The dietary sweetener sucralose is a negative modulator of T cell-mediated responses.

Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years1. Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners2-5. In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation. Mechanistically, sucralose affects the membrane order of T cells, accompanied by a reduced efficiency of T cell receptor signalling and intracellular calcium mobilization. Mice given sucralose show decreased CD8+ T cell antigen-specific responses in subcutaneous cancer models and bacterial infection models, and reduced T cell function in models of T cell-mediated autoimmunity. Overall, these findings suggest that a high intake of sucralose can dampen T cell-mediated responses, an effect that could be used in therapy to mitigate T cell-dependent autoimmune disorders.

Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine.

Reactive oxygen species (ROS) participate in numerous cell responses, including proliferation, DNA damage, and cell death. Based on these disparate activities, both promotion and inhibition of ROS have been proposed for cancer therapy. However, how the ROS response is determined is not clear. We examined the activities of ROS in a model of Apc deletion, where loss of the Wnt target gene Myc both rescues APC loss and prevents ROS accumulation. Following APC loss, Myc has been shown to up-regulate RAC1 to promote proliferative ROS through NADPH oxidase (NOX). However, APC loss also increased the expression of TIGAR, which functions to limit ROS. To explore this paradox, we used three-dimensional (3D) cultures and in vivo models to show that deletion of TIGAR increased ROS damage and inhibited proliferation. These responses were suppressed by limiting damaging ROS but enhanced by lowering proproliferative NOX-derived ROS. Despite having opposing effects on ROS levels, loss of TIGAR and RAC1 cooperated to suppress intestinal proliferation following APC loss. Our results indicate that the pro- and anti-proliferative effects of ROS can be independently modulated in the same cell, with two key targets in the Wnt pathway functioning to integrate the different ROS signals for optimal cell proliferation.

Anterior cingulate glutamate levels associate with functional activation and connectivity during sensory integration in schizophrenia: a multimodal 1H-MRS and fMRI study.

BACKGROUND: Glutamatergic dysfunction has been implicated in sensory integration deficits in schizophrenia, yet how glutamatergic function contributes to behavioural impairments and neural activities of sensory integration remains unknown. METHODS: Fifty schizophrenia patients and 43 healthy controls completed behavioural assessments for sensory integration and underwent magnetic resonance spectroscopy (MRS) for measuring the anterior cingulate cortex (ACC) glutamate levels. The correlation between glutamate levels and behavioural sensory integration deficits was examined in each group. A subsample of 20 pairs of patients and controls further completed an audiovisual sensory integration functional magnetic resonance imaging (fMRI) task. Blood Oxygenation Level Dependent (BOLD) activation and task-dependent functional connectivity (FC) were assessed based on fMRI data. Full factorial analyses were performed to examine the Group-by-Glutamate Level interaction effects on fMRI measurements (group differences in correlation between glutamate levels and fMRI measurements) and the correlation between glutamate levels and fMRI measurements within each group. RESULTS: We found that schizophrenia patients exhibited impaired sensory integration which was positively correlated with ACC glutamate levels. Multimodal analyses showed significantly Group-by-Glutamate Level interaction effects on BOLD activation as well as task-dependent FC in a 'cortico-subcortical-cortical' network (including medial frontal gyrus, precuneus, ACC, middle cingulate gyrus, thalamus and caudate) with positive correlations in patients and negative in controls. CONCLUSIONS: Our findings indicate that ACC glutamate influences neural activities in a large-scale network during sensory integration, but the effects have opposite directionality between schizophrenia patients and healthy people. This implicates the crucial role of glutamatergic system in sensory integration processing in schizophrenia.

Modulating the therapeutic response of tumours to dietary serine and glycine starvation.

The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis, many others rely on exogenous serine for optimal growth. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

Corrigendum: Modulating the therapeutic response of tumours to dietary serine and glycine starvation.

This corrects the article DOI: 10.1038/nature22056.

