Gd-EOB-DTPA-enhanced MRI for evaluation of liver function: Comparison betewwn signal-intensity-based indices and T1 relaxometry

Gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) is a paramagnetic hepatobiliary magnetic resonance (MR) contrast agent. Due to its OATP1B1/B3-dependent hepatocyte-specific uptake and paramagnetic properties increasing evidence has emerged to suggest that Gd-EOBDTPA- enhanced MRI can be potentially used for evaluation of liver function. In this paper we compare the diagnostic performance of Gd-EOB-DTPA-enhanced relaxometry-based and commonly used signal-intensity (SI)-based indices, including the hepatocellular uptake index (HUI) and SI-based indices corrected by spleen or muscle, for evaluation of liver function, determined using the Indocyanin green clearance (ICG) test. Simple linear regression model showed a significant correlation of the plasma disappearance rate of ICG (ICG-PDR) with all Gd-EOB-DTPA-enhanced MRI-based liver function indices with a significantly better correlation of relaxometry-based indices on ICG-PDR compared to SI-based indices. Among SI-based indices, HUI achieved best correlation on ICG-PDR and no significant difference of respective correlations on ICG-PDR could be shown. Assessment of liver volume and consecutive evaluation of multiple linear regression model revealed a stronger correlation of ICG-PDR with both (SI)-based and T1 relaxometry-based indices. Thus, liver function can be estimated quantitatively from Gd-EOB-DTPA-enhanced MRI-based indices. Here, indices derived from T1 relaxometry are superior to SI-based indices, and all indices benefit from taking into account respective liver volumes

Gd-EOB-DTPA-enhanced MR relaxometry for the detection and staging of liver fibrosis

Gd-EOB-DTPA, a liver-specific contrast agent with T1-shortening effects, is routinely used in clinical routine for detection and characterization of focal liver lesions and has recently received increasing attention as a tool for the quantitative analyses of liver function. We report the relationship between the extent of Gd-EOB-DTPA-induced T1 relaxation and the degree of liver fibrosis, which was assessed according to the METAVIR score. For the T1 relaxometry, a transverse 3D VIBE sequence with inline T1 calculation was acquired prior to and 20 minutes after Gd-EOB-DTPA administration. The reduction rates of the T1 relaxation time (rrT1) between the pre- and postcontrast images were calculated, and the optimal cutoff values for the fibrosis stages were determined with receiver operating characteristic (ROC) curve analyses. The rrT1 decreased with the severity of liver fibrosis and regression analysis revealed a significant correlation of the rrT1 with the stage of liver fibrosis (r = -0.906, p = 78% and specificities >= 94% for the differentiation of different fibrosis stages. Gd-EOB-DTPA-enhanced T1 relaxometry is a reliable tool for both the detection of initial hepatic fibrosis and the staging of hepatic fibrosis

Effects of acetyl-DL-leucine on cerebellar ataxia (ALCAT trial): study protocol for a multicenter, multinational, randomized, double-blind, placebo-controlled, crossover phase III trial

BACKGROUND: Cerebellar ataxia (CA) is a frequent and often disabling condition that impairs motor functioning and impacts on quality of life (QoL). No medication has yet been proven effective for the symptomatic or even causative treatment of hereditary or non-hereditary, non-acquired CA. So far, the only treatment recommendation is physiotherapy. Therefore, new therapeutic options are needed. Based on three observational studies, the primary objective of the acetyl-DL-leucine on ataxia (ALCAT) trial is to examine the efficacy and tolerability of a symptomatic therapy with acetyl-DL-leucine compared to placebo on motor function measured by the Scale for the Assessment and Rating of Ataxia (SARA) in patients with CA. METHODS/DESIGN: An investigator-initiated, multicenter, European, randomized, double-blind, placebo-controlled, 2-treatment 2-period crossover phase III trial will be carried out. In total, 108 adult patients who meet the clinical criteria of CA of different etiologies (hereditary or non-hereditary, non-acquired) presenting with a SARA total score of at least 3 points will be randomly assigned in a 1:1 ratio to one of two different treatment sequences, either acetyl-DL-leucine (up to 5 g per day) followed by placebo or vice versa. Each sequence consists of two 6-week treatment periods, separated by a 4-week wash-out period. A follow-up examination is scheduled 4 weeks after the end of treatment. The primary efficacy outcome is the absolute change in the SARA total score. Secondary objectives are to demonstrate that acetyl-DL-leucine is effective in improving (1) motor function measured by the Spinocerebellar Ataxia Functional Index (SCAFI) and SARA subscore items and (2) QoL (EuroQoL 5 dimensions and 5 level version, EQ-5D-5 L), depression (Beck Depression Inventory, BDI-II) and fatigue (Fatigue Severity Score, FSS). Furthermore, the incidence of adverse events will be investigated. DISCUSSION: The results of this trial will inform whether symptomatic treatment with the modified amino-acid acetyl-DL-leucine is a worthy candidate for a new drug therapy to relieve ataxia symptoms and to improve patient care. If superiority of the experimental drug to placebo can be established it will also be re-purposing of an agent that has been previously used for the symptomatic treatment of dizziness. TRIAL REGISTRATION: The trial was prospectively registered at www.clinicaltrialsregister.eu (EudraCT no. 2015-000460-34) and at https://www.germanctr.de (DRKS-ID: DRKS00009733 )

