A longitudinal study of free leptin index in pre-eclamptic pregnancies.

The ratio between circulating levels of leptin and soluble leptin receptor (sOB-R), the free leptin index (FLI), is used as a marker of leptin resistance. Therefore, the aim of our study was to investigate the FLI in mild pre-eclamptic pregnancies in a nested case-control study within a prospective observational study. Circulating levels of leptin and sOB-R levels rise significantly during pregnancy in healthy (p < 0.05) (n = 46) and pre-eclamptic pregnancies (p < 0.05) (n = 20). Serum levels of leptin were significantly higher in pre-eclamptic compared to healthy pregnancies at second and third trimesters of pregnancy (p < 0.05). Additionally, serum levels of sOB-R were significantly lower in pre-eclamptic pregnancies during the second and third trimesters of pregnancy compared to healthy pregnancies (p < 0.05). Moreover, we found that FLI did not vary significantly during pregnancy in healthy women (p > 0.05), while it increases in pre-eclamptic pregnancies (p < 0.05). Indeed, FLI was significantly higher at second and third trimesters of pregnancy in pre-eclamptic compared to healthy pregnancies (p < 0.05). In addition, FLI was significantly higher in the luteal phase compared with the follicular phase of the menstrual cycle in eumenorrheic women (p < 0.05). Receiver operating characteristic (ROC) curve analysis revealed the ability of leptin (AUC = 0.72) and FLI (AUC = 0.67) as a reliable predictor for mild pre-eclampsia during the second trimester of pregnancy. In conclusion, our findings show that FLI were significantly increased in mild pre-eclamptic pregnancies and allowed us to hypothesize that this rise might alter leptin bioavailability and bioactivity which might lead to the sympathetic hyperactivity and the hypertensive disorders during pregnancy.

Tractography passes the test: Results from the diffusion-simulated connectivity (disco) challenge.

Estimating structural connectivity from diffusion-weighted magnetic resonance imaging is a challenging task, partly due to the presence of false-positive connections and the misestimation of connection weights. Building on previous efforts, the MICCAI-CDMRI Diffusion-Simulated Connectivity (DiSCo) challenge was carried out to evaluate state-of-the-art connectivity methods using novel large-scale numerical phantoms. The diffusion signal for the phantoms was obtained from Monte Carlo simulations. The results of the challenge suggest that methods selected by the 14 teams participating in the challenge can provide high correlations between estimated and ground-truth connectivity weights, in complex numerical environments. Additionally, the methods used by the participating teams were able to accurately identify the binary connectivity of the numerical dataset. However, specific false positive and false negative connections were consistently estimated across all methods. Although the challenge dataset doesn't capture the complexity of a real brain, it provided unique data with known macrostructure and microstructure ground-truth properties to facilitate the development of connectivity estimation methods.

Incorporating outlier information into diffusion-weighted MRI modeling for robust microstructural imaging and structural brain connectivity analyses.

The white matter structures of the human brain can be represented using diffusion-weighted MRI tractography. Unfortunately, tractography is prone to find false-positive streamlines causing a severe decline in its specificity and limiting its feasibility in accurate structural brain connectivity analyses. Filtering algorithms have been proposed to reduce the number of invalid streamlines but the currently available filtering algorithms are not suitable to process data that contains motion artefacts which are typical in clinical research. We augmented the Convex Optimization Modelling for Microstructure Informed Tractography (COMMIT) algorithm to adjust for these signals drop-out motion artefacts. We demonstrate with comprehensive Monte-Carlo whole brain simulations and in vivo infant data that our robust algorithm is capable of properly filtering tractography reconstructions despite these artefacts. We evaluated the results using parametric and non-parametric statistics and our results demonstrate that if not accounted for, motion artefacts can have severe adverse effects in human brain structural connectivity analyses as well as in microstructural property mappings. In conclusion, the usage of robust filtering methods to mitigate motion related errors in tractogram filtering is highly beneficial, especially in clinical studies with uncooperative patient groups such as infants. With our presented robust augmentation and open-source implementation, robust tractogram filtering is readily available.

Tractostorm 2: Optimizing tractography dissection reproducibility with segmentation protocol dissemination.

