate survival functions of treatment groups and to compute marginal treatment effects, such as the difference in survival rates between treatments at a landmark time. The derived estimates of the marginal treatment effect are uniformly consistent under general conditions when data are from randomized clinical trials. For data from observational studies, however, these statistical quantities are often biased due to treatment-selection bias. Propensity score-based methods estimate the survival function by adjusting for the disparity of propensity scores between treatment groups. Unfortunately, misspecification of the regression model can lead to biased estimates. Using an empirical likelihood (EL) method in which the moments of the covariate distribution of treatment groups are constrained to equality, we obtain consistent estimates of the survival functions and the marginal treatment effect. Equating moments of the covariate distribution between treatment groups simulate the covariate distribution that would have been obtained if the patients had been randomized to these treatment groups. We establish the consistency and the asymptotic limiting distribution of the proposed EL estimators. We demonstrate that the proposed estimator is robust to model misspecification. Simulation is used to study the finite sample properties of the proposed estimator. The proposed estimator is applied to a lung cancer observational study to compare two surgical procedures in treating early-stage lung cancer patients.

Ontogeny and development of the tritocerebral commissure giant (TCG): an identified neuron in the brain of the grasshopper Schistocerca gregaria.

The tritocerebral commissure giant (TCG) of the grasshopper Schistocerca gregaria is one of the best anatomically and physiologically described arthropod brain neurons. A member of the so-called Ventral Giant cluster of cells, it integrates sensory information from visual, antennal and hair receptors, and synapses with thoracic motor neurons in order to initiate and regulate flight behavior. Its ontogeny, however, remains unclear. In this study, we use bromodeoxyuridine incorporation and cyclin labeling to reveal proliferative neuroblasts in the region of the embryonic brain where the ventral giant cluster is located. Engrailed labeling confirms the deutocerebral identity of this cluster. Comparison of soma locations and initial neurite projections into tracts of the striate deutocerebrum help identify the cells of the ventral cluster in both the embryonic and adult brain. Reconstructions of embryonic cell lineages suggest deutocerebral NB1 as being the putative neuroblast of origin. Intracellular dye injection coupled with immunolabeling against neuron-specific horseradish peroxidase is used to identify the VG1 (TCG) and VG3 neurons from the ventral cluster in embryonic brain slices. Dye injection and backfilling are used to document axogenesis and the progressive expansion of the dendritic arbor of the TCG from mid-embryogenesis up to hatching. Comparative maps of embryonic neuroblasts from several orthopteroid insects suggest equivalent deutocerebral neuroblasts from which the homologous TCG neurons already identified in the adult brain could originate. Our data offer the prospect of identifying further lineage-related neurons from the cluster and so understand a brain connectome from both a developmental and evolutionary perspective.

Trends of hospitalizations for syncope/collapse in the United States from 2004 to 2013-An analysis of national inpatient sample.

INTRODUCTION: Syncope/collapse is a common reason for emergency department visits, and approximately 30-40% of these individuals are hospitalized. We examined changes in hospitalization rates, in-hospital mortality, and cost of syncope/collapse-related hospital care in the United States from 2004 to 2013. METHODS: We used the US Nationwide Inpatient Sample (NIS) from 2004 to 2013 to identify syncope/collapse-related hospitalizations using ICD-9, code 780.2, as the principal discharge diagnosis. Data are presented as mean ± SEM. RESULTS: From 2004 to 2013, there was a 42% reduction in hospitalizations with a principal discharge diagnosis of syncope/collapse from 54,259 (national estimate 253,591) in 2004 to 31,427 (national estimate 156,820) in 2013 (P < 0.0001). The mean length of hospital stays decreased (2.88 ± 0.04 days in 2004 vs. 2.54 ± 0.02 in 2013; P < 0.0001), while in-hospital mortality did not change (0.28% in 2004 vs. 0.18% in 2013; P  =  0.12). However, mean charges (inflation adjusted) for syncope/collapse-related hospitalization increased by 43.6% from $17,514 in 2004 to $25,160 in 2013 (P < 0.0001). The rates of implantation of permanent pacemakers and implantable cardioverter defibrillator remained low during these hospitalizations, and decreased over time (P for both < 0.0001). CONCLUSIONS: Hospitalization rates for syncope/collapse have decreased significantly in the US from 2004 to 2013. Despite a modest reduction in length of stay, the cost of syncope/collapse-related hospital care has increased.

