Why (not) go east? Comparison of findings from FDA Investigational New Drug study site inspections performed in Central and Eastern Europe with results from the USA, Western Europe, and other parts of the world

Since the mid-1990s, investigational sites in the countries of Central and Eastern Europe (CEE) have been increasingly utilized by pharmaceutical companies because of their high productivity in terms of patient enrolment into clinical trials. Based on the FDA’s publicly accessible Clinical Investigator Inspection List, we present an analysis of findings and outcome classifications from FDA inspections during Investigational New Drug (IND) studies and compare the results for the CEE region to those from Western European countries and the USA. Data from all 5531 FDA clinical trials inspections that occurred between 1994 (when the FDA first performed inspections in CEE) and the end of 2010 were entered into the database for comparative analysis. Of these, 4865 routine data audit (DA) inspections were analyzed: 401 from clinical trials performed in Western Europe, 230 in CEE, 3858 in the USA, and 376 in other countries. The average number of deficiencies per inspection ranged between 0.99 for CEE and 1.97 in Western Europe. No deficiencies were noted during 16.6%, 39.0%, and 21.5% of the inspections in Western Europe, CEE and USA, respectively. The percentages of inspections after which no follow-up action was indicated were 36.9% for Western Europe, 55.7% for CEE, and 44.3% for US sites. CEE was also the region with the lowest percentage of inspections that required official or voluntary action. On the basis of FDA inspection data, the high productivity of CEE sites appears to be accompanied by regulatory compliance as well as by data quality standards that are not inferior to those in Western regions

Nonparametric relevance-shifted multiple testing procedures for the analysis of high-dimensional multivariate data with small sample sizes

<p>Abstract</p> <p>Background</p> <p>In many research areas it is necessary to find differences between treatment groups with several variables. For example, studies of microarray data seek to find a significant difference in location parameters from zero or one for ratios thereof for each variable. However, in some studies a significant deviation of the difference in locations from zero (or 1 in terms of the ratio) is biologically meaningless. A relevant difference or ratio is sought in such cases.</p> <p>Results</p> <p>This article addresses the use of relevance-shifted tests on ratios for a multivariate parallel two-sample group design. Two empirical procedures are proposed which embed the relevance-shifted test on ratios. As both procedures test a hypothesis for each variable, the resulting multiple testing problem has to be considered. Hence, the procedures include a multiplicity correction. Both procedures are extensions of available procedures for point null hypotheses achieving exact control of the familywise error rate. Whereas the shift of the null hypothesis alone would give straight-forward solutions, the problems that are the reason for the empirical considerations discussed here arise by the fact that the shift is considered in both directions and the whole parameter space in between these two limits has to be accepted as null hypothesis.</p> <p>Conclusion</p> <p>The first algorithm to be discussed uses a permutation algorithm, and is appropriate for designs with a moderately large number of observations. However, many experiments have limited sample sizes. Then the second procedure might be more appropriate, where multiplicity is corrected according to a concept of data-driven order of hypotheses.</p

Induction treatment in high-grade B-cell lymphoma with a concurrent MYC and BCL2 and/or BCL6 rearrangement: a systematic review and meta-analysis

Background and aimHigh-grade B cell lymphomas with concomitant MYC and BCL2 and/or BCL6 rearrangements (HGBCL-DH/TH) have a poor prognosis when treated with the standard R-CHOP-like chemoimmunotherapy protocol. Whether this can be improved using intensified regimens is still under debate. However, due to the rarity of HGBCL-DH/TH there are no prospective, randomized controlled trials (RCT) available. Thus, with this systematic review and meta-analysis we attempted to compare survival in HGBCL-DH/TH patients receiving intensified vs. R-CHOP(-like) regimens.MethodsThe PubMed and Web of Science databases were searched for original studies reporting on first-line treatment in HGBCL-DH/TH patients from 08/2014 until 04/2022. Studies with only localized stage disease, ≤10 patients, single-arm, non-full peer-reviewed publications, and preclinical studies were excluded. The quality of literature and the risk of bias was assessed using the Methodological Index for Non-Randomized Studies (MINORS) and National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Random-effect models were used to compare R-CHOP-(like) and intensified regimens regarding 2-year overall survival (2y-OS) and 2-year progression-free survival (2y-PFS).ResultsAltogether, 11 retrospective studies, but no RCT, with 891 patients were included. Only four studies were of good quality based on aforementioned criteria. Intensified treatment could improve 2y-OS (hazard ratio [HR]=0.78 [95% confidence interval [CI] 0.63-0.96]; p=0.02) as well as 2y-PFS (HR=0.66 [95% CI 0.44-0.99]; p=0.045).ConclusionsThis meta-analysis indicates that intensified regimens could possibly improve 2y-OS and 2y-PFS in HGBCL-DH/TH patients. However, the significance of these results is mainly limited by data quality, data robustness, and its retrospective nature. There is still a need for innovative controlled clinical trials in this difficult to treat patient population.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42022313234

Quantitative normal values of helical flow, flow jets and wall shear stress of healthy volunteers in the ascending aorta.

