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Background Spinal cord herniation (SCH) remains a challenging diagnosis for neuroradiologists and may require treatment challenging for neurosurgeons. Most cord herniations are usually found at anterior thoracic levels. Clinical presentation A 28-year-old woman presented at our department with a 7-year history of progressive myelopathy. MR analysis showed a displacement of the spinal cord in a lateral thoracic dural defect. The herniated cord was released using a microscope and the patient significantly recovered 6 months after surgery. Conclusion We present a unique case of pure lateral SCH. In the light of reviewed literature and operative findings, the underlying pathophysiological mechanisms are discussed.

Neurobeachin (NBEA) was initially identified as a candidate gene for autism. Recently, variants in NBEA have been associated with neurodevelopmental delay and childhood epilepsy. Here, we report on a novel NBEA missense variant (c.5899G > A, p.Gly1967Arg) in the Domain of Unknown Function 1088 (DUF1088) identified in a child enrolled in the Undiagnosed Diseases Network (UDN), who presented with neurodevelopmental delay and seizures. Modeling of this variant in the Caenorhabditis elegans NBEA ortholog, sel-2, indicated that the variant was damaging to in vivo function as evidenced by altered cell fate determination and trafficking of potassium channels in neurons. The variant effect was indistinguishable from that of the reference null mutation suggesting that the variant is a strong hypomorph or a complete loss-of-function. Our experimental data provide strong support for the molecular diagnosis and pathogenicity of the NBEA p.Gly1967Arg variant and the importance of the DUF1088 for NBEA function.

Background Non-tunneled hemodialysis catheters are currently used for critically ill patients with acute kidney injury requiring extracorporeal renal replacement therapy. Strategies to prevent catheter dysfunction and infection with catheter locks remain controversial. Methods In a multicenter, randomized, controlled, double-blind trial, we compared two strategies for catheter locking of non-tunneled hemodialysis catheters, namely trisodium citrate at 4% (intervention group) versus unfractionated heparin (control group), in patients aged 18 years or older admitted to the intensive care unit and in whom a first non-tunneled hemodialysis catheter was to be inserted by the jugular or femoral vein. The primary endpoint was length of event-free survival of the first non-tunneled hemodialysis catheter. Secondary endpoints were: rate of fibrinolysis, incidence of catheter dysfunction and incidence of catheter-related bloodstream infection (CRBSI), all per 1000 catheter-days; number of hemorrhagic events requiring transfusion, length of stay in intensive care and in hospital; 28-day mortality. Results Overall, 396 randomized patients completed the trial: 199 in the citrate group and 197 in the heparin group. There was no significant difference in baseline characteristics between groups. The duration of event-free survival of the first non-tunneled hemodialysis catheter was not significantly different between groups: 7 days (IQR 3–10) in the citrate group and 5 days (IQR 3–11) in the heparin group (p = 0.51). Rates of catheter thrombosis, CRBSI, and adverse events were not statistically different between groups. Conclusions In critically ill patients, there was no significant difference in the duration of event-free survival of the first non-tunneled hemodialysis catheter between trisodium citrate 4% and heparin as a locking solution. Catheter thrombosis, catheter-related infection, and adverse events were not statistically different between the two groups. Trial registration Registered with Clinicaltrials.gov under the number NCT01962116. Registered 14 October 2013.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Dijon Football Côte d"Or OnBehalf CLEO-CD Background Congestive heart failure (CHF) can be destabilized by Covid-19 (C19) lockdown. Purpose To evaluate the impact of lockdown in CHF patients. Methods 150 out-patients from the HF Clinic of our hospital were invited to answer to a phone-call interview during the 7th week of first C19 lockdown . Results From 124 questionnaires, more than 1/5 felt worse and almost 1/4 declared a psychologic distress. CHF medications were modified in 10%. Decrease in physical activity was observed in 2/5. Almost 1/2 declared increased screen time; smokers often increased consumption. Adherence to dietary counselling was reduced by 1/6, increase in weight and HF symptoms were common. Some patients benefitted from a teleconsultation. Conclusions Our patients exhibited well-being impairment and unhealthy behaviours. Medication adherence was not diminished and the reduction in care access was counterbalanced by a switch toward telehealth. Main results 124 patients 75 Male (M) 49 Female (F) p value between M and F Age, years 71.0 ± 14.0 68.9 ± 13.7 74.3 ± 14.0 0.03 Urban/Rural 82/42 49/26 33/16 0.84 HFrEF* 87 62 25 2 kg 34 22 (29.3) 12 0.68 Switch for teleconsultation (##) 16 11 (34.4) 5 1 Teleconsultation (total) 23 14 9 1 Decrease in physical activity 52 25 (33.3) 27 0.02 Increase in screen time 57 31 (41.3) 26 0.27 Increase in cigarette consumption (9 smokers) 4 3 1 1 Decrease in dietary adherence (###) 22 (17.7) 15 (20.0) 7 (14.3) 0.47 *HFrEF; # Kessler-6 score ≥ 5; ## from planned physical examination; ### salt, water, alcohol

Activating mutations of MYD88 (MYD88L265P being the far most frequent) are found in most cases of Waldenström macroglobulinemia (WM) as well as in various aggressive B-cell lymphoma entities with features of plasma cell (PC) differentiation, such as activated B-cell type diffuse large B-cell lymphoma (DLBCL). To understand how MYD88 activation exerts its transformation potential, we developed a new mouse model in which the MYD88L252P protein, the murine ortholog of human MYD88L265P, is continuously expressed in CD19 positive B-cells together with the Yellow Fluorescent Protein (Myd88L252P mice). In bone marrow, IgM B and plasma cells were expanded with a CD138 expression continuum from IgMhigh CD138low to IgMlow CD138high cells and the progressive loss of the B220 marker. Serum protein electrophoresis (SPE) longitudinal analysis of 40 Myd88L252P mice (16 to 56 weeks old) demonstrated that ageing was first associated with serum polyclonal hyper gammaglobulinemia (hyper Ig) and followed by a monoclonal immunoglobulin (Ig) peak related to a progressive increase in IgM serum levels. All Myd88L252P mice exhibited spleen enlargement which was directly correlated with the SPE profile and was maximal for monoclonal Ig peaks. Myd88L252P mice exhibited very early increased IgM PC differentiation. Most likely due to an early increase in the Ki67 proliferation index, IgM lymphoplasmacytic (LP) and plasma cells continuously expanded with age being first associated with hyper Ig and then with monoclonal Ig peak. This peak was consistently associated with a spleen LP-like B-cell lymphoma. Clonal expression of both membrane and secreted µ chain isoforms was demonstrated at the mRNA level by high throughput sequencing. The Myd88L252P tumor transcriptomic signature identified both proliferation and canonical NF-κB p65/RelA activation. Comparison with MYD88L265P WM showed that Myd88L252P tumors also shared the typical lymphoplasmacytic transcriptomic signature of WM bone marrow purified tumor B-cells. Altogether these results demonstrate for the first time that continuous MYD88 activation is specifically associated with clonal transformation of differentiating IgM B-cells. Since MYD88L252P targets the IgM PC differentiation continuum, it provides an interesting preclinical model for development of new therapeutic approaches to both WM and aggressive MYD88 associated DLBCLs.

