Cytology and Genetics

Retraction Note to: "Sodium Ferulate Inhibits High-Fat Diet-Induced Inflammatory Factors Expression in Human Umbilical Vein Endothelial Cells"

Erratum to: Molecular Organization of 5S Ribosomal DNА of Deschampsia antarctica The title of the article should read as follows: Molecular Organization of 5S Ribosomal DNА of Deschampsia antarctica

1–34 PTH Effect on the Chondroprogenitor Cells Differentiation, As Well As on the Microstructure of the Subchondral None Tissue, and the Regeneration of Articular Cartilage in Rats Abstract The purpose of the present study was to investigate the impact of intermittent and constant administration of 1–34 PTH fragment on bovine chondroprogenitor cells differentiation contained in chondrogenic and osteogenic media. In addition, regeneration of the cartilage tissue of non-native rats and the dependence of this process on the level of parathyroid hormone, as well as changes in the subchondral bone, were studied. Monolayer cultures of bovine chondroprogenitor cells contained in osteogenic and chondrogenic medium with periodic and constant addition of 1–34 PTH, were examined by immunofluorescence analysis to reveal appropriate markers. Rats' knee joints have been operated with the full thickness defect formation, and further investigation of the regeneration processes depending on the introduction of the PTH in vivo by histochemical analysis of the operated knee joints. The findings suggest that the modulating effect of PTH on chondrogenic differentiation of stem cells and the therapeutic potential of this hormone for cartilage regeneration.

Analysis of α-Tubulin Gene Expression During Cold Acclimation of Winter and Spring Soft Wheat Abstract The expression profiles of 15 α-tubulin genes in spring and winter wheat varieties during cold acclimation were studied. Among the studied genes, two subfamilies (three genes in each) were identified with elevated expression levels detected at the initial stages of cold acclimation. The Tuba-2-3 gene, which, within its subfamily, is characterized by the most significant amplitude of the increase in the initial expression level, deserves special attention. In addition, the greatest differences in expression levels between varieties were found for this gene within its subfamily. For the winter variety, higher expression levels of this tubulin gene remaining for a long time (up to the seventh day of acclimation) were detected. A significant initial increase in expression levels for all α-tubulin genes of the fourth subfamily reaching maximum values during further acclimation was revealed. The high initial values of the expression levels of genes from this subfamily may also indicate their important role in the resistance of wheat microtubules to low temperatures in the early stages of cold acclimation.

Placenta Growth Factor Influences miR-483-5p, miR-483-3p, miR-4669 and miR-16-5p Expression in MKN-45-Derived Spheroid Body-Forming Cells Abstract Placenta growth factor (PlGF) is a crucial player of the human gastric cancer development. PlGF signalling pathway affects the expression of genes involving in angiogenesis and metastasis. Studies have hinted association between abnormal intracellular signal transduction and miRNAs expression profile in cancer initiation and progression. Changes in the expression of miR-483-5p, miR-483-3p, miR-16-5p and miR-4669 are reported in the spheroid body (SB)-forming cells derived from gastric cancer cell line MKN-45. Given the importance of PlGF and also the expression change of the above mentioned miRNAs in gastric cancer, this study was designed to investigate the effect of siRNA-mediated knockdown of Plgf on the expression of these miRNAs in the MKN-45 derived SB-forming cells. In addition, bioinformatics analysis was performed on the miRNAs to predict their potential targets that associated with survival, apoptosis and angiogenesis processes. Results showed that with except miR-483-3p, which was down-regulated, another 3 miRNAs were significantly up-regulated in the Plgf-knockdown samples. Furthermore, the in silico analysis revealed that these miRNAs influence the expression of a set of genes, which are involved in various signal transduction pathways. Moreover, it showed that they affect cellular processes, including proliferation, apoptosis and angiogenesis. In conclusion, the current study reveals that down-regulation of Plgf influences the miRNAs expression in MKN-45 derived SB-forming cells. Moreover, our findings indicate that miR-483-5p, miR-483-3p and miR-16-5p can induce cancer initiation and progression through targeting genes involved in the cell cycle, apoptosis and angiogenesis processes.

Reporting of B-Chromosomes in Trachyspermum ammi (L.) Sprague (Ajwain) Abstract To the best of our knowledge this is the first study regarding the reporting of B chromosomes in this plant species. During the meiotic study of Trachyspermum ammi (L.) Sprague, maximum two B chromosomes were reported in diploid plants which were retained in induced autotetraploid after the treatment of 0.2% colchicine at seedling stage. In the present study, the meiotic behaviour of B-chromosomes was analyzed in Trachyspermum ammi (L.) Sprague. The presence of B chromosomes and their number in the plant species of higher ploidy level is controversial. The existence of B chromosomes in polyploids varies from species to species. In the present case, no change has been observed in the number of B chromosomes despite the duplication of A chromosomes in autotetraploid plant. The unaffected number of B chromosomes represents their peculiar behaviour of inheritance. The plant species show adaptive mechanism for their retention in population. In the present study, significant changes (p < 0.05) have been observed in the chiasma frequency and pollen fertility of both diploid carrier plant as compare to non-carrier ones. Furthermore, the chromosomal associations have also been considered with observed number of B chromosomes in autotetraploid carrier plant. In autotetraploid carrier plant, the frequencies of multivalents were found to be quite low in comparison to diploid carrier plant.

Isolation, Characterization and Association among Phosphate Solubilizing Bacteria from Sugarcane Rhizosphere Abstract One of the premium qualities of Phosphate solubilizing bacteria is to solubilize insoluble phosphorus to make it available for plant roots to be engrossed. To check the ability for phosphate solubilization, production of indole acetic acid, antagonistic activity against fungal pathogen and intrinsic antibiotic resistance phosphorous solubilizing bacterial isolates were isolated and screened. In total, 12 PSB were found rod shaped cells being gram negative. Different levels of antibiotic resistance were observed by rhizobacterial isolates against four antibiotics (Ampicillin, Kanamycin, Tetracycline and Streptomycin 25, 30, 30 and 10 μg/mL respectively). The isolates S7 and S20 showed antifungal activity against Fusarium oxysporum. Conversion of insoluble phosphorous Ca3(PO4) into IAA was observed by all PSB Isolates. Two phosphorous solubilizing bacterial isolates sequences were submitted in NCBI database. Conclusively, good antifungal activity with greater ability to solubilize insoluble phosphorus can be achieved by combine application of rhizobacterial isolates with S22. Further, it is an eco-friendly and cost effective strategy to improve crop production.

Genetic Structure in Different Subsequent Generations of Sexually Mature Rapana venosa Mollusks from the Same Biotope Abstract Two Rapana venosa (R. venosa) samples representing different age groups from the same biotope (Odes'ka zatoka) were compared, using allozyme analysis, by their genetic structure. The genotypes were tested at 19 loci of nine enzymes. The genepool of the collected R. venosa samples was generally characterized by genetic disequilibrium and the elevated level of actual heterozygosity at the studied polymorphic loci (on average, at 16–18%). Sexually mature mollusk generations belonging to different age groups from the same biotope had a comparably lower relatedness between each other than the mollusk samples from different aquatic areas of the Black Sea. However, the genetic distance between the studied R. venosa groups was at the level of local populations in all cases. The analysis of the contribution made by evolutionary factors has shown the leading role of migrations in the formation of the R. venosa genepool in the northern part of the Black Sea.