The impact of childhood trauma on thalamic functional connectivity in patients with obsessive-compulsive disorder.

BACKGROUND: Childhood trauma is a vulnerability factor for the development of obsessive-compulsive disorder (OCD). Empirical findings suggest that trauma-related alterations in brain networks, especially in thalamus-related regions, have been observed in OCD patients. However, the relationship between childhood trauma and thalamic connectivity in patients with OCD remains unclear. The present study aimed to examine the impact of childhood trauma on thalamic functional connectivity in OCD patients. METHODS: Magnetic resonance imaging resting-state scans were acquired in 79 patients with OCD, including 22 patients with a high level of childhood trauma (OCD_HCT), 57 patients with a low level of childhood trauma (OCD_LCT) and 47 healthy controls. Seven thalamic subdivisions were chosen as regions of interest (ROIs) to examine the group difference in thalamic ROIs and whole-brain resting-state functional connectivity (rsFC). RESULTS: We found significantly decreased caudate-thalamic rsFC in OCD patients as a whole group and also in OCD_LCT patients, compared with healthy controls. However, OCD_HCT patients exhibited increased thalamic rsFC with the prefrontal cortex when compared with both OCD_LCT patients and healthy controls. CONCLUSIONS: Taken together, OCD patients with high and low levels of childhood trauma exhibit different pathological alterations in thalamic rsFC, suggesting that childhood trauma may be a predisposing factor for some OCD patients.

Altered brain structural and functional connectivity in schizotypy.

BACKGROUND: Schizotypy refers to schizophrenia-like traits below the clinical threshold in the general population. The pathological development of schizophrenia has been postulated to evolve from the initial coexistence of 'brain disconnection' and 'brain connectivity compensation' to 'brain connectivity decompensation'. METHODS: In this study, we examined the brain connectivity changes associated with schizotypy by combining brain white matter structural connectivity, static and dynamic functional connectivity analysis of diffusion tensor imaging data and resting-state functional magnetic resonance imaging data. A total of 87 participants with a high level of schizotypal traits and 122 control participants completed the experiment. Group differences in whole-brain white matter structural connectivity probability, static mean functional connectivity strength, dynamic functional connectivity variability and stability among 264 brain sub-regions of interests were investigated. RESULTS: We found that individuals with high schizotypy exhibited increased structural connectivity probability within the task control network and within the default mode network; increased variability and decreased stability of functional connectivity within the default mode network and between the auditory network and the subcortical network; and decreased static mean functional connectivity strength mainly associated with the sensorimotor network, the default mode network and the task control network. CONCLUSIONS: These findings highlight the specific changes in brain connectivity associated with schizotypy and indicate that both decompensatory and compensatory changes in structural connectivity within the default mode network and the task control network in the context of whole-brain functional disconnection may be an important neurobiological correlate in individuals with high schizotypy.

Co-occurrence of schizo-obsessive traits and its correlation with altered executive control network functional connectivity.

The prevalence of obsessive-compulsive symptoms (OCS) in schizophrenia patients is as around 30%. Evidence suggested that mild OCS could reduce symptoms of schizophrenia, supporting the presence of compensatory functions. However, severe OCS could aggravate various impairments in schizophrenia patients, supporting the "double jeopardy hypothesis". Patients with schizo-obsessive comorbidity, schizophrenia patients and obsessive-compulsive disorder patients have been found to have similarities in executive dysfunctions and altered resting-state functional connectivity within the executive control network (ECN). Executive functions could be associated with the ECN. However, little is known as to whether such overlap exists in the subclinical populations of individuals with schizo-obsessive traits (SOT), schizotypal individuals and individuals with high levels of obsessive-compulsive symptoms (OCS). In this study, we recruited 30 schizotypal individuals, 25 individuals with OCS, 29 individuals with SOT and 29 controls for a resting-state ECN-related functional connectivity (rsFC) and a go/shift/no-go task. We found that individuals with SOT exhibited increased rsFC within the ECN compared with controls, while schizotypal individuals exhibited the opposite. Individuals with OCS exhibited decreased rsFC within the ECN and between the ECN and the default mode network (DMN), relative to controls. No significant correlational results between altered rsFC related to the ECN with executive function performance were found after corrections for multiple comparisons in three subclinical groups. Our findings showed that individuals with SOT had increased rsFC within the ECN, while schizotypal individuals and individuals with OCS showed the opposite. Our findings provide evidence for possible neural substrates of subclinical comorbidity of OCS and schizotypy.