Objective Immunomodulatory drugs (IMIDs: thalidomide, lenalidomide and pomalidomide) are widely used in patients with multiple myeloma (MM). The aim of our study was to validate a questionnaire to evaluate the self-capacity of MM patients to manage IMID treatment including side effects. Methods We used a method adapted from the recommendations of the European Organisation for Research and Treatment of Cancer (EORTC) to validate a French questionnaire for patients with MM treated with IMIDs. Results The face validity was evaluated in 15 patients and the construct validity in 56 patients. For discriminant validity, two groups were constituted by gender and depending on whether they had a previous IMID treatment. The median questionnaire score was 11.33/16 (IQR 9.75-12.08) with a minimum of 5.2 and a maximum of 14.75. For discriminant validity, a statistically significant difference was observed for patient capacity to contact healthcare professionals in specific situations and drug intake in case of swallowing disorder. Convergent validity showed an acceptable reliability for the scores of the different questions. Conclusion The questionnaire has shown to be a valid tool for the assessment of the adherence and side-effect management skills for MM patients with IMID treatment.

International audience

Aims Cardiovascular co‐morbidities like congestive heart failure (CHF) alter the course of coronavirus disease 2019. Factors associated with the outbreak and lockdown can exacerbate CHF. Methods and results We analysed the answers of 124 randomly selected CHF outpatients (mean age 71.0 ± 14.0 years, 60.5% male) interviewed by phone during the sixth and seventh weeks of the lockdown. Most patients were treated for New York Heart Association class II (38.7%) and reduced ejection fraction HF (70.2%). Psychological distress (Kessler 6 score ≥ 5) was common (18.5%), and 21.8% felt worse than before the lockdown. Few patients (n = 10) adjusted their intake of HF medications, always on medical prescription. Decreased physical activity was common (41.9%) and more frequent in women (P = 0.025) and urban dwellers (P = 0.009). Almost half of respondents (46.0%) declared increased screen time, but only few declared more alcohol intake (4.0%). Weight gain was common (27.4%), and 44.4% of current smokers increased tobacco consumption. Adherence to recommended salt or fluid intake restrictions was reduced in 14.5%. Increase in HF symptoms was commonly reported (21.8%) and tended to be higher in women than in men (P = 0.074). Of the 23 patients who had a phone teleconsultation during the pandemic, 16 had initially planned an in‐person consultation that they switched for teleconsultation. Conclusions During the lockdown, psychological distress and decreased well‐being were common in CHF outpatients, and there was an increase in unhealthy lifestyle behaviours. These changes may negatively impact short‐term and long‐term prognoses. Medication adherence was maintained, and limitations in access to care were partly counterbalanced by use of telehealth.

Purpose Daratumumab is the first anti-CD38 monoclonal antibody of the class approved for recurrent and refractory multiple myeloma. Grade 3 and 4 Infusion-Related Reactions (IRRs) are frequent during the first and second infusions. Due to the risks associated with severe IRRs, daratumumab is systematically administered over a period of 3.5 hours. The main objective of this study was to evaluate the safety of a 90-minute daratumumab infusion from the third infusion. Patients and methods All patients who had received two or more doses of daratumumab in monotherapy or in combination with standard infusion rates were included. We excluded patients enrolled in clinical trials. For the rapid infusion protocol, 20% of the dose was administered over 30 minutes and the remaining 80% over 60 minutes. Results From April 1 to May 31, 2019, 25 patients received 53 90-minute infusions of daratumumab. Premedication included corticosteroids, antipyretics, antihistamines, and if necessary a leukotriene receptor antagonist. No grade 3 or grade 4 IRRs were observed. Conclusion From the third infusion, we found that a rapid administration of daratumumab (90 vs 210 minutes) was well tolerated and safe. It would be interesting to test this regimen from the second infusion.

International audience; Hepatocellular carcinoma is the fourth leading cause of cancer death. For unresectable intermediate-stage hepatocellular carcinoma, the standard treatment is transarterial chemoembolization. To date, the overall survival at three years remains low, and there is currently no consensus about the best anticancer agent and optimal treatment regimen. We report the case of a hepatocellular carcinoma patient with a vascular contraindication to embolization who achieved a complete response after four intra-arterial infusions of idarubicin emulsified with lipiodol. The patient maintained his response over a three-year period without any hepatocellular carcinoma treatment, demonstrating the major role of the anticancer agent in the efficacy of transarterial therapies for intermediate-stage hepatocellular carcinoma.

Cisplatin-pemetrexed is the first-line chemotherapy for advanced, metastatic non-squamous non-small cell lung cancer (NSCLC), but the risk of kidney toxicity limits the therapeutic schedule. We performed a retrospective study of patient survival at 1 year and glomerular filtration rate (GFR) outcomes in cisplatin-pemetrexed-treated NSCLC patients. Patients (P) treated for NSCLC between 2008 and 2014 were divided into two groups according to GFR at diagnosis: G1 (GFR ≥ 90 mL/min/1.73 m2) and G2 (GFR between 60 and 89 mL/min/1.73 m2). GFR were compared in the two groups at 3 and 12 months. The following statistical methods were used: multivariate generalized estimating equation model for GFR outcome, Kaplan-Meier method for patient survival rate, and Cox model for analysing survival criteria. A total of 112 patients were included in the study (G1 = 87 P, G2 = 25 P). At 12 months, mean GFR significantly decreased by 28.4 mL/min/1.73 m2 (− 22.3%, p = 0.001) in G1 and. 13.8 mL/min/1.73 m2 (− 17.2%, p = 0.001) in G2. Median patient survival was 9.6 months (1.1–52.4) in G1 and 19.7 months (3.7–56.9) in G2. A better overall survival was significantly correlated with GFR between 60 and 89 mL/min/1.73 m2 at diagnosis (p = 0.04), and higher cumulated doses of pemetrexed (p = 0.003) and cisplatin (p = 0.001). The better survival rate in G2 and its correlation with pemetrexed and cisplatin treatments suggest that, until other therapeutic choices become available, a cautious increase in dosage could be investigated as a way to improve poor prognoses.

Background Mechanical thrombectomy for acute ischemic stroke recently proved its superiority to standard medical management alone. With the increasing number of procedures, practitioners are exposed to unexpected situations that may lead to failure of access and significantly worse clinical outcome. Being able to plan the procedure and use alternative techniques may be useful in case of peculiar anatomy. Case Description We report here the case of a 60-year-old man referred to our institution for an acute ischemic stroke. The patient had an initial National Institutes of Health Stroke Scale score of 19. The patient's medical history revealed an unspecified cervical treatment at the level of C5-C6 20 years previously. Magnetic resonance imaging showed a left M1 occlusion and the absence of ipsilateral common carotid. The digital subtraction angiography revealed an anastomosis through the left inferior and superior thyroid artery. Mechanical thrombectomy was performed through direct cervical access with a TICI 3 recanalization score. Conclusions Absence of viable access to perform mechanical thrombectomy during acute ischemic stroke is a rare but pejorative event. Direct common carotid puncture, even in its distal segment, when necessary is a feasible technique to perform internal carotid catheterization.

The primary objective was to assess the remission rate, and the secondary objectives were to evaluate the early complications and recurrence rate and to define the predictive factors for the remission and recurrence rates. This prospective single-center study included 230 consecutive patients, operated on by a single surgeon for Cushing’s disease via a transsphenoidal endoscopic endonasal approach, over a 6-year period (2008–2013). The patients included in this series were all adults (>18 years of age), who presented with clinical and biological characteristics of Cushing’s disease confirmed based on dedicated MRI pituitary imaging. Biochemical remission was defined as a postoperative serum cortisol level