Secondary Metabolome and Transcriptome of Streptom y ces albus J1074 in Liquid Medium SG2 Abstract Streptomyces albus J1074 is one of the most popular chassis for heterologous expression of actinobacterial biosynthetic gene clusters (BGCs). Considerable efforts are invested into understanding all the physiological and genetic aspects of secondary metabolism of J1074 in order to maximize the expression of heterologous BGCs. It has to be noted that the J1074 genome itself is home to numerous (>20) BGCs, whose expression varies widely. Therefore, the identification of the factors limiting the expression of J1074 BGCs might help improve this strain for heterologous expression purposes. As first steps towards this goal, herein we describe the secondary metabolome of J1074 in liquid medium SG2, previously shown by us to support the production of antibacterial and antifungal compounds. We compare the results of metabolomic studies with the transcriptome of J1074 in SG2 after 60 h of growth. Results of our studies are discussed in the context of current knowledge on the J1074 transcriptome and metabolome data.

Reproductive Function of Cows with Different Genotypes for TNF α Locus and Estimation of Sperm Fertility by the DNA Fragmentation Method Abstract SNP polymorphism of the TNFα gene's promoter region at position 824 A→G in Holstein cows of TOO Bayserke-Agro is represented by the following genetic variants: AA, 22.4%; AG, 63.8%; GG, 13.8%; the frequency of alleles A and G was 0.54 and 0.46, respectively. The population under study revealed an excessive frequency of the heterozygous genotype AG, 21.49 individuals, while other genotypes showed a deficit of homozygous variants GG and AA, by 11.16 and 10.32 individuals, respectively. The traits of reproductive function were high in cows with genotype GG: the interval between calving and productive insemination was 259 days, the insemination index was 2.63, the proportion of animals inseminated after more than 91 days was minimal (47.36%) in individuals with the homozygous genotype GG. As an additional criterion for estimating the fertility of bull sperm, the DNA fragmentation method is recommended: the maximum permissible level of sperm cells with DNA fragmentation in frozen sperm is between 13.00 and 17.15%.

Nuclear Medicine and Molecular Imaging

Lesion-Wise Comparison of Pre-Therapy and Post-Therapy Effective Half-Life of Iodine-131 in Pediatric and Young Adult Patients with Differentiated Thyroid Cancer Undergoing Radioiodine Therapy Abstract Purpose The effective half-life of radioiodine is an important parameter for dosimetry in differentiated thyroid cancer patients, particularly in children. We determined the pre-therapy and post-therapy effective half-life in different types of lesions, i.e., remnant, node, or lung metastases. Methods Of 84 patients recruited, 27 were < 18 years (group 1) and the remaining 57 were between 18 and 21 years (group 2). A total of 114 studies were conducted and 253 lesions were analyzed. Serial whole-body scans were acquired at 24, 48, and ≥ 72 h after administration of iodine-131. Region of interests was drawn over lesions to determine counts in the lesion. Time versus counts graphs were plotted and mono-exponentially fitted to determine effective half-life. Results The post-therapy effective half-life was found to be lesser than pre-therapy effective half-life in all types of lesions and in all groups. Median effective half-life was found maximum in intact lobe, minimum in the lung, and intermediate in remnant and nodes. In the assessment of all lesions together, pre- and post-therapy median and interquartile range (IQR) effective half-life were 59.8 (37–112) h and 48.6 (35.2–70.8) h (p < 0.0001) in group 1, 73.9 (46.2–112.7) h and 60 (57.4–85.9) h (p < 0.0001) in group 2, and 68.6 (41.53–112.36) h and 54.7 (36–80.6) h (p < 0.0001) in combined group, respectively. Importantly, the pre- and post-therapy median effective half-life serially dropped after each successive cycles of iodine-131. Conclusions There was a significant difference in pre-therapy and post-therapy effective half-life in all types of lesions. These results may have implications in calculating the correct therapeutic dose in children and in young adults.

Use of Molecular Imaging in Clinical Drug Development: a Systematic Review Abstract Background Molecular imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can provide the crucial pharmacokinetic-pharmacodynamic information of a drug non-invasively at an early stage of clinical drug development. Nevertheless, not much has been known how molecular imaging has been actually used in drug development studies. Methods We searched PubMed using such keywords as molecular imaging, PET, SPECT, drug development, and new drug, or any combination of those to select papers in English, published from January 1, 1990, to December 31, 2015. The information about the publication year, therapeutic area of a drug candidate, drug development phase, and imaging modality and utility of imaging were extracted. Results Of 10,264 papers initially screened, 208 papers met the eligibility criteria. The more recent the publication year, the bigger the number of papers, particularly since 2010. The two major therapeutic areas using molecular imaging to develop drugs were oncology (47.6%) and the central nervous system (CNS, 36.5%), in which efficacy (63.5%) and proof-of-concept through either receptor occupancy (RO) or other than RO (29.7%), respectively, were the primary utility of molecular imaging. PET was used 4.7 times more frequently than SPECT. Molecular imaging was most frequently used in phase I clinical trials (40.8%), whereas it was employed rarely in phase 0 or exploratory IND studies (1.4%). Conclusions The present study confirmed the trend that molecular imaging has been more actively employed in recent clinical drug development studies although its adoption was rather slow and rare in phase 0 studies.

Efforts in the Formation and Development of Nuclear Medicine in Vietnam Abstract The foundations of nuclear medicine in Vietnam were established from 1970. Until now, after 48 years of development, in Vietnam, we have some basic equipment including 31 SPECT, 4 SPECT/CT machines, 11 PET/CT scanners, five cyclotrons, and one nuclear reactor. Many nuclear medicine techniques in diagnosis and treatment have been routinely performed at provincial and central level health facilities such as tumor scintigraphy, thyroid scintigraphy, bone scintigraphy, kidney scintigraphy, cardiac scintigraphy, and radio-isotope therapy with I-131 and P-32. Selective internal radiation therapy with Y-90 microsphere and I-125 radioactive seed implantation has been also successfully applied in some big hospitals. However, there are still many difficulties for Vietnam as the lack of new widely used radioisotopes such as Ga-67, Cu-64, Samarium-153, and Lutetium-177 and the lack of nuclear medicine specialists. In the future, we are putting our efforts on the applications of new isotopes in diagnosis and treatment of cancers (theranostic) like Ga-68-DOTATATE, Lutetium-177-DOTATATE, Ga-68-PSMA, and Lutetium-177-PSMA, equipping modern nuclear medicine diagnostic tools, strengthening the human resources training in nuclear medicine. At the same time, we are trying our best to strengthen the cooperation with international nuclear medicine societies in over the world.

Gallbladder Paraganglioma Associated with SDHD Mutation: a Potential Pitfall on 18 F-FDOPA PET Imaging Abstract A 36-year-old male patient initially presented with hypertension, tinnitus, bilateral carotid masses, a right jugular foramen, and a periaortic arch mass with an elevated plasma dopamine level but an otherwise normal biochemical profile. On surveillance MRI 4 years after initial presentation, he was found to have a 2.2-cm T2 hyperintense lesion with arterial enhancement adjacent to the gallbladder, which demonstrated avidity on 68Ga-DOTATATE PET/CT and retrospectively on 18F-FDOPA PET/CT but was non-avid on 18F-FDG PET/CT. Biochemical work-up including plasma catecholamines, metanephrines, and chromogranin A levels were found to be within normal limits. This lesion was surgically resected and was confirmed to be a paraganglioma (PGL) originating from the gallbladder wall on histopathology. Pheochromocytoma (PHEO) and PGL are rare tumors of the autonomic nervous system. Succinate dehydrogenase subunit D (SDHD) pathogenic variants of the succinate dehydrogenase complex are usually involved in parasympathetic, extra-adrenal, multifocal head, and neck PGLs. We report an unusual location of PGL in the gallbladder associated with SDHD mutation which could present as a potential pitfall on 18F-FDOPA PET/CT as its normal excretion occurs through biliary system and gallbladder. This case highlights the superiority of 68Ga-DOTATATE in comparison to 18F-FDOPA and 18F-FDG in the detection of SDHD-related parasympathetic PGL. ClinicalTrials.gov Identifier: NCT00004847.