The segmentation of brain structures is a key component of many neuroimaging studies. Consistent anatomical definitions are crucial to ensure consensus on the position and shape of brain structures, but segmentations are prone to variation in their interpretation and execution. White-matter (WM) pathways are global structures of the brain defined by local landmarks, which leads to anatomical definitions being difficult to convey, learn, or teach. Moreover, the complex shape of WM pathways and their representation using tractography (streamlines) make the design and evaluation of dissection protocols difficult and time-consuming. The first iteration of Tractostorm quantified the variability of a pyramidal tract dissection protocol and compared results between experts in neuroanatomy and nonexperts. Despite virtual dissection being used for decades, in-depth investigations of how learning or practicing such protocols impact dissection results are nonexistent. To begin to fill the gap, we evaluate an online educational tractography course and investigate the impact learning and practicing a dissection protocol has on interrater (groupwise) reproducibility. To generate the required data to quantify reproducibility across raters and time, 20 independent raters performed dissections of three bundles of interest on five Human Connectome Project subjects, each with four timepoints. Our investigation shows that the dissection protocol in conjunction with an online course achieves a high level of reproducibility (between 0.85 and 0.90 for the voxel-based Dice score) for the three bundles of interest and remains stable over time (repetition of the protocol). Suggesting that once raters are familiar with the software and tasks at hand, their interpretation and execution at the group level do not drastically vary. When compared to previous work that used a different method of communication for the protocol, our results show that incorporating a virtual educational session increased reproducibility. Insights from this work may be used to improve the future design of WM pathway dissection protocols and to further inform neuroanatomical definitions.

Tractography dissection variability: What happens when 42 groups dissect 14 white matter bundles on the same dataset?

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.

Efficacy and safety of tivozanib in recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer, an NCCN phase II trial.

OBJECTIVE: Tivozanib is a potent selective pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor with a long half-life. This study assessed its activity in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer (OC). METHODS: This open-label phase II study used a Simon's two-stage design. Eligible patients had recurrent, platinum-resistant OC and measurable or detectable disease. There was no limit on the number of prior regimens. Treatment consisted of tivozanib 1.5 mg orally once daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity assessment. RESULTS: Thirty-one patients were enrolled, and 30 were treated. The median age was 59.5 years, and median number of prior regimens was 4 (range 1-9). Twenty-four patients were evaluable for response, and four (16.7%) achieved a partial response (PR; ORR = 16.7%). An additional fourteen (58.3%) patients had stable disease (SD). The clinical benefit rate (PR + SD) was 75.0%, and the median duration of objective response was 5.7 months. For all patients on trial, the median PFS was 4.1 months (95% confidence interval (CI): 1.7-5.8) and OS 8.6 months (95% CI: 5.4-12.5). There were no treatment-related deaths. Serious adverse events occurred in 13.3% of patients and included small intestinal perforation or obstruction and stroke. Grade 3-4 adverse events occurred in 60% of patients, including hypertension (26.7%) and fatigue (10%). CONCLUSIONS: Tivozanib is effective in patients with recurrent OC, with moderate toxicity and no treatment-related deaths, supporting its further development.

Limits to anatomical accuracy of diffusion tractography using modern approaches.

Diffusion MRI fiber tractography is widely used to probe the structural connectivity of the brain, with a range of applications in both clinical and basic neuroscience. Despite widespread use, tractography has well-known pitfalls that limits the anatomical accuracy of this technique. Numerous modern methods have been developed to address these shortcomings through advances in acquisition, modeling, and computation. To test whether these advances improve tractography accuracy, we organized the 3-D Validation of Tractography with Experimental MRI (3D-VoTEM) challenge at the ISBI 2018 conference. We made available three unique independent tractography validation datasets - a physical phantom and two ex vivo brain specimens - resulting in 176 distinct submissions from 9 research groups. By comparing results over a wide range of fiber complexities and algorithmic strategies, this challenge provides a more comprehensive assessment of tractography's inherent limitations than has been reported previously. The central results were consistent across all sub-challenges in that, despite advances in tractography methods, the anatomical accuracy of tractography has not dramatically improved in recent years. Taken together, our results independently confirm findings from decades of tractography validation studies, demonstrate inherent limitations in reconstructing white matter pathways using diffusion MRI data alone, and highlight the need for alternative or combinatorial strategies to accurately map the fiber pathways of the brain.

Efficacy and safety of niraparib as maintenance treatment in older patients (≥ 70 years) with recurrent ovarian cancer: Results from the ENGOT-OV16/NOVA trial.

OBJECTIVE: To analyze the safety and efficacy of niraparib in patients aged ≥70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial. METHODS: The trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors. RESULTS: Patients aged ≥70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged ≥70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients ≥70 years and 17.2 months in patients <70 years. Frequency, severity of AEs, and dose reductions in the niraparib arm were similar in patients aged <70 and ≥ 70 years population. The most common grade ≥ 3 AEs in patients ≥70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%). CONCLUSIONS: For patients ≥70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population.