Vagal afferent activation suppresses systemic inflammation via the splanchnic anti-inflammatory pathway.

Electrical stimulation of the vagus nerve (VNS) is a novel strategy used to treat inflammatory conditions. Therapeutic VNS activates both efferent and afferent fibers; however, the effects attributable to vagal afferent stimulation are unclear. Here, we tested if selective activation of afferent fibers in the abdominal vagus suppresses systemic inflammation. In urethane-anesthetized rats challenged with lipopolysaccharide (LPS, 60 µg/kg, i.v.), abdominal afferent VNS (2 Hz for 20 min) reduced plasma tumor necrosis factor alpha (TNF) levels 90 min later by 88% compared with unmanipulated animals. Pre-cutting the cervical vagi blocked this anti-inflammatory action. Interestingly, the surgical procedure to expose and prepare the abdominal vagus for afferent stimulation ('vagal manipulation') also had an anti-inflammatory action. Levels of the anti-inflammatory cytokine IL-10 were inversely related to those of TNF. Prior bilateral section of the splanchnic sympathetic nerves reversed the anti-inflammatory actions of afferent VNS and vagal manipulation. Sympathetic efferent activity in the splanchnic nerve was shown to respond reflexly to abdominal vagal afferent stimulation. These data demonstrate that experimentally activating abdominal vagal afferent fibers suppresses systemic inflammation, and that the efferent neural pathway for this action is in the splanchnic sympathetic nerves.

Auxiliary variable-enriched biomarker-stratified design.

Clinical trials in the era of precision medicine require assessment of biomarkers to identify appropriate subgroups of patients for targeted therapy. In a biomarker-stratified design (BSD), biomarkers are measured on all patients and used as stratification variables. However, such a trial can be both inefficient and costly, especially when the prevalence of the subgroup of primary interest is low and the cost of assessing the biomarkers is high. Efficiency can be improved and costs reduced by using enriched biomarker-stratified designs, in which patients of primary interest, typically the biomarker-positive patients, are oversampled. We consider a special type of enrichment design, an auxiliary variable-enriched design (AEBSD), in which enrichment is based on some inexpensive auxiliary variable that is positively correlated with the true biomarker. The proposed AEBSD reduces the total cost of the trial compared with a standard BSD when the prevalence rate of true biomarker positivity is small and the positive predictive value (PPV) of the auxiliary biomarker is larger than the prevalence rate. In addition, for an AEBSD, we can immediately randomize the patients selected in the screening process without waiting for the result of the true biomarker test, reducing the treatment waiting time. We propose an adaptive Bayesian method to adjust the assumed PPV while the trial is ongoing. Numerical studies and an example illustrate the approach. An R package is available.

On Enrichment Strategies for Biomarker Stratified Clinical Trials.

In the era of precision medicine, drugs are increasingly developed to target subgroups of patients with certain biomarkers. In large all-comer trials using a biomarker stratified design, the cost of treating and following patients for clinical outcomes may be prohibitive. With a fixed number of randomized patients, the efficiency of testing certain treatments parameters, including the treatment effect among biomarker-positive patients and the interaction between treatment and biomarker, can be improved by increasing the proportion of biomarker positives on study, especially when the prevalence rate of biomarker positives is low in the underlying patient population. When the cost of assessing the true biomarker is prohibitive, one can further improve the study efficiency by oversampling biomarker positives with a cheaper auxiliary variable or a surrogate biomarker that correlates with the true biomarker. To improve efficiency and reduce cost, we can adopt an enrichment strategy for both scenarios by concentrating on testing and treating patient subgroups that contain more information about specific treatment parameters of primary interest to the investigators. In the first scenario, an enriched biomarker stratified design enriches the cohort of randomized patients by directly oversampling the relevant patients with the true biomarker, while in the second scenario, an auxiliary-variable-enriched biomarker stratified design enriches the randomized cohort based on an inexpensive auxiliary variable, thereby avoiding testing the true biomarker on all screened patients and reducing treatment waiting time. For both designs, we discuss how to choose the optimal enrichment proportion when testing a single hypothesis or two hypotheses simultaneously. At a requisite power, we compare the two new designs with the BSD design in terms of the number of randomized patients and the cost of trial under scenarios mimicking real biomarker stratified trials. The new designs are illustrated with hypothetical examples for designing biomarker-driven cancer trials.