Tracer Accumulation in Relation to Venous Thrombus on 18 F-DOPA PET/CT in a Case of Persistent Hyperinsulinemic Hypoglycemia of Infancy Abstract 18F-DOPA PET/CT is commonly done in patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) to look for any focal lesion in the pancreas. We present the findings in a 20-day-old neonate with PHHI who underwent 18F-DOPA PET/CT. The scan showed diffuse uptake in the pancreas with no focal lesion, physiologic excretion into the genito-urinary system, and interestingly tracer accumulation was seen in the inferior vena cava and ilio-femoral veins which is a non-physiological site for tracer accumulation. The uptake corresponded to a large venous thrombus which was confirmed by a venous Doppler.

Promotion of Nuclear Medicine-Related Sciences in Developing Countries

Theranostics in Bangladesh: Current Status, Challenges, and Future Perspective Abstract Background and Current Status of Theranostics Therapeutic nuclear medicine (NM) in Bangladesh began in the early 1980s with the application of radioactive iodine for treatment of thyroid cancer and primary hyperthyroidism. Since then, NM practice has remarkably developed in the country with the advancement of instrumentation, radiopharmacy, and information technology. The government took the initiative to establish four PET-CT centers at different NM centers, including one at the National Institute of Nuclear Medicine and Allied Sciences (NINMAS). A further development is the installation of a cyclotron center (18-MeV cyclotron) at NINMAS by the government's fund. Currently, NM is providing good health services to oncology patients throughout the country. More than 20 NM centers are functioning in different parts of the country, and therapeutic NM has an important place. However, conventional radioactive iodine still remains the major theranostic application. Challenges and Future Perspective The expansion and development of therapeutic NM for other cancers have been limited due to a number of challenging factors. A brief overview of the history and current status of NM in Bangladesh is presented here with an examination of factors that pose as obstacles to the introduction and development of new therapeutic technologies. Finally, future perspectives are discussed with ways to mitigate existing problems and challenges.

Nuclear Theranostics in Taiwan Abstract Boron neutron capture therapy and Y-90 radioembolization are emerging therapeutic methods for uncontrolled brain cancers and hepatic cancers, respectively. These advanced radiation therapies are heavily relied on theranostic nuclear medicine imaging before the therapy for the eligibility of patients and the prescribed-dose simulation, as well as the post-therapy scanning for assessing the treatment efficacy. In Taiwan, the Taipei Veterans General Hospital is the only institute performing the BNCT and also the leading institute performing Y-90 radioembolization. In this article, we present our single institute experiences and associated theranostic nuclear medicine approaches for these therapies.

Development of Predictive Models in Patients with Epiphora Using Lacrimal Scintigraphy and Machine Learning Abstract Purpose We developed predictive models using different programming languages and different computing platforms for machine learning (ML) and deep learning (DL) that classify clinical diagnoses in patients with epiphora. We evaluated the diagnostic performance of these models. Methods Between January 2016 and September 2017, 250 patients with epiphora who underwent dacryocystography (DCG) and lacrimal scintigraphy (LS) were included in the study. We developed five different predictive models using ML tools, Python-based TensorFlow, R, and Microsoft Azure Machine Learning Studio (MAMLS). A total of 27 clinical characteristics and parameters including variables related to epiphora (VE) and variables related to dacryocystography (VDCG) were used as input data. Apart from this, we developed two predictive convolutional neural network (CNN) models for diagnosing LS images. We conducted this study using supervised learning. Results Among 500 eyes of 250 patients, 59 eyes had anatomical obstruction, 338 eyes had functional obstruction, and the remaining 103 eyes were normal. For the data set that excluded VE and VDCG, the test accuracies in Python-based TensorFlow, R, multiclass logistic regression in MAMLS, multiclass neural network in MAMLS, and nuclear medicine physician were 81.70%, 80.60%, 81.70%, 73.10%, and 80.60%, respectively. The test accuracies of CNN models in three-class classification diagnosis and binary classification diagnosis were 72.00% and 77.42%, respectively. Conclusions ML-based predictive models using different programming languages and different computing platforms were useful for classifying clinical diagnoses in patients with epiphora and were similar to a clinician's diagnostic ability.

Theranostics in India: a Particularly Exquisite Concept or an Experimental Tool Abstract The term theranostics is a combination of a diagnostic tool that helps to define a right therapeutic tool for specific disease and paves the approach towards personalized or precision medicine. In Nuclear Medicine, a diagnostic radionuclide is labeled with the target and once expression is documented, the same target is labeled with a therapeutic radionuclide and treatment is executed. The theranostic concept was applied first time in 1964 in the treatment of thyroid cancer with I-131 (RAI). Over the years, other theranostic radiotracers became available indigenously from the Bhabha Atomic Research Centre (BARC) in the country. Currently Lu-177 is produced in India and peptides like DOTATATE and PSMA are available in a kit form indigenously. At the present time, the radionuclide therapies of oncological disorders which are being performed in India are mainly for neuroendocrine tumors (NET) and metastatic castration resistant prostate cancer (mCRPC). The main constraints pertaining to this concept is the cost of treatment and awareness among the clinicians which are gradually being taken care of by the private health insurance and our participation in disease management group meetings respectively. The theranostic concept has become popular over the years and has the potential for sustained growth.

PharmacoEconomics

Correction to: Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal The title of the article should read:

Correction to: Economic Evaluations Alongside Efficient Study Designs Using Large Observational Datasets: the PLEASANT Trial Case Study The original article can be found online.

Doxycycline Added to Prednisolone in Outpatient-Treated Acute Exacerbations of COPD: A Cost-Effectiveness Analysis Alongside a Randomised Controlled Trial Abstract Background Most patients with mild to severe chronic obstructive pulmonary disease (COPD) experience exacerbations, which are also associated with increased healthcare costs. Despite limited evidence of antibiotics' benefits for exacerbations in outpatients, antibiotics are frequently prescribed. The aim of this study was to investigate whether doxycycline added to prednisolone is cost-effective compared to placebo plus prednisolone for the treatment of COPD acute exacerbations. Methods An economic evaluation from the societal perspective was performed alongside a 2-year randomised trial in 301 COPD patients in the Netherlands. The primary outcome was cost per quality-adjusted life year (QALY). The secondary outcome was cost per exacerbation prevented. Healthcare utilisation and loss of productivity were measured using retrospective questionnaires and clinical report forms. Missing data were imputed using multiple imputations by chained equations. Bootstrapping was employed to estimate statistical uncertainty surrounding cost-effectiveness outcomes. A sensitivity analysis from the healthcare perspective was performed. Results On average, costs in the doxycycline group were €898 higher than in the placebo group [95% confidence interval (CI) − 2617 to 4409] for the 2 years of follow-up. QALY values were higher in the doxycycline group (0.03; 95% CI − 0.00 to 0.06), but patients in this group suffered 0.01 more exacerbations than patients in the placebo group (95% CI − 0.14 to 0.11). Cost-effectiveness acceptability curves showed that the probability of doxycycline being cost-effective compared to placebo was 61% and 43% at a willingness-to-pay threshold of €34,000 per QALY and per exacerbation avoided, respectively. The sensitivity analysis showed similar results from the healthcare system perspective. Conclusions In patients with mild to severe COPD treated for exacerbations in an outpatient setting, doxycycline added to prednisolone is not cost-effective compared to prednisolone plus placebo over a 2-year period.