FDA Approval of PARP Inhibitors and the Impact on Genetic Counseling and Genetic Testing Practices.

In December 2014, the FDA approved olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) for ovarian cancer patients who have failed three or more lines of chemotherapy and have a germline BRCA1/2 mutation identified through a companion diagnostic test (BRACAnalysis CDx™ (CDx™)) offered exclusively by Myriad Genetic Laboratories. This study explored the impact of PARPi/CDx™ on genetic counselors' (GCs) counseling and testing practices. One hundred twenty three GCs responded to an online survey regarding pre- and post-FDA approval referral patterns, testing strategies/influences, and anecdotal experiences with insurance coverage of PARPi for BRCA1/2 positive patients through a non-CDx™ platform. Following PARPi approval, 40% of respondents reported an increase in overall referrals of ovarian cancer patients and 20% had an increase in post-test counseling only referrals. The majority (61.9%) of respondents reported no change in genetic testing strategy, and there was no change in factors influencing choice of testing laboratory. Nearly all (98.1%) respondents who had experience with insurance covering PARPi indicated approval with mutations identified via non-CDx™ testing. Respondents indicated an increase in referral volume following FDA approval of PARPi/CDx™, but did not report changes in testing practices. Respondents were not aware of PARPi insurance coverage denial in the absence of CDx™.

Ovarian Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Ovarian Cancer focuses on the less common ovarian histopathologies (LCOHs), because new algorithms were added for LCOHs and current algorithms were revised for the 2016 update. The new LCOHs algorithms include clear cell carcinomas, mucinous carcinomas, and grade 1 (low-grade) serous carcinomas/endometrioid epithelial carcinomas. The LCOHs also include carcinosarcomas (malignant mixed Müllerian tumors of the ovary), borderline epithelial tumors (also known as low malignant potential tumors), malignant sex cord-stromal tumors, and malignant germ cell tumors.

A Novel Postbiotic Product Based on Weissella cibaria for Enhancing Disease Resistance in Rainbow Trout: Aquaculture Application.

Postbiotics are innovative tools in animal husbandry, providing eco-friendly solutions for disease management within the industry. In this study, a new postbiotic product was evaluated for its impact on the health of rainbow trout (Oncorhynchus mykiss). In vivo studies were conducted to assess the safety of the Weissella cibaria strains used in postbiotic production. Additionally, this study evaluated the impact of diet supplementation with 0.50% postbiotics on growth performance during a 30-day feeding trial; the gut microbial communities, immunomodulation, and protection against Yersinia ruckeri infection were evaluated. The strains did not harm the animals during the 20-day observation period. Furthermore, the effect of postbiotics on growth performance was not significant (p < 0.05). The treated group showed a significant increase in acid-lactic bacteria on the 30th day of the feeding trial, with counts of 3.42 ± 0.21 log CFU/mL. Additionally, there was an up-regulation of the pro-inflammatory cytokine IL-1ß in head kidney samples after 48 h of feed supplementation, whereas cytokines IL-10, IL-8, INF-γ, and TNF-α were down-regulated. The findings indicate that rainbow trout fed with postbiotics saw an improvement in their survival rate against Y. ruckeri, with a 20.66% survival improvement in the treated group. This study proves that incorporating postbiotics from two strains of W. cibaria previously isolated from rainbow trout into the diet of fish has immunomodulatory effects, enhances intestinal microbial composition, and improves fish resistance against Y. ruckeri.

A novel imaging marker of cortical "cellularity" in multiple sclerosis patients.

Pathological data showed focal inflammation and regions of diffuse neuronal loss in the cortex of people with multiple sclerosis (MS). In this work, we applied a novel model ("soma and neurite density imaging (SANDI)") to multishell diffusion-weighted MRI data acquired in healthy subjects and people with multiple sclerosis (pwMS), in order to investigate inflammation and degeneration-related changes in the cortical tissue of pwMS. We aimed to (i) establish whether SANDI is applicable in vivo clinical data; (ii) investigate inflammatory and degenerative changes using SANDI soma fraction (fsoma)-a marker of cellularity-in both cortical lesions and in the normal-appearing-cortex and (iii) correlate SANDI fsoma with clinical and biological measures in pwMS. We applied a simplified version of SANDI to a clinical scanners. We then provided evidence that pwMS exhibited an overall decrease in cortical SANDI fsoma compared to healthy subjects, suggesting global degenerative processes compatible with neuronal loss. On the other hand, we have found that progressive pwMS showed a higher SANDI fsoma in the outer part of the cortex compared to relapsing-remitting pwMS, possibly supporting current pathological knowledge of increased innate inflammatory cells in these regions. A similar finding was obtained in subpial lesions in relapsing-remitting patients, reflecting existing pathological data in these lesion types. A significant correlation was found between SANDI fsoma and serum neurofilament light chain-a biomarker of inflammatory axonal damage-suggesting a relationship between SANDI soma fraction and inflammatory processes in pwMS again. Overall, our data show that SANDI fsoma is a promising biomarker to monitor changes in cellularity compatible with neurodegeneration and neuroinflammation in the cortex of MS patients.