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy

International study on inter-reader variability for circulating tumor cells in breast cancer

Introduction Circulating tumor cells (CTCs) have been studied in breast cancer with the CellSearch® system. Given the low CTC counts in non-metastatic breast cancer, it is important to evaluate the inter-reader agreement. Methods CellSearch® images (N = 272) of either CTCs or white blood cells or artifacts from 109 non-metastatic (M0) and 22 metastatic (M1) breast cancer patients from reported studies were sent to 22 readers from 15 academic laboratories and 8 readers from two Veridex laboratories. Each image was scored as No CTC vs CTC HER2- vs CTC HER2+. The 8 Veridex readers were summarized to a Veridex Consensus (VC) to compare each academic reader using % agreement and kappa (κ) statistics. Agreement was compared according to disease stage and CTC counts using the Wilcoxon signed rank test. Results For CTC definition (No CTC vs CTC), the median agreement between academic readers and VC was 92% (range 69 to 97%) with a median κ of 0.83 (range 0.37 to 0.93). Lower agreement was observed in images from M0 (median 91%, range 70 to 96%) compared to M1 (median 98%, range 64 to 100%) patients (P < 0.001) and from M0 and <3CTCs (median 87%, range 66 to 95%) compared to M0 and ≥3CTCs samples (median 95%, range 77 to 99%), (P < 0.001). For CTC HER2 expression (HER2- vs HER2+), the median agreement was 87% (range 51 to 95%) with a median κ of 0.74 (range 0.25 to 0.90). Conclusions The inter-reader agreement for CTC definition was high. Reduced agreement was observed in M0 patients with low CTC counts. Continuous training and independent image review are require

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy

International study on inter-reader variability for circulating tumor cells in breast cancer

Introduction: Circulating tumor cells (CTCs) have been studied in breast cancer with the CellSearch® system. Given the low CTC counts in non-metastatic breast cancer, it is important to evaluate the inter-reader agreement.Methods: CellSearch® images (N = 272) of either CTCs or white blood cells or artifacts from 109 non-metastatic (M0) and 22 metastatic (M1) breast cancer patients from reported studies were sent to 22 readers from 15 academic laboratories and 8 readers from two Veridex laboratories. Each image was scored as No CTC vs CTC HER2- vs CTC HER2+. The 8 Veridex readers were summarized to a Veridex Consensus (VC) to compare each academic reader using % agreement and kappa (κ) statistics. Agreement was compared according to disease stage and CTC counts using the Wilcoxon signed rank test.Results: For CTC definition (No CTC vs CTC), the median agreement between academic readers and VC was 92% (range 69 to 97%) with a median κ of 0.83 (range 0.37 to 0.93). Lower agreement was observed in images from M0 (median 91%, range 70 to 96%) compared to M1 (median 98%, range 64 to 100%) patients (P < 0.001) and from M0 and <3CTCs (median 87%, range 66 to 95%) compared to M0 and ≥3CTCs samples (median 95%, range 77 to 99%), (P < 0.001). For CTC HER2 expression (HER2- vs HER2+), the median agreement was 87% (range 51 to 95%) with a median κ of 0.74 (range 0.25 to 0.90).Conclusions: The inter-reader agreement for CTC definition was high. Reduced agreement was observed in M0 patients with low CTC counts. Continuous training and independent image review are required

mTOR-Mediated Regulation of Group 3 Innate Lymphoid Cell Numbers and Cytokine Responses