Modeling Covariate-Adjusted Survival for Economic Evaluations in Oncology Abstract Background and Objectives In economic evaluations in oncology, adjusted survival should be generated if imbalances in prognostic/predictive factors across treatment arms are present. To date, no formal guidance has been developed regarding how such adjustments should be made. We compared various covariate-adjusted survival modeling approaches, as applied to the ENDEAVOR trial in multiple myeloma that assessed carfilzomib plus dexamethasone (Cd) versus bortezomib plus dexamethasone (Vd). Methods Overall survival (OS) data and baseline characteristics were used for a subgroup (bortezomib-naïve/one prior therapy). Four adjusted survival modeling approaches were compared: propensity score weighting followed by fitting a Weibull model to the two arms of the balanced data (weighted data approach); fitting a multiple Weibull regression model including prognostic/predictive covariates to the two arms to predict survival using the mean value of each covariate and using the average of patient-specific survival predictions; and applying an adjusted hazard ratio (HR) derived from a Cox proportional hazard model to the baseline risk estimated for Vd. Results The mean OS estimated by the weighted data approach was 6.85 years (95% confidence interval [CI] 4.62–10.70) for Cd, 4.68 years (95% CI 3.46–6.74) for Vd, and 2.17 years (95% CI 0.18–5.06) for the difference. Although other approaches estimated similar differences, using the mean value of covariates appeared to yield skewed survival estimates (mean OS was 7.65 years for Cd and 5.40 years for Vd), using the average of individual predictions had limited external validity (implausible long-term OS predictions with > 10% of the Vd population alive after 30 years), and using the adjusted HR approach overestimated uncertainty (difference in mean OS was 2.03, 95% CI − 0.17 to 6.19). Conclusions Adjusted survival modeling based on weighted or matched data approaches provides a flexible and robust method to correct for covariate imbalances in economic evaluations. The conclusions of our study may be generalizable to other settings. Trial Registration ClinicalTrials.gov identifier NCT01568866 (ENDEAVOR trial).

Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung Cancer: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal Abstract The National Institute for Health and Care Excellence (NICE) invited the company that manufactures ceritinib (Zykadia®, Novartis) to submit evidence on the clinical and cost effectiveness of the drug, as a first-line treatment for adults with anaplastic lymphoma kinase (ALK)-positive (+) advanced non-small-cell lung cancer (NSCLC), as part of the Institute's single technology appraisal (STA) process. The CRD (Centre for Reviews and Dissemination) and CHE (Centre for Health Economics) Technology Assessment Group at the University of York was commissioned to act as the Evidence Review Group (ERG). This paper describes the Company's submission (CS), the ERG review and NICE's subsequent decisions. The evidence submitted in support of ceritinib, as the first-line treatment in ALK+ advanced NSCLC, was a phase III, international, multicentre, open-label randomised controlled trial (RCT) comparing ceritinib with pemetrexed/cisplatin plus pemetrexed maintenance therapy (chemotherapy [CT] group). The results indicated that ceritinib prolonged progression-free survival (PFS) compared with CT. The only comparator considered in the CS was crizotinib. The evidence selected in support of crizotinib was PROFILE 1014, an open-label RCT of crizotinib, compared with pemetrexed/cisplatin CT (without maintenance therapy), in previously untreated advanced or metastatic ALK+ NSCLC. The design and population of PROFILE 1014 was similar to that of ASCEND-4, though there were some differences between the trials. The Company considered it not possible to perform an 'anchor-based' analysis of first-line ceritinib and crizotinib, and presented a Matching-Adjusted Indirect Comparison (MAIC) of ceritinib and crizotinib using only the ALK inhibitor arm of ASCEND-4 and PROFILE 1014. The indirect comparison suggests that ceritinib may be more effective in prolonging PFS than crizotinib. The ERG agreed that an indirect comparison using only the ALK inhibitor arm of the trials was the only option available in the present assessment; however, a number of limitations and potential bias were identified in this analysis. The Company's model estimated that ceritinib was cost effective when compared with crizotinib. However, the ERG highlighted several concerns with the Company's analysis; the ERG's preferred base case estimated an incremental cost-effectiveness ratio of £69,255 per quality-adjusted life-year (no patient access scheme [PAS] included). The ERG considered the economic analysis to be sensitive to changes in assumption used, partly due to the due to the immaturity of the overall survival data from trials, which leads to uncertainty around the extrapolation used. The NICE Appraisal Committee concluded that ceritinib is recommended, within its marketing authorisation, as an option for untreated ALK+ advanced NSCLC in adults, if the Company provides it with the discount agreed in the PAS.

Cost-Effectiveness of Betrixaban Compared with Enoxaparin for Venous Thromboembolism Prophylaxis in Nonsurgical Patients with Acute Medical Illness in the United States Abstract Background Studies show that the risk of venous thromboembolism (VTE) continues post-discharge in nonsurgical patients with acute medical illness. Betrixaban is the first anticoagulant approved in the United States (US) for VTE prophylaxis extending beyond hospitalization. Objective The aim was to establish whether betrixaban for VTE prophylaxis in nonsurgical patients with acute medical illness at risk of VTE in the US is cost-effective compared with enoxaparin. Methods A cost-effectiveness analysis was conducted, estimating the cost per quality-adjusted life-year (QALY) gained with betrixaban (35–42 days) compared with enoxaparin (6–14 days) from a US payer perspective over a lifetime horizon. A decision tree (DT) estimated primary VTE events, thrombotic events, and treatment complications in the first 3 months based on data from the phase III Acute Medically Ill VTE Prevention with Extended Duration Betrixaban study. A Markov model estimated recurrent events and long-term complication risks from published literature. EuroQoL-5 Dimensions utility data and costs inflated to 2017 US dollars (US$) were from published literature. Results were discounted at 3.0% per annum. Deterministic and probabilistic sensitivity analyses explored uncertainty. Results Betrixaban dominated enoxaparin, with savings of US$784 and increased QALYs of 0.017 per patient. In addition, betrixaban dominated enoxaparin across all sensitivity analyses, but was most sensitive to utilities and DT probabilities. Furthermore, probabilistic sensitivity analysis found that betrixaban was more cost-effective than enoxaparin at all willingness-to-pay thresholds. Conclusion Betrixaban can be considered cost-effective for nonsurgical patients with acute medical illness at risk of VTE, requiring longer VTE prophylaxis from hospitalization through post-discharge.