Validation of Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials.

PURPOSE: The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma. MATERIALS AND METHODS: Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)-log HROS and log HRPFS-measured in R2 from a weighted least-square (WLS) regression model and the CBCS model. RESULTS: The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8-3.5 months) and the median OS was 7.2 months (95% CI, 6.5-8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age. CONCLUSIONS: The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma. The Oncologist 2017;22:189-198Implications for Practice: For better disease management and for more efficient clinical trial designs, it is important to know if progression-free survival (PFS) is a good surrogate endpoint for overall survival in malignant mesothelioma. With a relatively large database of 17 phase II trials and 716 patients from Cancer and Leukemia Group B and North Central Cancer Treatment Group, we conducted statistical analyses and found that there is no evidence to suggest that PFS is a valid surrogate endpoint for OS for malignant mesothelioma. Future research work is needed to find alternative surrogate endpoints for OS.

Cardiotoxicity and cardiomyopathy in children and young adult survivors of hematopoietic stem cell transplant.

Cardiomyopathy is common in long-term survivors of pediatric hematopoietic stem cell transplant (HSCT). Events occurring before and after HSCT when combined with specific insults during HSCT likely contribute to long-term risk. Strategies for detecting subclinical cardiomyopathy prior to patients developing overt heart failure are under investigation. Changes in HSCT preparative regimens and cardioprotective medications administered during chemotherapy may alter the risk for cardiomyopathy. Interventions in long-term survivors such as lifestyle modification and cardioactive medications are of increasing importance. Herein we review the causes of cardiac injury, discuss strategies for detection of cardiomyopathy, and evaluate therapeutic options for long-term HSCT survivors.

Relationship between obesity and clinical outcome in adults with acute myeloid leukemia: A pooled analysis from four CALGB (alliance) clinical trials.

Obesity has been previously suggested as an adverse prognostic marker in patients with acute leukemia. To evaluate the relationship between obesity and clinical outcome, disease-free survival (DFS) and overall survival (OS), in patients with acute myelogenous leukemia (AML), including acute promyelocytic leukemia (APL), we performed a pooled analysis of four CALGB (Alliance) clinical trials. Our study included 446 patients with APL from CALGB 9710, and 1,648 patients between 18 and 60 years of age with non-APL AML from CALGB 9621, 10503, and 19808. Obesity was defined as BMI ≥30 kg/m(2). Multivariate Cox proportional-hazard regression models were fitted for DFS and OS. Obesity was seen in 50% and 38% of APL and non-APL AML patients, respectively. In APL patients, obesity was associated with worse DFS (HR 1.53, 95% CI 1.03-2.27; P = 0.04) and OS (HR 1.72, 95% CI 1.15-2.58; P = 0.01) after adjusting for age, sex, performance status, race, ethnicity, treatment arm and baseline white blood cell count. Obesity was not significantly associated with DFS or OS in the non-APL AML patients. In conclusion, our study indicates that obesity has significant prognostic value for DFS and OS in APL patients, but not for non-APL AML patients.

Research misconduct and data fraud in clinical trials: prevalence and causal factors.

The disclosure of cases of research misconduct in clinical trials, conventionally defined as fabrication, falsification or plagiarism, has been a disturbingly common phenomenon in recent years. Such cases can potentially harm patients enrolled on the trials in question or patients treated based on the results of those trials and can seriously undermine the scientific and public trust in the validity of clinical trial results. Here, I review what is known about the prevalence of research misconduct in general and the contributing or causal factors leading to the misconduct. The evidence on prevalence is unreliable and fraught with definitional problems and with study design issues. Nevertheless, the evidence taken as a whole seems to suggest that cases of the most serious types of misconduct, fabrication and falsification (i.e., data fraud), are relatively rare but that other types of questionable research practices are quite common. There have been many individual, institutional and scientific factors proposed for misconduct but, as is the case with estimates of prevalence, reliable empirical evidence on the strength and relative importance of these factors is lacking. However, it seems clear that the view of misconduct as being simply the result of aberrant or self-delusional personalities likely underestimates the effect of other important factors and inhibits the development of effective prevention strategies.

Time-dependent classification accuracy curve under marker-dependent sampling.