Shared and distinct reward neural mechanisms among patients with schizophrenia, major depressive disorder, and bipolar disorder: an effort-based functional imaging study.

Unwillingness to exert effort for rewards has been found in patients with schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD), but the underlying shared and distinct reward neural mechanisms remain unclear. This study aimed to compare the neural correlates of such impairments across different diagnoses. The neural responses in an effort-expenditure for reward task (EEfRT) were assessed in 20 SCZ patients, 23 MDD patients, 17 BD patients, and 30 healthy controls (HC). The results found shared activation in the cingulate gyrus, the medial frontal gyrus, and the middle frontal gyrus during the EEfRT administration. Compared to HC, SCZ patients exhibited stronger variations of functional connectivity between the right caudate and the left amygdala, the left hippocampus and the left putamen, with increase in reward magnitude. In MDD patients, an enhanced activation compared to HC in the right superior temporal gyrus was found with the increase of reward magnitude. The variations of functional connectivity between the caudate and the right cingulate gyrus, the left postcentral gyrus and the left inferior parietal lobule with increase in reward magnitude were weaker than that found in HC. In BD patients, the degree of activation in the left precuneus was increased, but that in the left dorsolateral prefrontal cortex was decreased with increase in reward probability compared to HC. These findings demonstrate both shared and distinct reward neural mechanisms associated with EEfRT in patients with SCZ, MDD, and BD, implicating potential intervention targets to alleviate amotivation in these clinical disorders.

Altered empathy-related resting-state functional connectivity in patients with bipolar disorder.

Empathy is the ability to generate emotional responses (i.e., cognitive empathy) and to make cognitive inferences (i.e., affective empathy) to other people's emotions. Empirical evidence suggests that patients with bipolar disorder (BD) exhibit impairment in cognitive empathy, but findings on affective empathy are inconsistent. Few studies have examined the neural mechanisms of cognitive and affective empathy in patients with BD. In this study, we examined the empathy-related resting-state functional connectivity (rsFC) in BD patients. Thirty-seven patients with BD and 42 healthy controls completed the self-report Questionnaires of Cognitive and Affective Empathy (QCAE), the Yoni behavioural task, and resting-sate fMRI brain scans. Group comparison of empathic ability was conducted. The interactions between group and empathic ability on seed-based whole brain rsFC were examined. BD patients scored lower on the Online Simulation subscale of the QCAE and showed positive correlations between cognitive empathy and the rsFC of the dorsal Medial Prefrontal Cortex (dmPFC) with the lingual gyrus. The correlations between cognitive empathy and the rsFC of the temporal-parietal junction (TPJ) with the fusiform gyrus, the cerebellum and the parahippocampus were weaker in BD patients than that in healthy controls. These findings highlight the underlying neural mechanisms of empathy impairments in BD patients.

Distinct clinical manifestations of obsessive-compulsive disorder are associated with cortical thickness alteration.