Nivolumab for Treating Metastatic or Unresectable Urothelial Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal Abstract As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Bristol-Myers Squibb) of nivolumab (Opdivo®) to submit evidence of its clinical and cost effectiveness for metastatic or unresectable urothelial cancer. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG), which produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission to NICE. Nivolumab was compared with docetaxel, paclitaxel, best supportive care and retreatment with platinum-based chemotherapy (cisplatin plus gemcitabine, but only for patients whose disease has had an adequate response in first-line treatment). Two ongoing, phase I/II, single-arm studies for nivolumab were identified, but no studies directly compared nivolumab with any specified comparator. Evidence from directly examining the single arms of the trial data indicated little difference between the outcomes measured from the nivolumab and comparator studies. A simulated treatment comparison (STC) analysis was used in an attempt to reduce the bias induced by naïve comparison, but there was no clear evidence that risk of bias was reduced. Multiple limitations in the STC were identified and remained. The effect of an analysis based on different combinations of covariates in the prediction model remains unknown. The ERG's concerns regarding the economic analysis included the use of a non-established response-based survival analysis method, which introduced additional uncertainty. The use of time-dependent hazard ratios produced overfitting and was not represented in the probabilistic sensitivity analysis. The use of a treatment stopping rule to cap treatment cost left treatment effectiveness unaltered. A relevant comparator was excluded from the base-case analysis. The revised ERG deterministic base-case incremental cost-effectiveness ratios based on the company's Appraisal Consultation Document response were £58,791, £78,869 and £62,352 per quality-adjusted life-year gained versus paclitaxel, docetaxel and best supportive care, respectively. Nivolumab was dominated by cisplatin plus gemcitabine in the ERG base case. Substantial uncertainties about the relative treatment effectiveness comparing nivolumab against all comparators remained. NICE did not recommend nivolumab, within its marketing authorisation, as an option for treating locally advanced, unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy, and considered that nivolumab was not suitable for use within the Cancer Drugs Fund.

An Educational Review About Using Cost Data for the Purpose of Cost-Effectiveness Analysis Abstract This paper provides an educational review covering the consideration of costs for cost-effectiveness analysis (CEA), summarising relevant methods and research from the published literature. Cost data are typically generated by applying appropriate unit costs to healthcare resource-use data for patients. Trial-based evaluations and decision analytic modelling represent the two main vehicles for CEA. The costs to consider will depend on the perspective taken, with conflicting recommendations ranging from focusing solely on healthcare to the broader 'societal' perspective. Alternative sources of resource-use are available, including medical records and forms completed by researchers or patients. Different methods are available for the statistical analysis of cost data, although consideration needs to be given to the appropriate methods, given cost data are typically non-normal with a mass point at zero and a long right-hand tail. The choice of covariates for inclusion in econometric models also needs careful consideration, focusing on those that are influential and that will improve balance and precision. Where data are missing, it is important to consider the type of missingness and then apply appropriate analytical methods, such as imputation. Uncertainty around costs should also be reflected to allow for consideration on the impacts of the CEA results on decision uncertainty. Costs should be discounted to account for differential timing, and are typically inflated to a common cost year. The choice of methods and sources of information used when accounting for cost information within CEA will have an effect on the subsequent cost-effectiveness results and how information is presented to decision makers. It is important that the most appropriate methods are used as overlooking the complicated nature of cost data could lead to inaccurate information being given to decision makers.

Cost-Effectiveness of Treatment Options for Neuropathic Pain: a Systematic Review Abstract Background Neuropathic pain significantly reduces an individual's quality of life and places a significant economic burden on society. As such, many cost-effectiveness analyses (CEAs) have been published for treatments available for neuropathic pain. Objectives The primary objective of this systematic review was to provide a detailed summary of the estimates of cost-effectiveness from published CEAs comparing available treatments for neuropathic pain. The secondary objectives were to identify the key drivers of cost-effectiveness and to assess the quality of published CEAs in neuropathic pain. Methods We searched Embase, MEDLINE, Cochrane CENTRAL and seven other databases to identify CEAs reporting the costs, health benefits (e.g., quality-adjusted life-years or disability-adjusted life-years) and summary statistics, such as incremental cost-effectiveness ratios, of treatments for neuropathic pain. We excluded studies reporting diseases other than neuropathic pain, those for which the full text was not available (e.g., conference abstracts), studies not written in English or not published in peer-reviewed journals, and narrative reviews, editorials and opinion papers. Titles and abstract reviews, full-text reviews, and data extraction were all performed by two independent reviewers, with disagreement resolved by a third reviewer. Mean costs, health benefits, and summary statistics were reported and qualitatively compared across studies, stratified by time horizon. Drivers of cost-effectiveness were assessed using reported one-way sensitivity analyses. The quality of all included studies was evaluated using the Tufts CEA Registry Quality Score and study reporting using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) checklist. Results A total of 22 studies were identified and included in this systematic review. Included studies were heterogeneous in the treatments compared, methodology and design, perspectives, and time horizons considered, making cross-study comparisons difficult. No single treatment was consistently the most cost-effective across all studies, but tricyclic antidepressants were the preferred treatment at a willingness-to-pay threshold of $US50,000 per quality-adjusted life-year in several studies with a short time horizon and a US payer perspective. Among the 14 studies reporting one-way sensitivity analyses, drivers of cost-effectiveness included utility values for health states and the likelihood of pain relief with treatment. The quality of the identified CEAs was moderate to high, and overall reporting largely met CHEERS recommendations. Limitations To assess drivers of cost-effectiveness and quality, we only included studies with the full text available and thus excluded some CEAs that reported cost-effectiveness results. The heterogeneity of the included studies meant that the study results could not be synthesized and comparison across studies was limited. Conclusions Though many pulished studies have evaluated the cost-effectiveness of treatments for neuropathic pain, significant heterogeneity between CEAs prevented synthesis of the results. Standardized methodology and improved reporting would allow for more reliable comparisons across studies.

Beneluxa: What are the Prospects for Collective Bargaining on Pharmaceutical Prices Given Diverse Health Technology Assessment Processes?

Molecular Diagnosis & Therapy

Mutational Landscape of Resistance to Thyroid Hormone Beta (RTHβ) Abstract Resistance to thyroid hormone beta (RTHβ) is a syndrome characterized by reduced responsiveness of peripheral tissues to thyroid hormone (TH). In most cases, the disorder is associated with germline pathogenic variants in the thyroid hormone receptor beta (THRB) gene. This paper summarizes the clinical and biochemical presentation of the disease, providing a comprehensive overview on molecular genetic features. Particular care is given in reporting all identified THRB variants with an assessed or unknown clinical significance. Our aim is to offer a useful tool for clinical and genetic specialists in order to ease clinical diagnosis and genetic counseling.

Modeling the Outcome of Systematic TPMT Genotyping or Phenotyping Before Azathioprine Prescription: A Cost-Effectiveness Analysis Abstract Background Thiopurine S-methyltransferase (TPMT) testing, either by genotyping or phenotyping, can reduce the incidence of adverse severe myelotoxicity episodes induced by azathioprine. The comparative cost-effectiveness of TPMT genotyping and phenotyping are not known. Objective Our aim was to assess the cost-effectiveness of phenotyping-based dosing of TPMT activity, genotyping-based screening and no screening (reference) for patients treated with azathioprine. Methods A decision tree was built to compare the conventional weight-based dosing strategy with phenotyping and with genotyping using a micro-simulation model of patients with inflammatory bowel disease from the perspective of the French health care system. The time horizon was set up as 1 year. Only direct medical costs were used. Data used were obtained from previous reports, except for screening test and admission costs, which were from real cases. The main outcome was the cost-effectiveness ratios, with an effectiveness criterion of one averted severe myelotoxicity episode. Results The total expected cost of the no screening strategy was €409/patient, the total expected cost of the phenotyping strategy was €427/patient, and the total expected cost of the genotyping strategy was €476/patient. The incremental cost-effectiveness ratio was €2602/severe myelotoxicity averted in using the phenotyping strategy, and €11,244/severe myelotoxicity averted in the genotyping strategy compared to the no screening strategy. At prevalence rates of severe myelotoxicity > 1%, phenotyping dominated genotyping and conventional strategies. Conclusion The phenotype-based strategy to screen for TPMT deficiency dominates (cheaper and more effective) the genotype-based screening strategy in France. Phenotype-based screening dominates no screening in populations with a prevalence of severe myelosuppression due to azathioprine of > 1%.