Background To ascertain the safety and mid-term outcomes of Rotarex®S rotational atherectomy plus thrombectomy device (Straub Medical AG, Wangs, Switzerland) with or without adjunctive treatment (e.g., percutaneous transluminal angioplasty, PTA/drug-coated balloon, DCB/stenting) in patients with in-stent restenosis (ISR) or occlusion in the iliac and/or infrainguinal arteries. Methods French multicenter retrospective study of all patients treated by in-stent percutaneous mechanical debulking (PMD) of the lower limbs with Rotarex®S device between January 2013 and November 2018. Results The cohort consisted of 128 patients (88 men and 40 women), aged 39-94 years (mean, 66.7±12 years). All patients presented with cardio-vascular risk factors. Overall, 51.5% of patients had critical limb ischemia. The study demonstrated a technical success of 96.9% in the population with PMD and adjunctive PTA (95/128, 74.2%) or adjunctive DCB (16/128, 12.5%) or both (13/128, 10.2%). At 12-months follow-up, the primary clinical success/patency rate was 92.3% and the secondary clinical success/patency rate was 91.4%. Rate of limb salvage was 93.7%. Overall 32 (25%) reinterventions were reported with mean time from Rotarex®S treatment to reintervention of 7.1±8.2 months. Target lesion revascularization (TLR) was 19.5% (25/128). Seven (5.5%) patients developed distal embolism that responded to endovascular treatment. At mean follow-up, major adverse events (MAE) observed were death (18/128, 14.1%), myocardial infarction (MI) (9/128, 7.0%), stroke (2/128, 1.6%) and renal failure (3/128, 2.3%). Conclusions Recanalization with Rotarex®S rotational atherectomy plus thrombectomy device is a practical choice for arterial ISR/occlusions of the iliac and/or infrainguinal arteries, regardless of the age of the thrombus, with satisfying TLR. Only adjunctive PTA is often necessary to further improve the recanalization.

Summary Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.

Objective: To describe the responses, toxicities and outcomes of HCC patients treated by transarterial chemoembolization (TACE) using idarubicin-loaded TANDEM beads. Materials and Methods: Seventy-two consecutive patients (mean age: 71 years (58&ndash, 84 years)) with HCC were treated by TACE using idarubicin-loaded TANDEM in a first line, over a five-year period. Most patients (89%) had liver cirrhosis classified as Child&ndash, Pugh A (90%). BCLC B classification applied in 85% of cases. Baseline tumor burden was limited to one to three nodules in 92% of cases, unilobar in 88% cases, with a median tumor diameter of 55 mm (range: 13&ndash, 150 mm). Toxicity was assessed using NCI CTC AE v4.0. Response was assessed using mRECIST criteria. Time-to-treatment failure (TTTF) and overall survival (OS) were also calculated based on Kaplan&ndash, Meier method. Result: Of 141 TACE sessions performed with bead sizes of 100 and 75 &micro, m in 42 (29.8%) and 99 (70.2%) sessions, respectively. In 78% of all TACE sessions, the full dose of idarubicin-loaded beads was injected. Grade 3&ndash, 4 AE were observed after 73 (52%) sessions, most of them being biological. Multi-organ failure was observed three days after the first TACE in a Child B patients, unfortunately leading to death. Overall, the best objective response rate (ORR) was 65%. Median follow-up lasted 14.3 months (95% CI: 11.2&ndash, 18.8 months). Median TTTF and OS were 14.4 months (95% CI: 7.2&ndash, 24.6 months) and 34.6 months (95% CI: 24.7&mdash, not reached) respectively. Conclusion: In this retrospective study involving well-selected HCC patients, high ORR and long TTTF and OS are observed after TACE using idarubicin-loaded TANDEM. A randomized trial is needed.

Background According to the Code of Public Health, the pharmacist advises and informs the patient to ensure the right use and high drug adherence. In clinical trials (CT), investigational medicinal products (IMP) are dispensed by the pharmacy department. A copy of the prescription is given to the patients in ambulatory: it is a support to information for the patient available at any time at home. In our hospital, prescriptions for CT are usually provided by the sponsor. Purpose The purpose of this work was to evaluate information about IMP on the prescriptions provided by the sponsors and to propose areas for improvement. Material and methods All the CTs with at least one IMP was taken at home and opened in the pharmacy department of a university hospital on 1 January 2018 were included in this retrospective study. A checklist of eight criteria deemed essential to inform the patient regarding his treatment was created in accordance with the regulations. Results A total of 93 CTs were evaluated, 35% were institutional CTs. Eleven per cent (n=10) of the prescriptions contained none of the listed criteria. For each criterion, the proportion of prescriptions including the information was 83% for dosage, 69% for product’s conditioning, 43% for treatment’s duration, 25% for time of taking, 19% for intake, 5% for storage temperature, 2% for adverse reactions and 0% for drug interactions. Eighty-eight per cent (n=82) of the evaluated CTs were oral IMP and 30% (n=25) were chemotherapies. Conclusion The most frequent information on prescriptions is the dosage and the packaging of the IMP. At the other end, information on what to do in case of adverse events and drug interactions are rare or non-existent. The pharmacist has an important and essential role in dispensing pharmaceutical advice for CT.1 A collaboration between services and pharmacy is planned in order to establish a standard prescription for CTs with specific information. Improving the quality of prescription information will optimise the safety of IMP taking. Reference and/or acknowledgements Schoenenberger JA, et al. Assessment of the information on investigational oral treatment provided to patients in clinical trials. Euro J Hospl Pharm 2012;(19):230–1. No conflict of interest.

Alzheimer's dementia (AD) is the sixth leading cause of death in the U.S., with an estimated $305 billion cost of care in 2020. Currently there are no cures or therapies to ameliorate the disease progression and symptoms. Growing evidence links a diet characterized by high antioxidant components with benefits to cognitive function, which is indicative of the preventative potential of dietary inteventions. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study is a 3-year, multicenter, randomized controlled trial to test the effects of the MIND diet on cognitive function in 604 individuals at risk for AD. Men and women ages 65 to 84 years were recruited. Eligible participants were randomized to either the MIND diet with mild caloric restriction or their usual diet with mild caloric restriction. Cognitive assessments, medical history, blood pressure, anthropometric measurements, and blood and urine sample collections will be taken at baseline and follow-up visits. MRI scans will be completed on approximately half of the enrolled participants at the start and end of the study. Unique features of the MIND study include: 1) a dietary pattern, rather than single nutrient or food, tested in an at-risk population; 2) foods featured as key components of the MIND diet (i.e. extra-virgin olive oil, blueberries, and nuts) provided for participants; and 3) MRI scans of brain structure and volume that may provide potential mechanistic evidence on the effects of the diet. Results from the study will be crucial to the development of dietary guidelines for the prevention of AD.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is increasing in incidence. The overall prognosis of patients with liver cancer is poor. The Barcelona Clinic Liver Cancer (BCLC) classification in 5 stages is endorsed by European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD). This classification is recommended for treatment allocation. Because a small proportion of patients are suitable for curative surgical treatment, various locoregional therapies are widely used to manage patients with HCC. The image-guided therapies, also called interventional radiology or interventional oncology (IO) techniques consisted in percutaneous or endovascular approach. This article reviews the different IO treatments available in HCC patients and the strength of the data.

Background COVID-19 outbreak and lockdown is a situation associating social and physical isolation, limited care access, psychological stress, and potential adoption of unhealthy lifestyle behaviours such as smoking. In a cohort of outpatients with chronic cardiac diseases, including congestive heart failure (CHF) and chronic coronary syndromes (CCS), we aimed to evaluate the impact of Covid-19 outbreak on tobacco consumption. Patients and methods During the 6th week of lockdown (which had started on March, 17th), 150 randomly selected CHF patients (from the Dijon HF-Clinic) and 250 CCS patients from the RICO survey were invited to answer an anonymous questionnaire. The 20-min lasting phone interview was conducted by 8 trained research assistants. The questionnaire, which was validated through internal and external control procedures, addressed medical, lifestyle topics and psychological distress through Kessler 6 score (K6) ≥ 5. Results Among the 400 patients, 325 were responders (81.2%), including 201 CCS and 124 CHF. Among the current smokers (n = 43), 13 (30.3%) declared increased tobacco consumption, including one woman who started smoking during the lockdown and one man who relapsed after quitting. The main reported explanations for increased smoking was stress (7) and inactivity (5); none declared the influence of media messages on a potential protective effect of nicotine as a cause of increase. Main results are summarized in Table 1 . Conclusion During COVID-19 lockdown, a significant rate of cardiac patients has increased their tobacco consumption, which is often associated with psychological distress and other deleterious lifestyle behaviours, in particular in men. These alarming findings may have major implications for disease destabilization and event recurrence in such high-risk patients at both short and long term. This may help to define preventive strategies to target after lockdown relief in chronic cardiac populations.