Group 3 innate lymphoid cells (ILC3s) are most abundant at surface barrier regions, particularly in the mucosa of the intestinal tract. ILC3 subsets produce various cytokines under homeostatic and activating conditions and act as inducers of lymphoid tissue development. ILC3-derived IL-22 contributes to tissue homeostasis, tissue repair and protection against infections. On the other hand, ILC3-mediated IFN-g responses participate in the pathogenesis of intestinal inflammatory diseases. It is not fully understood which molecular pathways regulate the protective versus the pathogenic outcome of ILC3 immune responses in the intestine. Mechanistic target of rapamycin complexes (mTORC) 1 and 2 integrate activation signals and environmental cues, drive activation-induced metabolic adaptation and shape immune responses by regulating proliferation, differentiation and cytokine responses. Results obtained in T cells demonstrate that mTOR signaling incorporates cues from various sources including nutrient-, cell- and microbiota-derived metabolites and critically affects cell function. Given the known impact of these factors on the generation, differentiation and function of ILC3s, I hypothesized that mTORC1 and/or mTORC2 are critical regulators of ILC3 differentiation and function. To investigate the impact of mTOR signaling on ILC3s, I generated wildtype and Rag2-/- lymphopenic mouse strains with a conditional RORc promoter-driven deletion of Rptor and/or Rictor, the essential subunits of mTORC1 and mTORC2, respectively. mTORC1 and mTORC2 had a tissue-specific impact on ILC3 development and proliferation. Whereas small intestinal ILC3s required mTORC1 and to a lesser extent mTORC2, maintenance of colonic ILC3 numbers was independent of mTOR signaling. Small intestinal ILC3s from Rag2-/- mice exhibited a higher dependency on both mTORCs than small intestinal ILC3s from wildtype mice, indicating that mTOR is differentially regulated in ILC3s from lymphopenic and wildtype mice. Rptor- and Rictor-deficient ILC3s displayed significantly impaired IL-23/IL-1b-mediated IFN-g production, while IL-22 production was only marginally affected. Consistently, Rag2-/- mice with ILC3-specific deletion of Rptor or Rictor were more resistant to IFN-g-dependent a-CD40 colitis, but exhibited no obvious defects in IL-22-mediated defense against Citrobacter rodentium infection. Taken together, those findings suggest that mTORC1 and mTORC2 signaling occupy a critical role in IFN-g production of ILC3s in vitro and in vivo and thus represent central regulators of protective versus inflammatory responses in the intestine. This implies that therapeutic mTOR blockade may have beneficial effects in colitis patients by downmodulating the IFN-g response of ILC3s

A review of the perceptual and attentional-executive characteristics of dementia with Lewy bodies relative to Alzheimer's and Parkinson's disease

Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia disorder, after Alzheimer’s disease (AD). DLB is characterised clinically by cognitive fluctuations, visual hallucinations, rapid-eye-movement sleep behaviour disorder, and Parkinsonism. Differentiating DLB from AD and related disorders of Parkinson’s disease (PD) and Parkinson’s disease with dementia (PDD) can be difficult at early disease stages due to overlapping clinical and pathological features. Nevertheless, it has been shown that visuoperceptual, attention and executive deficits, relative to memory impairments, are especially prominent in the early stages of DLB compared with AD or PD. The importance of these impairments is reflected in the recent revision of the diagnostic consensus guidelines of DLB. As the last reviews of cognitive impairments in DLB were conducted over a decade ago (Collerton, Burn, McKeith & O’Brien, 2003; Metzler-Baddeley, 2007; Ralph, 2001), we provide an up-to-date review of the literature into perceptual and attention-executive functions in DLB. There is a need for better controlled studies into cognitive deficits, their neural correlates, and relationships to clinical symptoms in DLB, that go beyond standard clinical assessments. Evidence regarding visuoperception suggests that low-level functions may be relatively preserved while mid- and higher-level functions, that require the recruitment of attention and executive functions are disproportionally affected in DLB. Cognitive fluctuations and visual hallucinations may arise from a desynchronization of top-down attention and bottom-up sensory networks