Mechanism of imidazole inhibition of a GH1 ß-glucosidase.

Imidazole is largely employed in recombinant protein purification, including GH1 ß-glucosidases, but its effect on the enzyme activity is rarely taken into consideration. Computational docking suggested that imidazole interacts with residues forming the active site of the GH1 ß-glucosidase from Spodoptera frugiperda (Sfßgly). We confirmed this interaction by showing that imidazole reduces the activity of Sfßgly, which does not result from enzyme covalent modification or promotion of transglycosylation reactions. Instead, this inhibition occurs through a partial competitive mechanism. Imidazole binds to the Sfßgly active site, reducing the substrate affinity by about threefold, whereas the rate constant of product formation remains unchanged. The binding of imidazole within the active site was further confirmed by enzyme kinetic experiments in which imidazole and cellobiose competed to inhibit the hydrolysis of p-nitrophenyl ß-glucoside. Finally, imidazole interaction in the active site was also demonstrated by showing that it hinders access of carbodiimide to the Sfßgly catalytic residues, protecting them from chemical inactivation. In conclusion, imidazole binds in the Sfßgly active site, generating a partial competitive inhibition. Considering that GH1 ß-glucosidases share conserved active sites, this inhibition phenomenon is probably widespread among these enzymes, and this should be taken into account when considering the characterization of their recombinant forms.

In Vitro Evaluation of Postbiotics Produced from Bacterial Isolates Obtained from Rainbow Trout and Nile Tilapia against the Pathogens Yersinia ruckeri and Aeromonas salmonicida subsp. salmonicida.

The use of antibiotics in aquaculture leads to the proliferation of multidrug-resistant bacteria, and an urgent need for developing new alternatives to prevent and control disease has, thus, arisen. In this scenario, postbiotics represent a promising tool to achieve this purpose; thus, in this study, isolation and selection of bacteria to further produce and evaluate their postbiotics antibacterial activity against fish pathogens was executed. In this respect, bacterial isolates from rainbow trout and Nile tilapia were obtained and tested in vitro against Yersinia ruckeri and Aeromonas salmonicida subsp. salmonicida. From 369 obtained isolates, 69 were selected after initial evaluation. Afterwards, additional screening was carried out by spot-on-lawn assay to finally select twelve isolates; four were identified as Pediococcus acidilactici, seven as Weissella cibaria, and one as Weissella paramesenteroides by matrix assisted laser desorption/ionization, time-of-flight mass spectrometry (MALDI-TOF MS). Selected bacteria were used to obtain postbiotic products to test their antagonistic activity through coculture challenge and broth microdilution assays. The influence of incubation time prior to postbiotic production on antagonistic behavior was also recorded. Two isolates identified as W. cibaria were able to significantly reduce (p < 0.05) A. salmonicida subsp. salmonicida's growth in the coculture challenge up to 4.49 ± 0.05 Log CFU/mL, and even though the reduction in Y. ruckeri was not as effective, some inhibition on the pathogen's growth was reported; at the same time, most of the postbiotic products obtained showed more antibacterial activity when obtained from broth cultures incubated for 72 h. Based on the results obtained, the preliminary identification of the isolates that expressed the highest inhibitory activity was confirmed by partial sequencing as W. cibaria. Through our study, it can be concluded that postbiotics produced by these strains are useful to inhibit the growth of the pathogens and could, thereby, be applicable in further research to develop suitable tools as feed additives for disease control and prevention in aquaculture.

Personalized maps of T1 relaxometry abnormalities provide correlates of disability in multiple sclerosis patients.