OBJECTIVES 4D flow MRI enables quantitative assessment of helical flow. We sought to generate normal values and elucidate changes of helical flow (duration, volume, length, velocities and rotational direction) and flow jet (displacement, flow angle) as well as wall shear stress (WSS). METHODS We assessed the temporal helical existence (THEX), maximum helical volume (HVmax), accumulated helical volume (HVacc), accumulated helical volume length (HVLacc), maximum forward velocity (maxVfor), maximum circumferential velocity (maxVcirc), rotational direction (RD) and maximum wall shear stress (WSS) as reported elsewhere using the software tool Bloodline in 86 healthy volunteers (46 females, mean age 41 ± 13 years). RESULTS WSS decreased by 42.1% and maxVfor by 55.7% across age. There was no link between age and gender regarding the other parameters. CONCLUSION This study provides age-dependent normal values regarding WSS and maxVfor and age- and gender-independent normal values regarding THEX, HVmax, HVacc, HVLacc, RD and maxVcirc. KEY POINTS • 4D flow provides numerous new parameters; therefore, normal values are mandatory. • Wall shear stress decreases over age. • Maximum helical forward velocity decreases over age

Molecular profiling of pediatric meningiomas shows tumor characteristics distinct from adult meningiomas

In contrast to adults, meningiomas are uncommon tumors in childhood and adolescence. Whether adult and pediatric meningiomas differ on a molecular level is unclear. Here we report detailed genomic analyses of 37 pediatric meningiomas by sequencing and DNA methylation profiling. Histologically, the series was dominated by meningioma subtypes with aggressive behavior, with 70% of patients suffering from WHO grade II or III meningiomas. The most frequent cytogenetic aberrations were loss of chromosomes 22 (23/37 [62%]), 1 (9/37 [24%]), 18 (7/37 [19%]), and 14 (5/37 [14%]). Tumors with NF2 alterations exhibited overall increased chromosomal instability. Unsupervised clustering of DNA methylation profiles revealed separation into three groups: designated group 1 composed of clear cell and papillary meningiomas, whereas group 2A comprised predominantly atypical meningiomas and group 2B enriched for rare high-grade subtypes (rhabdoid, chordoid). Meningiomas from NF2 patients clustered exclusively within groups 1 and 2A. When compared with a dataset of 105 adult meningiomas, the pediatric meningiomas largely grouped separately. Targeted panel DNA sequencing of 34 tumors revealed frequent NF2 alterations, while other typical alterations found in adult non-NF2 tumors were absent. These data demonstrate that pediatric meningiomas are characterized by molecular features distinct from adult tumors

In vivo assessment of catheter positioning accuracy and prolonged irradiation time on liver tolerance dose after single-fraction 192Ir high-dose-rate brachytherapy

<p>Abstract</p> <p>Background</p> <p>To assess brachytherapy catheter positioning accuracy and to evaluate the effects of prolonged irradiation time on the tolerance dose of normal liver parenchyma following single-fraction irradiation with ¹⁹²Ir.</p> <p>Materials and methods</p> <p>Fifty patients with 76 malignant liver tumors treated by computed tomography (CT)-guided high-dose-rate brachytherapy (HDR-BT) were included in the study. The prescribed radiation dose was delivered by 1 - 11 catheters with exposure times in the range of 844 - 4432 seconds. Magnetic resonance imaging (MRI) datasets for assessing irradiation effects on normal liver tissue, edema, and hepatocyte dysfunction, obtained 6 and 12 weeks after HDR-BT, were merged with 3D dosimetry data. The isodose of the treatment plan covering the same volume as the irradiation effect was taken as a surrogate for the liver tissue tolerance dose. Catheter positioning accuracy was assessed by calculating the shift between the 3D center coordinates of the irradiation effect volume and the tolerance dose volume for 38 irradiation effects in 30 patients induced by catheters implanted in nearly parallel arrangement. Effects of prolonged irradiation were assessed in areas where the irradiation effect volume and tolerance dose volume did not overlap (mismatch areas) by using a catheter contribution index. This index was calculated for 48 irradiation effects induced by at least two catheters in 44 patients.</p> <p>Results</p> <p>Positioning accuracy of the brachytherapy catheters was 5-6 mm. The orthogonal and axial shifts between the center coordinates of the irradiation effect volume and the tolerance dose volume in relation to the direction vector of catheter implantation were highly correlated and in first approximation identically in the T1-w and T2-w MRI sequences (<it>p </it>= 0.003 and <it>p </it>< 0.001, respectively), as were the shifts between 6 and 12 weeks examinations (<it>p </it>= 0.001 and <it>p </it>= 0.004, respectively). There was a significant shift of the irradiation effect towards the catheter entry site compared with the planned dose distribution (<it>p </it>< 0.005). Prolonged treatment time increases the normal tissue tolerance dose. Here, the catheter contribution indices indicated a lower tolerance dose of the liver parenchyma in areas with prolonged irradiation (<it>p </it>< 0.005).</p> <p>Conclusions</p> <p>Positioning accuracy of brachytherapy catheters is sufficient for clinical practice. Reduced tolerance dose in areas exposed to prolonged irradiation is contradictory to results published in the current literature. Effects of prolonged dose administration on the liver tolerance dose for treatment times of up to 60 minutes per HDR-BT session are not pronounced compared to effects of positioning accuracy of the brachytherapy catheters and are therefore of minor importance in treatment planning.</p