International audience; Background A prior in vitro study showed that idarubicin was the most cytotoxic agent for hepatocellular carcinoma (HCC) cell lines. Idarubicin-loaded beads for transarterial chemoembolization (TACE) were previously evaluated for the appropriate dose in a phase I dose-escalation study. Purpose To evaluate objective response rate (ORR), safety, and survival after TACE by using idarubicin-loaded beads for unresectable HCC. Materials and Methods This prospective single-arm phase II study was conducted between January 2015 and January 2017. Participants with unresectable HCC were included in the trial and underwent TACE with idarubicin-eluting beads. The primary end point was 6-month ORR assessed with independent central review by using modified Response Evaluation Criteria in Solid Tumors. Secondary end points were best ORR during the first 6 months, overall survival, progression-free survival, time to progression, and safety. A two-stage Fleming statistical design was used. Results Forty-six study participants (mean age, 71.2 years ± 10.2; six women and 40 men) were included; 44 participants underwent at least one TACE session. The 6-month ORR was 52% (23 of 44). The best ORR achieved was 68% (30 of 44). Fourteen of 44 (32%) participants underwent a curative treatment after TACE. Median progression-free survival, time to progression, and overall survival were 6.6 months, 9.5 months, and 18.6 months, respectively. TACE was discontinued for toxicity in four of 44 (9%) participants. The most frequent grade 3-4 adverse events were elevated aspartate aminotransferase (14 of 44, 32%), elevated γ-glutamyl transpeptidase (eight of 44, 18%), hyperbilirubinemia (seven of 44, 16%), elevated alanine aminotransferase (seven of 44, 16%), and pain (seven of 44, 16%). Conclusion Idarubicin-eluting beads showed a good safety profile and promising objective response rate and time to progression when used as part of a transarterial chemoembolization regimen for unresectable hepatocellular carcinoma. © RSNA, 2019 See also the editorial by Padia in this issue.

IF 2.369 (2017); International audience; Transarterial chemoembolization (TACE) combines intra-arterial delivery of a chemotherapeutic agent with selective embolization to obtain a synergistic effect. TACE is recognized as the standard treatment of hepatocellular carcinoma patients at an intermediate stage. If conventional TACE, defined as the injection of an emulsion of a drug with ethiodized oil, still has a role to play, the development of drug-eluting beads has allowed many improvements and optimization of the technique. TANDEM® microspheres are second-generation drug-loadable microspheres. This device raised a special interest due to its tightly calibrated spherical microspheres, with small sizes down to 40 μm available. In this review, we describe the technical characteristics of these microspheres, analyze the scientific literature and hypothesize on the future perspectives.

IF 2.653; International audience; ObjectivesTo investigate the efficacy, safety and cost of a pomalidomide-dexamethasone regimen in patients with relapsed and refractory multiple myeloma (RRMM).MethodsAll patients (n=63) treated with pomalidomide-dexamethasone for RRMM in our university hospital between August 2013 and October 2015 were included.ResultsPomalidomide was discontinued early due to progression (before the 4th cycle) in 17 (27%) patients. No case was discontinued for intolerance. The only independent factor that predicted early pomalidomide discontinuation was time from diagnosis to pomalidomide initiation

Background & Aims Idarubicin shows high cytotoxicity against hepatocellular carcinoma (HCC) cells, a high hepatic extraction ratio, and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolisation) was conducted in patients with cirrhotic HCC to estimate the maximum-tolerated dose (MTD) and to assess the safety, efficacy, and pharmacokinetics of the drug, and the health-related quality of life achieved by patients. Methods Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation. The idarubicin dose was escalated according to a modified continuous reassessment method. The MTD was defined as the dose closest to that causing dose-limiting toxicity (DLT) in 20% of patients. Results A group of 15 patients were enrolled, including one patient at 10 mg, four patients at 15 mg, seven patients at 20 mg, and three patients at 25 mg. Only two patients experienced DLT: oedematous ascitic decompensation and abdominal pain at 20 and 25 mg, respectively. The calculated MTD of idarubicin was 20 mg. The most frequent grade ≥3 adverse events were biological. One month after the second session, the objective response rate was 29% (complete response, 0%; partial response, 29%) based on modified Response Evaluation Criteria In Solid Tumours. The median time to progression was 5.4 months [95% confidence limit (CI) 3.0–14.6 months] and median overall survival was 20.6 months (95% CI 5.7–28.7 months). Pharmacokinetic analysis of idarubicin showed that the mean Cmax of idarubicin after intra-arterial injection of the idarubicin-lipiodol emulsion is approximately half the Cmax after intravenous administration. Health-related quality of life results confirmed the good safety results associated with use of the drug. Conclusions The MTD of idarubicin was 20 mg after two chemolipiodolisation sessions. Encouraging safety results, and patient responses and survival were observed. A phase II trial has been scheduled. Lay summary There is a need for transarterial regimens that improve the responses and survival of patients with unresectable HCC. In this phase I trial, we showed that two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation was well tolerated and gave promising efficacy in terms of tumour control and patient survival.

Non-functioning pituitary adenoma may be totally asymptomatic and discovered “incidentally” during radiological examination for some other indication, or else induce tumoral signs with compression of the optic chiasm and pituitary dysfunction. Non-functioning adenomas are mainly gonadotroph, but may also be “silent”. Treatment strategy depends on initial clinical, biological, ophthalmological and radiological findings. The present French Society of Endocrinology Consensus work-group sought to update the pitfalls associated with hormone assay and outline a hormonal exploration strategy for diagnosis and follow-up, without overlooking the particularities of silent adenoma. We also drew up basic rules for initial exploration and radiological follow-up of both operated and non-operated pituitary adenomas.

Background Thalidomide, lenalidomide and pomalidomide belong to the immunomodulatory drug family (IMIDs). Data on IMID adherence are lacking. Purpose The purpose of the study was to evaluate adherence to IMIDs in patients with multiple myeloma. Material and methods All patients managed in our teaching hospital for a multiple myeloma who had at least two successive dispensations of IMIDs were included in a prospective study between 1 March 2016 and 15 May 2016. We used a cancer specific questionnaire to measure patient adherence to IMIDs 1 (10 questions; 10 points). Non-adherence was defined as a score 1 Clinical and dispensation data were obtained from medical and pharmaceutical software in our hospital. Results 63 adult patients were included. Mean patient age was 68.2±10.4 years; 67% were men. Patients received lenalidomide (54%), pomalidomide (25%) or thalidomide (21%). Median time since diagnosis was 2.8 years (range 0.2–17.1). More than half of the patients used tools to help them with their medication. The mean questionnaire score was 8.2±1.2 (range 4–10). Mean time to fulfil the questionnaire was 9.2±4.7 min. 41% of the patients had ever taken their medicine too late in comparison with usual time. 57% of patients thought they took too many medicines. 43% of patients did not know the name of their medicines. We observed a mean MPR of 0.95±0.10 (range 0.67–1.20). A total of 76% of patients were considered as adherent using the questionnaire and 72% using the MPR. Conclusion Adherence to IMIDs was not optimal in our population. The use of adherence questionnaire and/or MPR may help the pharmacist to detect non-adherent patients. In these patients, pharmaceutical interventions may be of major interest. References and/or acknowledgements 1. Daouphars M, Ouvry M, Lenain P, et al. Preliminary validation of self-assessment tool to measure imatinib adherence in patients with chronic myeloid leukaemia. Pharmacotherapy2013;33:152–6. No conflict of interest