Evaluating the classification accuracy of a candidate biomarker signaling the onset of disease or disease status is essential for medical decision making. A good biomarker would accurately identify the patients who are likely to progress or die at a particular time in the future or who are in urgent need for active treatments. To assess the performance of a candidate biomarker, the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) are commonly used. In many cases, the standard simple random sampling (SRS) design used for biomarker validation studies is costly and inefficient. In order to improve the efficiency and reduce the cost of biomarker validation, marker-dependent sampling (MDS) may be used. In a MDS design, the selection of patients to assess true survival time is dependent on the result of a biomarker assay. In this article, we introduce a nonparametric estimator for time-dependent AUC under a MDS design. The consistency and the asymptotic normality of the proposed estimator is established. Simulation shows the unbiasedness of the proposed estimator and a significant efficiency gain of the MDS design over the SRS design.

Electronic effects on the substitution reactions of benzhydrols and fluorenyl alcohols. Determination of mechanism and effects of antiaromaticity.

A range of substituted benzhydrols and fluorenols were prepared and subjected to acid catalysed methanolysis. Analysis of the rates of each of these processes showed correlation with Hammett σ(+) parameters as is consistent with the significant build-up of positive charge adjacent to the ring. In combination with the similarity of the electronic susceptibility of the processes, these data suggest that both reactions proceed through a unimolecular rate-determining step. This shows that the effect of fusion of the phenyl systems (and hence potentially introducing an antiaromatic carbocation intermediate) is only to slow the rate of reaction rather than change the mechanism of the process.

Putting corannulene in its place. Reactivity studies comparing corannulene with other aromatic hydrocarbons.

A series of aromatic hydrocarbons were investigated so as to compare the reactivity of corannulene with planar aromatic hydrocarbons. Corannulene was found to be more reactive than benzene, naphthalene and triphenylene to Friedel-Crafts acylation whilst electrophilic aromatic bromination was also used to confirm that triphenylene was less reactive than corannulene and that pyrene, perylene and acenaphthene were more so. The stabilisation of a neighbouring carbocation by the various aromatic systems was investigated through consideration of the rates of methanolysis of a series of benzylic alcohols. The reactivity series was found to parallel that observed for the electrophilic aromatic substitutions and both series are supported by computational studies. As such, a reactivity scale was devised that showed that corannulene was less reactive than would be expected for an aromatic planar species of similar pi electron count.

Recombinant interleukin-2 in patients aged younger than 60 years with acute myeloid leukemia in first complete remission: results from Cancer and Leukemia Group B 19808.

BACKGROUND: Recombinant interleukin-2 (rIL-2) induces cellular cytotoxicity against leukemia blasts. Patients with acute myeloid leukemia (AML) in first complete remission (CR) may harbor minimal residual disease that is susceptible to rIL-2-activated effector cells. METHODS: In the Cancer and Leukemia Group B (CALGB) 19808 study, patients with AML in first CR were randomly assigned after all planned chemotherapy to receive a 90-day course of subcutaneously administered rIL-2 or no further therapy. The primary objective was to compare disease-free survival (DFS) between the 2 treatment arms. A total of 534 patients achieved a CR, 214 of whom were randomized. Six courses of low-dose daily rIL-2 were given for the expansion of cytotoxic effector cells, each followed by 3-day high-dose boluses given to trigger cytotoxicity against minimal residual disease. RESULTS: On the protocol-specified intention-to-treat analysis, the hazards ratio for DFS was 0.75 (95% confidence interval, 0.52-1.09; P = .13); the 5-year DFS rate was 42% in the observation arm and 53% in the rIL-2 treatment arm. The hazards ratio for overall survival (OS) was 0.88 (95% confidence interval, 0.54-1.23; P = .34); the 5-year OS rate was 58% for the observation arm and 63% for the rIL-2 treatment arm. Twenty-five of the 107 patients randomized to treatment with rIL-2 either refused or were unable to initiate therapy and 30 patients did not complete their assigned therapy. However, significant toxicities were not commonly observed. The trial design did not anticipate the difficulties patients would encounter with protocol compliance. CONCLUSIONS: The efficacy of immunotherapy with rIL-2 administered after intensive postremission treatment was not assessed as planned because of unexpected refusals by patients and/or their physicians to comply with protocol-directed therapy. Neither DFS nor OS was found to be significantly improved.