Kidney Pathology Precedes and Predicts the Pathological Cascade of Cerebrovascular Lesions in Stroke Prone Rats

INTRODUCTION: Human cerebral small vessel disease (CSVD) has been hypothesized to be an age-dependent disease accompanied by similar vascular changes in other organs. SHRSP feature numerous vascular risk factors and may be a valid model of some aspects of human CSVD. Here we compare renal histopathological changes with the brain pathology of spontaneously hypertensive stroke-prone rats (SHRSP). MATERIAL AND METHODS: We histologically investigated the brains and kidneys of 61 SHRSP at different stages of age (12 to 44 weeks). The brain pathology (aggregated erythrocytes in capillaries and arterioles, microbleeds, microthromboses) and the kidney pathology (aggregated erythrocytes within peritubular capillaries, tubular protein cylinders, glomerulosclerosis) were quantified separately. The prediction of the brain pathology by the kidney pathology was assessed by creating ROC-curves integrating the degree of kidney pathology and age of SHRSP. RESULTS: Both, brain and kidney pathology, show an age-dependency and proceed in definite stages whereas an aggregation of erythrocytes in capillaries and arterioles, we parsimoniously interpreted as stases, represent the initial finding in both organs. Thus, early renal tubulointerstitial damage characterized by rather few intravasal erythrocyte aggregations and tubular protein cylinders predicts the initial step of SHRSPs' cerebral vascular pathology marked by accumulated erythrocytes. The combined increase of intravasal erythrocyte aggregations and protein cylinders accompanied by glomerulosclerosis and thrombotic renal microangiopathy in kidneys of older SHRSP predicts the final stages of SHRSPs' cerebrovascular lesions marked by microbleeds and thrombotic infarcts. CONCLUSION: Our results illustrate a close association between structural brain and kidney pathology and support the concept of small vessel disease to be an age-dependent systemic pathology. Further, an improved joined nephrologic and neurologic diagnostic may help to identify patients with CSVD at an early stage

Multitrophic Interaction in the Rhizosphere of Maize: Root Feeding of Western Corn Rootworm Larvae Alters the Microbial Community Composition

BACKGROUND: Larvae of the Western Corn Rootworm (WCR) feeding on maize roots cause heavy economical losses in the US and in Europe. New or adapted pest management strategies urgently require a better understanding of the multitrophic interaction in the rhizosphere. This study aimed to investigate the effect of WCR root feeding on the microbial communities colonizing the maize rhizosphere. METHODOLOGY/PRINCIPAL FINDINGS: In a greenhouse experiment, maize lines KWS13, KWS14, KWS15 and MON88017 were grown in three different soil types in presence and in absence of WCR larvae. Bacterial and fungal community structures were analyzed by denaturing gradient gel electrophoresis (DGGE) of the 16S rRNA gene and ITS fragments, PCR amplified from the total rhizosphere community DNA. DGGE bands with increased intensity were excised from the gel, cloned and sequenced in order to identify specific bacteria responding to WCR larval feeding. DGGE fingerprints showed that the soil type and the maize line influenced the fungal and bacterial communities inhabiting the maize rhizosphere. WCR larval feeding affected the rhiyosphere microbial populations in a soil type and maize line dependent manner. DGGE band sequencing revealed an increased abundance of Acinetobacter calcoaceticus in the rhizosphere of several maize lines in all soil types upon WCR larval feeding. CONCLUSION/SIGNIFICANCE: The effects of both rhizosphere and WCR larval feeding seemed to be stronger on bacterial communities than on fungi. Bacterial and fungal community shifts in response to larval feeding were most likely due to changes of root exudation patterns. The increased abundance of A. calcoaceticus suggested that phenolic compounds were released upon WCR wounding