Background Patients with relapsed and refractory multiple myeloma (RRMM) have a median survival of about 3–6 months. 1 Purpose The aim of the study was to analyse efficacy, safety and cost of pomalidomide in patients with RRMM. Material and methods All patients in whom a treatment by pomalidomide was initiated between August 2013 and October 2015 for a RRMM in our hospital were included. Outcomes were predictive factors of early pomalidomide discontinuation (before the third month), overall response rate (ORR, using International Multiple Myeloma Working Group criteria 2 ), overall survival (OS), safety and treatment cost. Results 63 patients (mean age 61 years) were included. All patients received pomalidomide with dexamethasone. Pomalidomide was discontinued early in 17 (27%) patients. Time from diagnosis to pomalidomide initiation -3 ) and a haemoglobin level below 11g/dL (hazard ratio 2.7 vs ≥11 g/dL; 95% CI 1.0–7.0; p=0.04). The most common grade ≥3 adverse events were neutropenia (14%) and infections (25%). The mean pomalidomide cost per patient was €79 717±46 296 (range €17 850–214 200). Conclusion Compared with the MM-003 phase III trial, 3 we reported similar safety data but a higher ORR (51% vs 21%). We demonstrated the long term favourable safety and efficacy profile of pomalidomide in RRMM patients, even in those with stable disease. References and/or acknowledgements Kumar SK, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with ImiDs and bortezomib. Leukaemia2001;226:149–57. Rajkumar SV, et al. Consensus recommendations for the uniform reporting of clinical trials. Blood2011;117:4691–5. Miguel JS, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003). Lancet Oncol2013;14:1055–66. No conflict of interest

Background Thalidomide, a potent member of the immunomodulatory drug family, induces both direct myeloma cell death and indirect antimyeloma response through its impact on the microenvironment. The drug is approved in multiple myeloma, and also in other rare diseases, such as severe recurrent aphthous stomatitis. Thalidomide is considered an effective drug in all of its indications; it is also an expensive drug. In an area of limited resources, studies for assessing thalidomide adherence are needed for healthcare professionals and payers alike. Purpose The purpose of the study was to evaluate adherence to thalidomide. Material and methods Patients who had at least two successive dispensations of thalidomide, whatever the indication, between 12 July 2015 and 12 July 2016 in our teaching hospital were included in a retrospective study. The medication possession ratio (MPR) was used to evaluate thalidomide adherence. MPR was calculated according to the following formula: MPR=number of days of medication supplied within the refill interval/number of days in refill interval. 1 Clinical and dispensation data were obtained from medical and pharmaceutical software in our hospital. Based on the literature, the threshold of 90% was used to define two patient categories: MPR Results 51 adult patients were included: 40 with multiple myeloma (78%), 6 with cutaneous lupus erythematosus/Jessner–Kanof disease, 4 with serious aphthous/Behcet’s disease and 1 with Miescher’s granuloma. Mean patient age was 63.7±13.9 years; 51% were women. We observed a mean MPR of 0.90±0.16 (range 0.37–1.20). The mean MPR was 0.94±0.13 (range 0.61–1.20) in patients with multiple myeloma and 0.77±0.21 (range 0.37–0.99) in patients with other diseases. A total of 61% of patients were considered as adherents. The percentage of adherent patients was significantly higher in patients with multiple myeloma than in patients with other diseases (70% vs 27%, respectively; p=0.015). Conclusion Data are lacking concerning thalidomide adherence. Optimising thalidomide adherence may increase the efficacy of thalidomide based regimens. Considering the high cost of thalidomide, efforts to increase thalidomide adherence may also reduce wasted money in dispensing pills that are not taken by patients. References and/or acknowledgements 1. Peterson AM, et al. A checklist for medication compliance and persistence studies using retrospective databases. Value Health2007;10:3–12. No conflict of interest

SummaryBackground A phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads was performed in cirrhotic patients with hepatocellular carcinoma (HCC). Aim To estimate the maximum-tolerated dose (MTD) and to assess safety, efficacy, pharmacokinetics and quality of life. Methods Patients received a single TACE session with injection of 2 mL drug-eluting beads (DEBs; DC Bead 300–500 μm) loaded with idarubicin. The idarubicin dose was escalated according to a modified continuous reassessment method. MTD was defined as the dose level closest to that causing dose-limiting toxicity (DLT) in 20% of patients. Results Twenty-one patients were enrolled, including nine patients at 5 mg, six patients at 10 mg, and six patients at 15 mg. One patient at each dose level experienced DLT (acute myocardial infarction, hyperbilirubinaemia and elevated aspartate aminotransferase (AST) at 5-, 10- and 15-mg, respectively). The calculated MTD of idarubicin was 10 mg. The most frequent grade ≥3 adverse events were pain, elevated AST, elevated γ-glutamyltranspeptidase and thrombocytopenia. At 2 months, the objective response rate was 52% (complete response, 28%, and partial response, 24%) by modified Response Evaluation Criteria in Solid Tumours. The median time to progression was 12.1 months (95% CI 7.4 months – not reached); the median overall survival was 24.5 months (95% CI 14.7 months – not reached). Pharmacokinetic analysis demonstrated the ability of DEBs to release idarubicin slowly. Conclusions Using drug-eluting beads, the maximum-tolerated dose of idarubicin was 10 mg per TACE session. Encouraging responses and median time to progression were observed. Further clinical investigations are warranted (NCT01040559).

Background Transarterial chemoembolisation (TACE) is an effective treatment for unresectable hepatocellular carcinoma (HCC), but can cause severe toxicity. Aim To identify predictive factors of severe TACE-related toxicity in patients with unresectable HCC. Methods All HCC patients who underwent TACE at the Dijon University Hospital between 2008 and 2011 were included in this retrospective study. Severe TACE-related toxicity was defined as the occurrence of any adverse event grade ≥4, or any adverse event that caused a prolongation of hospitalisation of >8 days, or any additional hospitalisation within 1 month after TACE. Factors predicting toxicity were identified using a logistic regression model. The robustness of the final model was confirmed using bootstrapping (500 replications). Results 124 patients were included, median age was 67 years and 90% were male; 22 patients (18%) experienced severe TACE-related toxicity. Factors that independently predicted severe TACE-related toxicity in multivariate analysis were total tumour size (OR, 1.15 cm −1 ; 95%CI, 1.04–1.26; p = 0.01), and high serum AST levels (OR, 1.10 per 10 IU/l; 95%CI, 1.01–1.21; p = 0.04). The results were confirmed by bootstrapping. Conclusions Total tumour size and high serum AST levels were predictive factors of severe TACE-related toxicity in this hospital-based series of patients with unresectable HCC.

The purpose of this review is to describe the diagnostic criteria for spinal cord arteriovenous shunts (SCAVSs) when using magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), and to discuss the extent to which the different MRI and MRA sequences and technical parameters provide the information that is required to diagnose these lesions properly. SCAVSs are divided into four groups according to location (paraspinal, epidural, dural, or intradural) and type (fistula or nidus); each type of lesion is described. SCAVSs are responsible for neurological symptoms due to spinal cord or nerve root involvement. MRI is usually the first examination performed when a spinal cord lesion is suspected. Recognition of the image characteristics of vascular lesions is mandatory if useful sequences are to be performed-especially MRA sequences. Because the treatment of SCAVSs relies mainly on endovascular therapies, MRI and MRA help with the planning of the angiographic procedure. We explain the choice of MRA sequences and parameters, the advantages and pitfalls to be aware of in order to obtain the best visualization, and the analysis of each lesion.