OBJECTIVES AND AIMS: Quantitative MRI (qMRI) has greatly improved the sensitivity and specificity of microstructural brain pathology in multiple sclerosis (MS) when compared to conventional MRI (cMRI). More than cMRI, qMRI also provides means to assess pathology within the normal-appearing and lesion tissue. In this work, we further developed a method providing personalized quantitative T1 (qT1) abnormality maps in individual MS patients by modeling the age dependence of qT1 alterations. In addition, we assessed the relationship between qT1 abnormality maps and patients' disability, in order to evaluate the potential value of this measurement in clinical practice. METHODS: We included 119 MS patients (64 relapsing-remitting MS (RRMS), 34 secondary progressive MS (SPMS), 21 primary progressive MS (PPMS)), and 98 Healthy Controls (HC). All individuals underwent 3T MRI examinations, including Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) for qT1 maps and High-Resolution 3D Fluid Attenuated Inversion Recovery (FLAIR) imaging. To calculate personalized qT1 abnormality maps, we compared qT1 in each brain voxel in MS patients to the average qT1 obtained in the same tissue (grey/white matter) and region of interest (ROI) in healthy controls, hereby providing individual voxel-based Z-score maps. The age dependence of qT1 in HC was modeled using linear polynomial regression. We computed the average qT1 Z-scores in white matter lesions (WMLs), normal-appearing white matter (NAWM), cortical grey matter lesions (GMcLs) and normal-appearing cortical grey matter (NAcGM). Lastly, a multiple linear regression (MLR) model with the backward selection including age, sex, disease duration, phenotype, lesion number, lesion volume and average Z-score (NAWM/NAcGM/WMLs/GMcLs) was used to assess the relationship between qT1 measures and clinical disability (evaluated with EDSS). RESULTS: The average qT1 Z-score was higher in WMLs than in NAWM. (WMLs: 1.366 ± 0.409, NAWM: -0.133 ± 0.288, [mean ± SD], p < 0.001). The average Z-score in NAWM in RRMS patients was significantly lower than in PPMS patients (p = 0.010). The MLR model showed a strong association between average qT1 Z-scores in white matter lesions (WMLs) and EDSS (R2 = 0.549, ß = 0.178, 97.5 % CI = 0.030 to 0.326, p = 0.019). Specifically, we measured a 26.9 % increase in EDSS per unit of qT1 Z-score in WMLs in RRMS patients (R2 = 0.099, ß = 0.269, 97.5 % CI = 0.078 to 0.461, p = 0.007). CONCLUSIONS: We showed that personalized qT1 abnormality maps in MS patients provide measures related to clinical disability, supporting the use of those maps in clinical practice.

CYP2D6 and CYP2C19 Genes Associated with Tricontinental and Latin American Ancestry of Pe-ruvians.

Precision medicine seeks to individualize the dose from the beginning of phar-macological therapy based on the characteristics of each patient, genes involved in the metabolic phenotype, ethnicity or miscegenation, with the purpose to minimize adverse effects and optimize drug efficacy. The objective was to re-view studies that describe the association of the CYP2D6 and CYP2C19 genes with the tricontinental and Latin American ancestry of Peruvians. A biblio-graphic search was carried out in PubMed/Medline and SciELO, with various descriptors in Spanish and English. The results of this review confirm that the ethnic origin of Peruvians is triconti-nental due to European (mainly Spanish), African and Asian migration, in addi-tion to Latin American migration, being 60.2% mixed, 25.8% Amerindian, 5.9% white, 3.6% African descent, 1.2% Chinese and Japanese descent, and 3.3% unspecified. Studies on CYP2C19*3, CYP2D6*2, *3 and *6 have been reported in Peruvians, and the frequency is similar to that studied in Ecuadori-ans and Colombians. The CYP2C19*3, CYP2D6*3, and CYP2D6*6 alleles found in Peruvians are common in Europeans, Africans, and Asians; while CYP2D6*4 in Africans and CYP2D6*2 related to Asians. In some studies, the ethnic/gene association has not been demonstrated; while others have shown a significant association, which is why further investigation is warranted. It is concluded that the studies on CYP2D6 and CYP2C19 genes associated with the tricontinental and Latin American ancestry of Peruvians are little, and ac-cording to what has been investigated, the CYP2C19*3, CYP2D6*2, *3, *4 and *6 alleles have more related to their ancestry.

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium.