Advances in Detection of Kidney Transplant Injury Abstract Early detection of graft injury after kidney transplantation is key to maintaining long-term good graft function. Graft injury could be due to a multitude of factors including ischaemia reperfusion injury, cell or antibody-mediated rejection, progressive interstitial fibrosis and tubular atrophy, infections and toxicity from the immunosuppressive drugs themselves. The current gold standard for assessing renal graft dysfunction is renal biopsy. However, biopsy is usually late when triggered by a change in serum creatinine and of limited utility in diagnosis of early injury when histological changes are equivocal. Therefore, there is a need for timely, objective and non-invasive diagnostic techniques with good early predictive value to determine graft injury and provide precision in titrating immunosuppression. We review potential novel plasma and urine biomarkers that offer sensitive new strategies for early detection and provide major insights into mechanisms of graft injury. This is a rapidly expanding field, but it is likely that a combination of biomarkers will be required to provide adequate sensitivity and specificity for detecting graft injury.

Detection of Solid Tumor Molecular Residual Disease (MRD) Using Circulating Tumor DNA (ctDNA) Abstract Circulating tumor DNA (ctDNA) is a component of cell-free DNA that is shed by malignant tumors into the bloodstream and other bodily fluids. Levels of ctDNA are typically low, particularly in patients with localized disease, requiring highly sophisticated methods for detection and quantification. Multiple liquid biopsy methods have been developed for ctDNA analysis in solid tumor malignancies and are now enabling detection and assessment of earlier stages of disease, post-treatment molecular residual disease (MRD), resistance to targeted systemic therapy, and tumor mutational burden. Understanding ctDNA biology, mechanisms of release, and clearance and size characteristics, in conjunction with the application of molecular barcoding and targeted error correction, have increased the sensitivity and specificity of ctDNA detection techniques. Combinatorial approaches including integration of ctDNA data with circulating protein biomarkers may further improve assay sensitivity and broaden the scope of ctDNA applications. Circulating viral DNA may be utilized to monitor disease in some virally induced malignancies. In spite of increasingly accurate methods of ctDNA detection, results need to be interpreted with caution given that somatic mosaicisms such as clonal hematopoiesis of indeterminate potential (CHIP) may give rise to genetic variants in the bloodstream unrelated to solid tumors, and the limited concordance observed between different commercial platforms. Overall, highly precise ctDNA detection and quantification methods have the potential to transform clinical practice via non-invasive monitoring of solid tumor malignancies, residual disease detection at earlier timepoints than standard clinical and/or imaging surveillance, and treatment personalization based on real-time assessment of the tumor genomic landscape.

Theranostics of Genetic Diseases

Omics Studies in Hemoglobinopathies Abstract Hemoglobinopathies include all genetic diseases of hemoglobin and are grouped into thalassemia syndromes and structural hemoglobin variants. The β-thalassemias constitute a group of severe anemias with monogenic inheritance, caused by β-globin gene mutations. This review is focused on omics studies in hemoglobinopathies and mainly β-thalassemia, and discusses genomic, epigenomic, transcriptomic, proteomic and metabolomic findings. Omics analyses have identified various disease modifiers with an impact on disease severity and efficacy of treatments. These modifiers have contributed to the understanding of globin genes regulation/hemoglobin switching and the development of novel therapies. How omics data and their integration can contribute to efficient patient stratification, therapeutic management, improvements in existing treatments and application of novel personalized therapies is discussed.

Disruptive Technology: CRISPR/Cas-Based Tools and Approaches Abstract Designer nucleases are versatile tools for genome modification and therapy development and have gained widespread accessibility with the advent of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) technology. Prokaryotic RNA-guided nucleases of CRISPR/Cas type, since first being adopted as editing tools in eukaryotic cells, have experienced rapid uptake and development. Diverse modes of delivery by viral and non-viral vectors and ongoing discovery and engineering of new CRISPR/Cas-type tools with alternative target site requirements, cleavage patterns and DNA- or RNA-specific action continue to expand the versatility of this family of nucleases. CRISPR/Cas-based molecules may also act without double-strand breaks as DNA base editors or even without single-stranded cleavage, be it as epigenetic regulators, transcription factors or RNA base editors, with further scope for discovery and development. For many potential therapeutic applications of CRISPR/Cas-type molecules and their derivatives, efficiencies still need to be improved and safety issues addressed, including those of preexisting immunity against Cas molecules, off-target activity and recombination and sequence alterations relating to double-strand-break events. This review gives a concise overview of current CRISPR/Cas tools, applications, concerns and trends.

Innovative Therapies for Cystic Fibrosis: The Road from Treatment to Cure Abstract Cystic fibrosis (CF), a life-threatening multiorgan genetic disease, is facing a new era of research and development using innovative gene-directed personalized therapies. The priority organ to cure is the lung, which suffers recurrent and chronic bacterial infection and inflammation since infancy, representing the main cause of morbidity and precocious mortality of these individuals. After the disappointing failure of gene-replacement approaches using gene therapy vectors, no single drug is presently available to repair all the CF gene defects. The impressive number of different CF gene mutations is now tackled with different chemical and biotechnological tools tailored to the specific molecular derangements, thanks to the extensive knowledge acquired over many years on the mechanisms of CF cell and organ pathology. This review provides an overview and recalls both the successes and limitations of the different experimental approaches, such as high-throughput screening on chemical libraries to discover CF gene correctors and potentiators, dual-acting compounds, read-through molecules, splicing defect repairing tools, cystic fibrosis transmembrane conductance regulator (CFTR) "amplifiers," CFTR interactome modulators and the first gene editing attempts.

Shwachman-Diamond Syndrome: Molecular Mechanisms and Current Perspectives Abstract Shwachman-Diamond syndrome (SDS) is a rare inherited disease mainly caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. However, it has recently been reported that other genes, including DnaJ heat shock protein family (Hsp40) member C21 (DNAJC21), elongation factor-like 1 (EFL1) and signal recognition particle 54 (SRP54) are also associated with an SDS-like phenotype. Interestingly, SBDS, DNAJC21, EFL1 and SRP54 are involved in ribosome biogenesis: SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking. These findings strengthen the postulate that SDS is a ribosomopathy. SDS is a multiple-organ disease mainly characterized by bone marrow failure, bone malformations, pancreatic insufficiency and cognitive disorders. Almost 15–20% of patients with SDS present myelodysplastic syndrome with a high risk of acute myeloid leukemia (AML) transformation. Unfortunately, besides bone marrow transplantation, no gene-based therapy for SDS has yet been developed. This review aims to recapitulate the recent findings on the molecular mechanisms of SDS underlying bone marrow failure, hematopoiesis and AML development and to draw a realistic picture of current perspectives.

Genetic Modifiers of Fetal Haemoglobin in Sickle Cell Disease Abstract Fetal haemoglobin (HbF) levels have a clinically beneficial effect on sickle cell disease (SCD). Patients with SCD demonstrate extreme variability in HbF levels (1–30%), a large part of which is likely genetically determined. The main genetic modifier loci for HbF persistence, HBS1L-MYB, BCL11A and the β-globin gene cluster in adults also act in SCD patients. Their effects are, however, modified significantly by a disease pathology that includes a drastically shortened erythrocyte lifespan with an enhanced survival of those red blood cells that carry HbF (F cells). We propose a model of how HbF modifier genes and disease pathology interact to shape HbF levels measured in patients. We review current knowledge on the action of these loci in SCD, their genetic architecture, and their putative functional components. At each locus, one strong candidate for a causative, functional DNA change has been proposed: Xmn1-HBG2 at the β-globin cluster, rs1427407 at BCL11A and the 3 bp deletion rs66650371 at HBS1L-MYB. These, however, explain only part of the impact of these loci and additional variants are yet to be identified. Further progress in understanding the genetic control of HbF levels requires that confounding factors inherent in SCD, such as ethnic complexity, the role of F cells and the influence of drugs, are suitably addressed. This will depend on international collaboration and on large, well-characterised patient cohorts with genome-wide single-nucleotide polymorphism or sequence data.