Background Immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide; IMID) are widely used in the treatment of multiple myeloma patients. To date, few data are available on IMID adherence in multiple myeloma patients. The aim of our study was to evaluate IMID adherence and to compare two indirect methods to measure IMID adherence in multiple myeloma patients: a specific questionnaire and the medication possession ratio (MPR). Another aim was to explore this specific questionnaire for the assessment of IMID adherence in multiple myeloma patients. Methods All consecutive multiple myeloma patients, with at least two consecutive dispensations of thalidomide, lenalidomide or pomalidomide in our hospital were included in this prospective study. IMID adherence was measured using a specific questionnaire and the medication possession ratio. Relationship between the questionnaire scores and variables of interest was evaluated by multiple linear regression with a robust variance estimator. Findings Sixty-three patients were included in our study. The mean questionnaire score was 8.2±1.2 and the mean medication possession ratio value was 0.97±0.06. A total of 76% of patients were considered adherent according to the questionnaire (i.e. score ≥ 8), 94% according to the medication possession ratio (i.e. MPR ≥ 0.90), and 70% according to the questionnaire and the medication possession ratio. No statistically significant linear association was observed between the questionnaire score and any variables of interest including medication possession ratio. All Cronbach’s alpha were relatively low (range 0.0342–0.2443), showing a low correlation of the different questions with the questionnaire score. Conclusions Our study is the first prospective study evaluating IMID adherence in multiple myeloma patients in real life. The high adherence to IMIDs reported here, regardless of the drug, is encouraging considering the efficacy, toxicity and elevated cost of IMIDs. The specific questionnaire should be used with caution to evaluate IMID adherence.

We hypothesized metabolomic profiling could be utilized to identify children who scored poorly on the communication component of the Ages and Stages Questionnaire (ASQ); which assesses development in childhood, and to provide candidate biomarkers for autism spectrum disorders (ASD). In a population of three-year-old children, 15 plasma metabolites, were significantly (p < 0.05) different between children who were categorized as having communication skills that were “on schedule” (n = 365 (90.6%)) as compared to those “requiring further monitoring/evaluation” (n = 38 (9.4%)) according to multivariable regression models. Five of these metabolites, including three endocannabinoids, were also dysregulated at age one (n = 204 “on schedule”, n = 24 “further monitoring/evaluation”) in the same children. Stool metabolomic profiling identified 11 significant metabolites. Both the plasma and stool results implicated a role for tryptophan and tyrosine metabolism; in particular, higher levels of N-formylanthranilic acid were associated with an improved communication score in both biosample types. A model based on the significant plasma metabolites demonstrated high sensitivity (88.9%) and specificity (84.5%) for the prediction of autism by age 8. These results provide evidence that ASQ communication score and metabolomic profiling of plasma and/or stool may provide alternative approaches for early diagnosis of ASD, as well as insights into the pathobiology of these conditions.

Background The costs of drug-induced hypoglycemia are a critical but often neglected component of value-based arguments to reduce tight glycemic control in older adults with type 2 diabetes. Methods An economic (decision-tree) analysis compared rates, costs, quality-adjusted life-years, and incremental costs per quality-adjusted life-year gained associated with mild, moderate and severe hypoglycemic events for 6 glucose-lowering medication classes in type 2 diabetic adults aged 65–79 versus those 80 years and older. The national U.S. (Center for Medicare Services) and Canadian public health payer perspectives were adopted. Findings Incidence rates of drug-induced hypoglycemia were the highest for basal insulin and sulfonylureas: 8.64 and 4.32 events per person-year in 65–79 year olds, and 12.06 and 6.03 events per person-year for 80 years and older. In both the U.S. and Canada, metformin dominated sulfonylureas, basal insulin and glucagon-like peptide1 receptor agonists. Relative to sulfonylureas, thiazolidinediones had the lowest incremental cost-effectiveness ratios in the U.S. and dominated sulfonylureas in Canada for adults 80 years and older. Relative to sulfonylureas, dipeptidyl peptidase4 inhibitors were cost-effective for adults 80 years and older in both countries, and for 65–79 year olds in Canada. Annual costs of hypoglycemia for older adults attaining very tight glycemic control with the use of insulin or sulfonylureas were estimated at U.S.$509,214,473 in the U.S. and CAN$65,497,849 in Canada. Conclusions Optimizing drug therapy for older type 2 diabetic adults through the avoidance of drug-induced hypoglycemia will dramatically improve patient health while also generating millions of dollars by saving unnecessary medical costs.

CERVOXY COLL ACL CLIN; International audience; OBJECTIVES: To investigate the relationship between the improved stability of an anticancer drug-lipiodol emulsion and pharmacokinetic (PK) profile for transarterial chemoembolisation (TACE) of hepatocellular carcinoma (HCC).METHODS: The stability of four doxorubicin- or idarubicin-lipiodol emulsions was evaluated over 7 days. PK and clinical data were recorded after TACE with the most stable emulsion in eight unresectable HCC patients, after institutional review board approval.RESULTS: The most stable emulsion was the one that combined idarubicin and lipiodol (1:2 v:v). At 7 days, the percentages of aqueous, persisting emulsion and oily phases were 50-0-50, 33-0-67, 31-39-30, and 10-90-0 for the doxorubicin-lipiodol (1:1 v:v), doxorubicin-lipiodol (1:2 v:v), idarubicin-lipiodol (1:1 v:v), and the idarubicin-lipiodol (1:2 v:v) emulsion, respectively. After TACE, mean idarubicin Cmax and AUC0-24h were 12.5 ± 9.4 ng/mL and 52 ± 16 ng/mL*h. Within 24 h after injection, 40% of the idarubicin was in the liver, either in vessels, tumours, or hepatocytes. During the 2 months after TACE, no clinical grade >3 adverse events occurred. One complete response, five partial responses, one stabilisation, and one progression were observed at 2 months.CONCLUSION: This study showed a promising and favourable PK and safety profile for the idarubicin-lipiodol (1:2 v:v) emulsion for TACE.KEY POINTS:• Transarterial chemoembolisation (TACE) regimens that improve survival in hepatocellular carcinoma are needed. • Improved emulsion stability for TACE resulted in a favourable pharmacokinetic profile. • Preliminary safety and efficacy data for the idarubicin-lipiodol emulsion for TACE were encouraging.

An Asian study showed that gamma glutamyl transpeptidase (GGT) can predict survival after transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). This study was designed to validate in a European population this biomarker as an independent predictor of outcome after TACE of HCC and to determine a threshold value for clinical use.In 88 consecutive patients treated by TACE for HCC, the optimal threshold for GGT serum level was determined by a ROC analysis. Endpoints were time-to-treatment failure (TTTF) and overall survival (OS). All multivariate models were internally validated using bootstrapping (90 replications).Median follow-up lasted 373 days, and median overall survival was 748 days. The optimal threshold for GGT was 165 U/L (sensitivity: 89.3%; specificity: 56.7%; area under the ROC curve: 0.7515). Median TTTF was shorter when GGT was ≥165 U/L (281 days vs. 850 days; P0.001). GGT ≥165 U/L (hazard ratio (HR) = 2.06; P = 0.02), WHO PS of 2 (HR = 5.4; P = 0.002), and tumor size (HR = 1.12; P = 0.014) were independently associated with shorter TTTF. Median OS was shorter when GGT was ≥165 U/L (508 days vs. not reached; P0.001). GGT ≥ 165 U/L (HR = 3.05; P = 0.029), WHO PS of 2 (HR = 12.95; P0.001), alfa-fetoprotein (HR = 2.9; P = 0.01), and tumor size (HR = 1.096; P = 0.013) were independently associated with shorter OS. The results were confirmed by bootstrapping.Our results provide in a European population the external validation of GGT as an independent predictor of outcome after TACE of HCC. A serum level of GGT ≥ 165 U/L is independently associated with both shorter TTTF and OS.