Purpose: The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC). Patients and Methods: This single-arm, open-label, multi-center phase II study enrolled patients with RECIST measurable advanced EC. Patients could have received < 1 prior platinum-based regimen and < one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared to historical control rate of 50%. Results: 46 patients were enrolled, and 43 were evaluable for ORR. Median age was 66 (range: 43-86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic EC. Patients received carboplatin AUC 6, paclitaxel 175mg/m2 and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles. ORR was 74.4% (32/43), higher than historic controls (p = 0.001). Median PFS was 10.6 months (95% CI 8.3-13.9 months). The most common grade 1-2 treatment related adverse event (TRAEs) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%) and neuropathy (13%), while the most common grade 3-4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T cell populations at baseline in responders. The CD8+ T cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared to non-responders. Conclusions: Addition of pembrolizumab to carboplatin and paclitaxel for advanced EC was tolerated and improved ORR compared to historical outcomes.

Hierarchical Microstructure Informed Tractography.

Background: Tractography uses diffusion magnetic resonance imaging to noninvasively infer the macroscopic pathways of white matter fibers and it is the only available technique to probe in vivo the structural connectivity of the brain. However, despite this unique and compelling ability and its wide range of possible neurological applications, tractography is still limited, lacks anatomical precision, and suffers from a serious sensitivity/specificity trade-off. For this reason, in the past few years, tractography postprocessing techniques have emerged and proved effective for improving the quality of the reconstructions. Among them, the Convex Optimization Modeling for Microstructure Informed Tractography formulation allows incorporating the anatomical prior that fibers are naturally organized in fascicles, and has obtained exceptional results in increasing the accuracy of the estimated tractograms. Methods: We propose an extension to this idea and introduce a multilevel grouping of the streamlines to capture the white matter arrangement in fascicles and subfascicles. We tested our proposed formulation in synthetic and in vivo data. Results: Our experiments show that using multiple levels allows considering information about the white matter organization more adequately and helps to improve further the accuracy of the resulting tractograms. Conclusion: This new formulation represents a further important step toward a more accurate structural connectivity estimation.

A new method for accurate in vivo mapping of human brain connections using microstructural and anatomical information.

Diffusion magnetic resonance imaging is a noninvasive imaging modality that has been extensively used in the literature to study the neuronal architecture of the brain in a wide range of neurological conditions using tractography. However, recent studies highlighted that the anatomical accuracy of the reconstructions is inherently limited and challenged its appropriateness. Several solutions have been proposed to tackle this issue, but none of them proved effective to overcome this fundamental limitation. In this work, we present a novel processing framework to inject into the reconstruction problem basic prior knowledge about brain anatomy and its organization and evaluate its effectiveness using both simulated and real human brain data. Our results indicate that our proposed method dramatically increases the accuracy of the estimated brain networks and, thus, represents a major step forward for the study of connectivity.

A small molecule inhibitor of the perinucleolar compartment, ML246, attenuates growth and spread of ovarian cancer.

BACKGROUND: Ovarian cancer remains a major health problem for women as it is often diagnosed at a late stage with metastatic disease. There are limited therapeutic agents and survival rates remain poor. The perinucleolar compartment (PNC) has been shown to be associated with malignancy and is considered a surrogate phenotypic marker for metastatic cancer cells. A small molecule, ML246, was derived from a screen against PNCs. In this study, the effect of ML246 on ovarian cancer growth and spread was investigated. METHODS: SKOV3 or OVCAR3 cells were treated with ML246 in vitro and PNC was visualized with immunofluorescent staining. Cell invasion was assessed using Matrigel-coated transwell systems. SKOV3 cells were xenografted orthotopically under the ovarian bursa of immunocompromised mice. Additionally, a patient derived ovarian cancer cell line was grafted subcutaneously. Mice were treated with ML246 and tumor growth and spread was assessed. RESULTS: PNCs were prevalent in the ovarian cancer cell lines OVCAR3 and SKOV3 with higher prevalence in OVCAR3 cells. Treatment with ML246 significantly reduced PNC prevalence in OVCAR3 and SKOV3 cells. Moreover, the invasive activity of both cell lines was significantly inhibited in vitro. Orthotopic implantation of SKOV3 cells resulted in growth of the tumor on the ovary as well as spread of tumor tissues outside of the primary site on organs into the abdominal cavity. Treatment with ML246 decreased the incidence of tumors outside of the ovary. In addition, a patient-derived xenograft (PDX) line was grafted subcutaneously to monitor tumor growth. ML246 significantly attenuated growth of tumors over a 5-week treatment period. CONCLUSIONS: PNC's are present in ovarian cancer cells and treatment with ML246 decreases invasion in vitro and tumor growth and spread in vivo. Additional studies are warranted to determine the efficacy of ML246 as an inhibitor of metastatic disease in ovarian cancer and to determine its precise mechanism of action.