BACKGROUND: Although brain structural changes have been reported in patients with obsessive-compulsive disorder (OCD), results from previous studies have been inconsistent. A growing number of studies have focused on obsessive beliefs and impulsivity which could be involved in the occurrence and maintenance of OCD symptoms. The present study aimed to examine whether there are distinct brain structural changes in patients with different OCD subgroups. METHODS: Eighty-nine patients with OCD and 42 healthy controls were recruited to undergo structural magnetic resonance imaging brain scan. OCD patients were classified into subgroups according to scores of the Obsessive Belief Questionnaire (OBQ-44) and the Barratt Impulsiveness Scale (BIS-11) using cluster analysis. Group comparisons in cortical thickness and subcortical volumes between all OCD patients and healthy controls, as well as between subgroups of OCD patients and healthy controls, were carried out. RESULTS: OCD patients with more obsessive beliefs and attentional impulsivity (OCD_OB_AT) had reduced cortical thickness at the inferior parietal gyrus, the superior and middle temporal gyrus and the insula compared with OCD patients with higher score on the non-planning impulsivity (OCD_NP, corrected p < 0.05). The whole group of OCD patients and both subgroups showed reduced cortical thickness at the superior parietal gyrus compared with controls (uncorrected p < 0.01, number of vertices > 100). CONCLUSION: Our results suggest that apart from distinct phenomenology, there are distinct neural correlates of different OCD subgroups based on obsessive beliefs and impulsivity. These neural correlates may have clinical significance and should be considered in future research.

Negative belief-updating bias for positive daily life events in individuals with schizophrenia and social anhedonia.

INTRODUCTION: Low-pleasure beliefs are found in both patients with schizophrenia (SZ) and individuals with high social anhedonia (SocAnh), and are associated with anhedonia. However, little is known about the development and maintenance of these low-pleasure beliefs in the clinical and subclinical populations. We investigated whether patients with SZ and individuals with high SocAnh have deficits in updating their beliefs, which may contribute to the understanding of the formation and maintenance of low-pleasure beliefs. METHODS: The Modified Belief Updating Task was administered to assess belief-updating patterns in a clinical sample (36 SZ patients and 30 matched controls) and a subclinical sample (27 individuals with high SocAnh and 30 matched controls). RESULTS: We found that compared with controls, SZ patients updated their beliefs to a greater extent and more frequently when receiving bad news for positive life events, but not for negative life events. Moreover, individuals with high SocAnh also exhibited similar patterns in updating their beliefs for positive life events after controlling depressive symptoms. CONCLUSIONS: Our findings suggest that negative belief-updating patterns for positive events may play an important role in the formation and maintenance of low-pleasure beliefs in patients with SZ and individuals with high SocAnh.

Curation and annotation of planarian gene expression patterns with segmented reference morphologies.

MOTIVATION: Morphological and genetic spatial data from functional experiments based on genetic, surgical and pharmacological perturbations are being produced at an extraordinary pace in developmental and regenerative biology. However, our ability to extract knowledge from these large datasets are hindered due to the lack of formalization methods and tools able to unambiguously describe, centralize and interpret them. Formalizing spatial phenotypes and gene expression patterns is especially challenging in organisms with highly variable morphologies such as planarian worms, which due to their extraordinary regenerative capability can experimentally result in phenotypes with almost any combination of body regions or parts. RESULTS: Here, we present a computational methodology and mathematical formalism to encode and curate the morphological outcomes and gene expression patterns in planaria. Worm morphologies are encoded with mathematical graphs based on anatomical ontology terms to automatically generate reference morphologies. Gene expression patterns are registered to these standard reference morphologies, which can then be annotated automatically with anatomical ontology terms by analyzing the spatial expression patterns and their textual descriptions. This methodology enables the curation and annotation of complex experimental morphologies together with their gene expression patterns in a centralized standardized dataset, paving the way for the extraction of knowledge and reverse-engineering of the much sought-after mechanistic models in planaria and other regenerative organisms. AVAILABILITY AND IMPLEMENTATION: We implemented this methodology in a user-friendly graphical software tool, PlanGexQ, freely available together with the data in the manuscript at https://lobolab.umbc.edu/plangexq. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Altered activation and functional connectivity in individuals with social anhedonia when envisioning positive future episodes.