Intracavernous carotid artery aneurysms (ICCAs) are rarely associated with life-threatening complications. We describe a 55-year-old woman who, after the rupture of an intracavernous carotid artery aneurysm, presented with a contralateral cavernous sinus syndrome and severe posterior fossa and spinal cord symptoms. Following parent artery occlusion, thrombosis of the posterior fossa and spinal cord veins caused a progressive worsening of the neurological status to a "locked-in" state. The patient fully recovered with anticoagulation therapy. Comprehension of the pathophysiological mechanism associated with the rupture of ICCA and early diagnosis of the related symptoms are essential in order to plan a correct treatment that includes the management of the aneurysm rupture and of possible complications related to venous thrombosis.

Objective: Further to a previous study whereby we reported that an in vitro emulsion of pirarubicin, amiodarone, and lipiodol was more stable and cytotoxic than a classic doxorubicin-lipiodol mixture, we designed a pilot study to evaluate efficacy and toxicity of a transarterial chemoembolization (TACE) procedure using a combination of pirarubicin, amiodarone, lipiodol, and gelatin sponge. Methods: The 43 patients included in this study underwent TACE for unresectable hepatocellular carcinoma. Computed tomography scans were performed to assess tumor response (RECIST) and lipiodol uptake after the first session. Median follow-up lasted 30 months. Endpoints were overall and progression-free survival. Survival was estimated using Kaplan Meier estimations and compared using log-rank tests. Univariate and multivariate Cox analyses were used to calculate hazard ratios with their 95% confidence interval (CI). Results: Twenty-seven (67.5%) patients had alcoholic cirrhosis. Mean tumor size was 9.5 cm (1―20 cm) and 37/43 were multifocal or diffuse. Cancer of the liver Italian program score was 0 in 7/40 and 1 in 16/40. Mean number of TACE sessions was 3.5 (1―11). There were 3 treatment-related deaths (2 severe sepsis, 1 bowel perforation). A partial response and a stable disease were observed in 12 (28%) and 29 (67%) patients, respectively. Median overall and progression-free survivals were 29 months (95% CI: 13.8―45) and 15 months (95% CI: 11.5―20.8), respectively. Cancer of the liver Italian program score ≤1 (P = 0.042) and lipiodol uptake >25% (P = 0.003) were independent prognostic factors for better overall survival. Conclusion: This new TACE procedure is safe with a high overall survival rate and certainly deserves phase III investigation to compare it with classic treatments such as doxorubicin-lipiodol TACE.

To the Editor, We recently read with great interest the article by Pascale et al. published in the 2015, 35(12) issue of Anticancer Research. The authors performed an in vitro screening study to compare the cytotoxic effects of eleven chemotherapeutic agents against VX2 and HepG2 cells in order to establish candidate drugs that can be tested on VX2 tumour model for transarterial chemoembolization (TACE) [1]. Among all effective treatments in the domain of cancers, TACE is for sure the procedure with the highest degree of heterogeneity in its realization around the world. In particular, guidelines did not mention the use of any specific chemotherapeutic agent for TACE of hepatocellular carcinoma (HCC). This is partly explained by the lack of robust preclinical data that could support the use of one or another chemotherapeutic agent and by the impossibility to compare TACE clinical studies because of different treatment regimens. Similarly to Pascale et al., we were also convinced for several years that the first step to improve efficacy of TACE for HCC is to select the most cytotoxic agent on HCC cell lines. The major strength of the study performed by Pascale et al. is that it evaluated the cytotoxicities of not only both agents that are currently being used for TACE of HCC but also those of recently targeted agents that have demonstrated their efficacy in various cancers: bevacizumab, lapatinib, sorafenib, and sunitinib. Another strength of the study is that it provided the comparison of eleven agents in the same experimental conditions, whereas in vitro screening studies included usually few agents. From one in vitro screening study to another one, experimental conditions such as time and concentration for exposure or type of cell line widely influence cytotoxicity of a drug. The authors recommended to test doxorubicin and sunitinib as first and second agents in the VX2 tumour model, respectively. It is surprising that the authors did not include idarubicin in the panel of tested agents. In a previous in vitro screening study including eleven chemotherapeutic agents, we demonstrated that idarubicin was by far the most cytotoxic agent on three HCC cell lines [2]. Based on this preclinical result, two first-in-human studies of lipiodol-TACE using idarubicin and of idarubicin-loaded drug-eluting beads were performed in unresectable HCC patients [3, 4]. Results were encouraging and a phase II trial of idarubicin-loaded drug-eluting beads is currently ongoing. Although we regret the absence of idarubicin in the in vitro screening study, we encourage Pascale et al. in their intention to test doxorubicin and other more cytotoxic agents in the VX2 tumour model. After in vitro screening studies, the next step to improve efficacy of TACE for HCC is to optimize drug delivery in the tumour. For that, histopathological studies are essential to characterize drug released in tumour tissues from different vectors: lipiodol, drug-eluting beads or other drug delivery systems. With the final objective of improving the & Boris Guiu b-guiu@chu-montpellier.fr

Summary What is known and objective Drug eluting beads (DEBs) theoretically improve the efficacy and safety of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). Nonetheless, their economic profile has not been assessed. Our retrospective before/after study aimed to compare efficacy, safety and economic profile of two strategies of TACE without (Period 1) or with the possibility of using DEBs (Period 2). Methods All HCC patients treated by TACE in our hospital between March 2006 and May 2013 were included. Economic analyses were performed from the French Public Health Insurance point of view according to the French Diagnosis-Related Group prospective payment system and from the analytic accountability. Results and discussion One hundred and sixty-one patients were included. Median time to treatment failure and overall survival were 13·1 and 23·8 months in Period 1 vs. 14·1 and 30·2 months in Period 2 (P = 0·45 and P = 0·40). Mean hospital durations and tariffs were 14·9 ± 7·7 days and € 11 472 ± 5901 in Period 1 vs. 12·4 ± 8·4 days and € 7654 ± 4625 in Period 2 (P = 0·03 and P

Responses of GH-secreting adenomas to multimodal management of acromegaly vary widely between patients. Understanding the behavioral patterns of GH-secreting adenomas by identifying factors predictive of their evolution is a research priority. The aim of this study was to clarify the relationship between the T2-weighted adenoma signal on diagnostic magnetic resonance imaging (MRI) in acromegaly and clinical and biological features at diagnosis. An international, multicenter, retrospective analysis was performed using a large population of 297 acromegalic patients recently diagnosed with available diagnostic MRI evaluations. The study was conducted at ten endocrine tertiary referral centers. Clinical and biochemical characteristics, and MRI signal findings were evaluated. T2-hypointense adenomas represented 52.9% of the series, were smaller than their T2-hyperintense and isointense counterparts (PP=0.0001), invaded the cavernous sinus less frequently (P=0.0002), and rarely caused optic chiasm compression (PP=0.067) and presented higher IGF1 values (P=0.01). Although in total, adenomas had a predominantly inferior extension in 45.8% of cases, in men this was more frequent (PP=0.0067). Most adenomas (45.1%) measured between 11 and 20 mm in maximal diameter and bigger adenomas were diagnosed at younger ages (P=0.0001). The T2-weighted signal differentiates GH-secreting adenomas into subgroups with particular behaviors. This raises the question of whether the T2-weighted signal could represent a factor in the classification of acromegalic patients in future studies.