Neuroradiology

European Society of Neuroradiology (ESNR)

Exploring new landmarks: analysis of Twitter usage during the 41st ESNR Annual Meeting Abstract We analyzed the use of Twitter during the 41st Annual Meeting of the European Society of Neuroradiology (ESNR) held in Rotterdam from 19 to 23 September 2018. The aim was to check the status of the European neuroradiology Twitter community and to discover which topics were discussed most often. The data were compared with a similar analysis performed during the Annual Meeting of the American Society of Neuroradiology (ASNR) in 2014. Even though the analysis demonstrated a low use of Twitter during the ESNR meeting, the platform still generated an important volume of impressions and engagement. This use was noted by the global community because topics of the meeting, such as the value of radiological reporting and advanced imaging, were discussed worldwide. These data, also compared to the American meeting, suggests a need for more prolific use and engagement with ESNR social media accounts in order to draw our members into discussions during meetings and to reinforce the place of European neuroradiology in the debate on key imaging topics as well as promoting society events.

Altered coupling of spontaneous brain activities and brain temperature in patients with adolescent-onset, first-episode, drug-naïve schizophrenia Abstract Purpose A recent study has reported that schizophrenia patients show an uncoupled association between intraventricular brain temperature (BT) and cerebral blood flow (CBF). CBF has been found to be closely coupled with spontaneous brain activities (SBAs) derived from resting-state BOLD fMRI metrics. Yet, it is unclear so far whether the relationship between the intraventricular BT and the SBAs may change in patients with adolescent-onset schizophrenia (AOS) compared with that in healthy controls (HCs). Methods The present study recruited 28 first-episode, drug-naïve AOS patients and 22 matched HCs. We measured the temperature of the lateral ventricles (LV) using diffusion-weighted imaging thermometry and measured SBAs using both regional homogeneity and amplitude of low-frequency fluctuation methods. A nonparametric Wilcoxon rank sum test was used to detect the difference in intraventricular BT between AOS patients and HCs with LV volume, age, and sex as covariates. We also evaluated the relationship between the intraventricular BT and the SBAs using partial correlation analysis controlling for LV volume, age, and sex. Results We found that HCs showed a significant negative correlation between the intraventricular BT and the local SBAs in the bilateral putamina and left superior temporal gyrus, while such a correlation was absent in AOS patients. Additionally, no significant difference between the two groups was found in the intraventricular BT. Conclusion These findings suggest that AOS patients may experience an uncoupling between intraventricular BT and SBAs in several schizophrenia-related brain areas, which may be associated with the altered relationships among intraventricular BT, CBF, and metabolism.

Atrophy of the ipsilateral mammillary body in unilateral hippocampal sclerosis shown by thin-slice-reconstructed volumetric analysis Abstract Purpose Conventional volumetric analysis could not detect ipsilateral atrophy of the mammillary body in patients with unilateral hippocampal sclerosis. By using thin-slice-reconstructed volumetric analysis, we investigated whether the mammillary body volume is smaller on the hippocampal sclerosis side than in healthy subjects or the non-hippocampal sclerosis side. Methods This retrospective study included 45 patients with unilateral hippocampal sclerosis and 30 healthy subjects. Three-dimensional T1WI of 1 mm thicknesses were oversampled to a thickness of 0.2 mm (thin-slice-reconstructed images), and the mammillary bodies were segmented manually to determine mammillary body volume on each side. Mammillary body volumes on the hippocampal sclerosis side were compared with those in healthy subjects or the non-hippocampal sclerosis side. Results In patients with right hippocampal sclerosis, right mammillary body volume was both significantly smaller than that in healthy subjects (30.3 ± 10.3 vs. 43.3 ± 8.07 mm3, P < 0.001) and significantly smaller than the left mammillary body volume in each patient (30.3 ± 10.3 vs. 41.4 ± 10.1 mm3, P < 0.001). Similarly, in patients with left hippocampal sclerosis, left mammillary body volume was both significantly smaller than that in healthy subjects (37.7 ± 11.2 vs. 47.0 ± 8.65 mm3, P < 0.001) and significantly smaller than right mammillary body volume in each patient (37.7 ± 11.2 vs. 42.5 ± 7.78 mm3, P = 0.044). Conclusions In this study, thin-slice-reconstructed volumetric analysis showed that, in patients with unilateral hippocampal sclerosis, mammillary body volume on the hippocampal sclerosis side is smaller than that in healthy subjects and the non-hippocampal sclerosis side.

Evaluation of 3D fat-navigator based retrospective motion correction in the clinical setting of patients with brain tumors Abstract Purpose A 3D fat-navigator (3D FatNavs)-based retrospective motion correction is an elegant approach to correct for motion as it requires no additional hardware and can be acquired during existing 'dead-time' within common 3D protocols. The purpose of this study was to clinically evaluate 3D FatNavs in the work-up of brain tumors. Methods An MRI-based fat-excitation motion navigator incorporated into a standard MPRAGE sequence was acquired in 40 consecutive patients with (or with suspected) brain tumors, pre and post-Gadolinium injection. Each case was categorized into key anatomical landmarks, the temporal lobes, the infra-tentorial region, the basal ganglia, the bifurcations of the middle cerebral artery, and the A2 segment of the anterior cerebral artery. First, the severity of motion in the non-corrected MPRAGE was assessed for each landmark, using a 5-point score from 0 (no artifacts) to 4 (non-diagnostic). Second, the improvement in image quality in each pair and for each landmark was assessed blindly using a 4-point score from 0 (identical) to 3 (strong correction). Results The mean image improvement score throughout the datasets was 0.54. Uncorrected cases with light and no artifacts displayed scores of 0.50 and 0.13, respectively, while cases with moderate artifacts, severe artifacts, and non-diagnostic image quality revealed a mean score of 1.17, 2.25, and 1.38, respectively. Conclusion Fat-navigator-based retrospective motion correction significantly improved MPRAGE image quality in restless patients during MRI acquisition. There was no loss of image quality in patients with little or no motion, and improvements were consistent in patients who moved more.

An integrated in utero MR method for assessing structural brain abnormalities and measuring intracranial volumes in fetuses with congenital heart disease: results of a prospective case-control feasibility study Abstract Purpose To refine methods that assess structural brain abnormalities and calculate intracranial volumes in fetuses with congenital heart diseases (CHD) using in utero MR (iuMR) imaging. Our secondary objective was to assess the prevalence of brain abnormalities in this high-risk cohort and compare the brain volumes with normative values. Methods We performed iuMR on 16 pregnant women carrying a fetus with CHD and gestational age ≥ 28-week gestation and no brain abnormality on ultrasonography. All cases had fetal echocardiography by a pediatric cardiologist. Structural brain abnormalities on iuMR were recorded. Intracranial volumes were made from 3D FIESTA acquisitions following manual segmentation and the use of 3D Slicer software and were compared with normal fetuses. Z scores were calculated, and regression analyses were performed to look for differences between the normal and CHD fetuses. Results Successful 2D and 3D volume imaging was obtained in all 16 cases within a 30-min scan. Despite normal ultrasonography, 5/16 fetuses (31%) had structural brain abnormalities detected by iuMR (3 with ventriculomegaly, 2 with vermian hypoplasia). Brain volume, extra-axial volume, and total intracranial volume were statistically significantly reduced, while ventricular volumes were increased in the CHD cohort. Conclusion We have shown that it is possible to perform detailed 2D and 3D studies using iuMR that allow thorough investigation of all intracranial compartments in fetuses with CHD in a clinically appropriate scan time. Those fetuses have a high risk of structural brain abnormalities and smaller brain volumes even when brain ultrasonography is normal.

Radiation exposure of image-guided intrathecal administration of nusinersen to adult patients with spinal muscular atrophy Abstract Purpose To examine diagnostic reference levels (DRL) and achievable doses (AD) of image-guided and size-specific dose estimates (SSDE) and organ and effective doses of CT-guided intrathecal nusinersen administration to adult patients with spinal muscular atrophy (SMA). Methods This study involved a total of 60 image-guided intrathecal nusinersen treatments between August 2017 and June 2018. Patient cohort comprised 14 adult patients with the following SMA types: type 2 (n = 9) and type 3 (n = 5) with a mean age of 33.6 years (age range 25–57 years). DRL, AD, SSDE, organ, and effective doses were assessed with a dose-monitoring program based on the Monte Carlo simulation techniques. Results DRL and AD for computed tomography are summarised as follows: in terms of CT-dose index (CTDIvol), DRL 56.4 mGy and AD 36.7 mGy; in terms of dose-length product (DLP), DRL 233.1 mGy cm and AD 120.1 mGy cm. DRL and AD for fluoroscopic guidance were distributed as follows: in terms of dose-area product (DAP), DRL 239.1 μGy m2 and AD 135.2 mGy cm2. Mean SSDE was 9.2 mGy. Mean effective dose of the CT-guided injections was 2.5 mSv (median 2.0 mSv, IQR 1.3–3.2 mSv). Highest organ doses in the primary beam of radiation were the small intestine 12.9 mSv, large intestine 9.5 mSv, and ovaries 3.6 mSv. Conclusion Radiation exposure of SMA patients measured as DRLs is generally not higher compared with patients without SMA despite severe anatomical hazards. Dose monitoring data may allow clinicians to stratify radiation risk, identify organs at risk, and adopt measures for specific radiation dose reduction.

Gadolinium retention in gliomas and adjacent normal brain tissue: association with tumor contrast enhancement and linear/macrocyclic agents Abstract Purpose To quantitate gadolinium deposits in gliomas and adjacent normal brain specimens, and to evaluate their association with tumor contrast enhancement and the type of gadolinium-based contrast agent (GBCA) used. Methods A total of 69 patients with primary glioma who underwent contrast-enhanced magnetic resonance imaging (MRI) prior to surgery were included in this retrospective study. Gadolinium was measured from histologically viable tumor, normal brain, and necrosis within the sample, when available, using inductively coupled plasma mass spectrometry (ICP-MS). Tumor contrast enhancement was categorized as none, minimal, or noticeable. Differences in gadolinium deposits by contrast enhancement and GBCA type were assessed. Results Seven patients received linear GBCA and 62 macrocyclic, respectively. At the time of surgery, gadolinium deposits were detected in 39 out of 69 (57%) tumor samples, 8 out of 13 (62%) normal brain, and 12 out of 14 (86%) necrotic specimens. Gadolinium was detected in both enhancing and non-enhancing tumors, but was greatest in gliomas with noticeable enhancement (p = 0.02). Administration of linear agents gadodiamide and gadopentetate dimeglumine resulted in significantly higher tumor gadolinium relative to macrocyclic gadoterate meglumine (p < 0.01 and p < 0.05, respectively). Normal brain and necrosis also showed higher gadolinium after exposure to linear gadodiamide (both p < 0.05). In multivariate regression, GBCA type (linear/macrocyclic) was the most powerful predictor of tumor gadolinium retention (p < 0.001). Conclusion Gadolinium can be detected in both enhancing and non-enhancing gliomas, neighboring normal brain, and necrosis. Gadolinium retention is higher after exposure to linear GBCAs compared with the macrocyclic gadoterate meglumine.

Grey matter activation by caloric stimulation in patients with unilateral peripheral vestibular hypofunction Abstract Purpose A combination of the caloric test with functional magnetic resonance imaging (fMRI) is a promising method for a comprehensive diagnostics of pathologies of the vestibular system. The aim of this study was to investigate the potential pattern of grey matter local activation in fMRI using cold and hot caloric stimulation in patients presenting unilateral peripheral vestibular injury. Methods Forty right-handed participants aged 27 to 56 with the diagnosis of right-sided peripheral vestibular hypofunction were included. Stimulation was performed separately for the right and the left ear with cold (C, 14–15 °C) stimulus and hot (H, 48–49 °C) stimulus. Grey matter activation was assessed in BOLD technique using a 3T scanner. Results We observed activity within the parieto-insular vestibular cortex (PIVC), thalamus, insula and retroinsular area, hippocampus, and cerebellum, as well as oculomotor centers located in the precentral gyrus, superior temporal gyrus, and intraparietal sulcus. Cold stimulus resulted in more areas of activation in response to the right ear activation rather than to the left ear. The ipsilateral activity was noted for insular cortex and intraparietal sulcus. The differences between hot and cold stimuli were noted for the right ear. Conclusions In this preliminary study, the combination of the caloric test and fMRI allowed to present specific pattern of grey matter activation in patients with unilateral peripheral vestibular injury. Further studies are necessary to develop patterns or cortical maps differentiating various balance disorders and to analyze the dynamics of cortical plasticity after the injury.

Asymmetric cavernous sinus enlargement: a novel finding in Sturge–Weber syndrome Abstract Purpose Enlargement of deep cerebral veins and choroid plexus engorgement are frequently reported in Sturge–Weber syndrome. We aim to describe cavernous sinus involvement in patients with this syndrome and to identify possible clinical-neuroimaging correlations. Methods Sixty patients with Sturge–Weber syndrome (31 females, mean age 4.5 years) and 120 age/sex-matched controls were included in this retrospective study. We performed a visual analysis to identify patients with asymmetric cavernous sinus enlargement. Then, we measured on axial T2WI the left (A), right (B), and bilateral (LL) transverse diameters of the cavernous sinus. We calculated the module of the difference |A-B| and the cavernous sinus asymmetry index as the ratio |A-B|/LL. Differences among groups were assessed by Mann–Whitney U and Kruskal–Wallis tests. Clinicoradiological associations were evaluated by Fisher exact test. Results We found seven subjects (11.6%) with asymmetric CS enlargement. The |A-B| and cavernous sinus asymmetry index were higher in patients with asymmetric CS enlargement compared with controls and patients without visible CS abnormalities (pB < 0.05). Asymmetric CS enlargement was always ipsilateral to facial port-wine stains (7/7), and, when present, to leptomeningeal vascular malformations (4/7). It was significantly associated with ipsilateral bone marrow changes (p = 0.013) and dilated veins (p = 0.002). Together with brain atrophy and deep venous dilatation, this sign was associated with neurological deficits (p < 0.05). Conclusions We expanded the spectrum of venous abnormalities in SWS, showing the presence of asymmetric cavernous sinus enlargement in more than one tenth of patients, likely related to increased venous drainage.