Purpose To present in vitro loading and release characteristics of idarubicin with ONCOZENE (CeloNova BioSciences, Inc, San Antonio, Texas) drug-eluting embolic (DEE) agents and in vivo pharmacokinetics data after transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents in patients with hepatocellular carcinoma. Materials and Methods Loading efficacy of idarubicin with ONCOZENE DEE agents 100 µm and DC Bead (Biocompatibles UK Ltd, Farnham, United Kingdom) DEE agents 100–300 µm was monitored at 10, 20, and 30 minutes loading time by high-pressure liquid chromatography. A T-apparatus was used to monitor the release of idarubicin from the two types of DEE agents over 12 hours. Clinical and 24-hour pharmacokinetics data were recorded after transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents in four patients with unresectable hepatocellular carcinoma. Results Idarubicin loading in ONCOZENE DEE agents was > 99% at 10 minutes. Time to reach 75% of the release plateau level was 37 minutes ± 6 for DC Bead DEE agents and 170 minutes ± 19 for ONCOZENE DEE agents both loaded with idarubicin 10 mg/mL. After transarterial chemoembolization with idarubicin-loaded ONCOZENE DEE agents, three partial responses and one complete response were observed with only two asymptomatic grade 3 biologic adverse events. Median time to maximum concentration for idarubicin in patients was 10 minutes, and mean maximum concentration was 4.9 µg/L ± 1.7. Mean area under the concentration-time curve from 0–24 hours was equal to 29.5 µg.h/L ± 20.5. Conclusions ONCOZENE DEE agents show promising results with very fast loading ability, a favorable in vivo pharmacokinetics profile with a sustained release of idarubicin during the first 24 hours, and encouraging safety and responses. Histopathologic and clinical studies are needed to evaluate idarubicin release around the DEE agents in tumor tissue and to confirm safety and efficacy.

We reviewed the cranial MRI and radionuclide cisternograms of four adults with postural headache indicating spontaneous intracranial hypotension (SIH). All four underwent clinical and radiological follow-up. MRI showed diffuse, thin meningeal enhancement; bilateral subdural fluid collections; and morphological abnormalities secondary to "sagging" of the brain. Radionuclide cisternography revealed direct or indirect signs of leakage of cerebrospinal fluid (CSF) along the spinal axis, and the symptoms resolved after the leak treated by epidural injection of blood at a level indicated by the cisternogram. The diffuse meningeal enhancement decreased but persisted on follow-up MRI, although the patients were asymptomatic. All morphologic abnormalities resolved during 3-5 months follow-up.

To compare three-dimensional (3D) time-of-flight magnetic resonance (MR) angiography with digital subtraction angiography (DSA) in the follow-up of intracranial aneurysms treated with selective endovascular placement of detachable coils.Sixty-eight consecutive patients with intracranial aneurysms were included in the prospective study. The goal was to evaluate 3D time-of-flight MR angiography versus DSA for the detection of a residual aneurysm neck or residual flow inside the coil mesh.Eighty-one MR angiographic and 83 DSA examinations were performed; 15 patients were examined with both modalities twice. MR angiography was not possible in two patients. In another patient, the quality of MR angiography was not sufficient to assess the treated aneurysm. In 72 of the remaining 80 MR angiographic and DSA examinations, there was good correlation between the two modalities. In 54 cases, neither image type showed remnants or recurrence, but in 18, both showed residual aneurysm. In eight cases, the MR angiographic and DSA results differed. In one of these cases, MR angiography depicted residual aneurysm but DSA depicted an arterial loop. In seven cases, a small (3-mm) remnant was not detected at MR angiography.Because very small aneurysm remnants or recurrences probably are not clinically important, MR angiography is an option for following up intracranial aneurysms treated with detachable coils and may partly replace DSA.

Because further surgery on postoperative aneurysm remnants can be difficult and lead to significant morbidity and mortality, endovascular treatment, using controlled detachable coils, was performed in three patients with such remnants. The endovascular approach was technically more difficult in these cases than in previously untreated patients. In one case, the "remodelling" technique was necessary. Given the successful outcome in these patients, endovascular treatment can be proposed as an alternative to another operation, when further surgery appears too risky or is refused by the patient.

The development of new devices, especially controlled detachable coils, has made the endovascular approach one of the modalities for the treatment of intracranial aneurysms. We describe the treatment and present the results of 35 patients treated by selective occlusion of basilar artery aneurysms in our department during a period of 2 years (November 1992-November 1994). This period of time was chosen to analyze a homogeneous population treated since the introduction of controlled detachable coils and also to be able to have as many follow-up angiographic controls of the treated aneurysms as possible. The clinical presentation was subarachnoid hemorrhage in 32 patients and transient ischemic attack in 1 patient. In another two patients, the aneurysms were incidentally discovered. The majority of the aneurysms were berry aneurysms. The aneurysms were located at the basilar bifurcation (23 patients), at the basilar tip between the posterior cerebral artery and the superior cerebellar artery (5 patients), on the basilar trunk (3 patients), and at the vertebrobasilar junction (4 patients). Endovascular treatment using coils was achieved in 34 patients, using Guglielmi detachable coils (Target Therapeutics, San Jose, CA) in 29 patients and mechanical detachable spirals (Balt, Montmorency, France) in 5 patients. One patient died during the positioning of the first coil into the aneurysmal sac. Twenty-five of 35 aneurysms (73.5%) were completely occluded. Nine aneurysms (26.5%) were only partially (> 90%) occluded. No subsequent bleeding occurred during the follow-up period. Two patients treated in the acute phase of subarachnoid hemorrhage died days or weeks after endovascular treatment because of complications related to the natural history of subarachnoid hemorrhage (vasospasm in one patient and pulmonary complications in the other). In three patients, clotting occurred during the endovascular procedure. In all three patients, occlusion of the aneurysmal sac was achieved despite clotting. Urokinase was administered to two of the three patients. In the remaining patient, no fibrinolytic therapy was initiated. The clinical outcomes were excellent for all three patients. In this study, the morbidity-mortality rate of the endovascular technique is low (3%). If we include complications related to the subarachnoid bleeding, the morbidity-mortality rate remains low (8.8%) Regarding basilar artery aneurysms, endovascular treatment (selective occlusion by controlled detachable coils) is now useful for some patients, especially those with small aneurysms. However, long-term anatomic follow-up is needed to accurately evaluate the role of this treatment modality in the management of basilar aneurysms.

Objectives The objective of this study was to explore the association between health-related quality of life (HRQoL) and the recommended phase 2 dose in a phase I clinical trial according to the Time to HRQoL deterioration approach (TTD). Setting This is a phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads performed in cirrhotic patients with hepatocellular carcinoma. Patients had to complete the EORTC QLQ-C30 HRQoL questionnaire at baseline and at days 15, 30 and 60 after TACE. Participants Patients aged ≥18 years with HCC unsuitable for curative treatments were evaluated for the study (N=21). Primary and secondary outcome measurements The primary objective was to determine the maximum tolerated dose (MTD) of idarubicin loaded after a single TACE session. MTD was defined as the dose level closest to that causing dose-limiting toxicity in 20% of patients. HRQoL was the secondary end point. Results Between March 2010 and March 2011, 9, 6 and 6 patients were included at idarubicin dose levels of 5, 10 and 15 mg, respectively. Calculated MTD of idarubicin was 10 mg. At the 10 mg idarubicin dose, patients presented a longer TTD than at 5 mg, for global health status (HR=0.91 (95% CI 0.18 to 4.72)), physical functioning (HR=0.38 (0.04 to 3.22)), fatigue (HR=0.67 (0.18 to 2.56)) and pain (HR=0.47 (0.05 to 4.24)). Conclusions These HRQoL results were consistent with the estimated MTD, with a median TTD for global health status of 41 days (21 to NA) at 5 mg, 23 days (20 to NA) at 10 mg and 25 days (17 to NA) at 15 mg. These results show the importance of studying HRQoL in phase I trials. Trial registration number NCT01040559; Post-results.