BACKGROUND: Anticipatory pleasure deficits are closely correlated with negative symptoms in schizophrenia, and may be found in both clinical and subclinical populations along the psychosis continuum. Prospection, which is an important component of anticipatory pleasure, is impaired in individuals with social anhedonia (SocAnh). In this study, we examined the neural correlates of envisioning positive future events in individuals with SocAnh. METHODS: Forty-nine individuals with SocAnh and 33 matched controls were recruited to undergo functional MRI scanning, during which they were instructed to simulate positive or neutral future episodes according to cue words. Two stages of prospection were distinguished: construction and elaboration. RESULTS: Reduced activation at the caudate and the precuneus when prospecting positive (v. neutral) future events was observed in individuals with SocAnh. Furthermore, compared with controls, increased functional connectivity between the caudate and the inferior occipital gyrus during positive (v. neutral) prospection was found in individuals with SocAnh. Both groups exhibited a similar pattern of brain activation for the construction v. elaboration contrast, regardless of the emotional context. CONCLUSIONS: Our results provide further evidence on the neural mechanism of anticipatory pleasure deficits in subclinical individuals with SocAnh and suggest that altered cortico-striatal circuit may play a role in anticipatory pleasure deficits in these individuals.

The 12-month prevalence of psychotic experiences and their association with clinical outcomes in Hong Kong: an epidemiological and a 2-year follow up studies.

BACKGROUND: The relationship between the subtypes of psychotic experiences (PEs) and common mental health symptoms remains unclear. The current study aims to establish the 12-month prevalence of PEs in a representative sample of community-dwelling Chinese population in Hong Kong and explore the relationship of types of PEs and common mental health symptoms. METHOD: This is a population-based two-phase household survey of Chinese population in Hong Kong aged 16-75 (N = 5719) conducted between 2010 and 2013 and a 2-year follow-up study of PEs positive subjects (N = 152). PEs were measured with Psychosis Screening Questionnaire (PSQ) and subjects who endorsed any item on the PSQ without a clinical diagnosis of psychotic disorder were considered as PE-positive. Types of PEs were characterized using a number of PEs (single v. multiple) and latent class analysis. All PE-positive subjects were assessed with common mental health symptoms and suicidal ideations at baseline and 2-year follow-up. PE status was also assessed at 2-year follow-up. RESULTS: The 12-month prevalence of PEs in Hong Kong was 2.7% with 21.1% had multiple PEs. Three latent classes of PEs were identified: hallucination, paranoia and mixed. Multiple PEs and hallucination latent class of PEs were associated with higher levels of common mental health symptoms. PE persistent rate at 2-year follow-up was 15.1%. Multiple PEs was associated with poorer mental health at 2-year follow-up. CONCLUSIONS: Results highlighted the transient and heterogeneous nature of PEs, and that multiple PEs and hallucination subtype of PEs may be specific indices of poorer common mental health.

The benefits of emotionally salient cues on event-based prospective memory in bipolar patients and schizophrenia patients.

Prospective memory (PM) refers to the ability to remember to carry out a delayed intention in the future. Evidence suggests that emotionally salient cues can enhance PM functions in healthy population, but whether the benefit exists in schizophrenia and bipolar patients remains unclear. This study aimed to examine and compare the potential enhancement effect of emotional PM cues in schizophrenia patients and bipolar patients. Twenty-eight clinically stable schizophrenia participants, 26 euthymic bipolar participants and 29 controls completed a computerized PM task involving PM cues with different types of valences (i.e., positive, neutral and negative). All the three groups showed better PM performance when negative PM cues were presented compared with positive and neutral PM cues. The sizes of the enhancement effects of negative PM cues were large (all Cohen's d ≥ 1.00) and comparable across three groups. Our findings suggested that patients with schizophrenia and bipolar disorders could benefit from negative PM cues to an extent similar to healthy individuals, thus extended the notion of psychosis continuum to the important area of emotion-cognition interaction.

The effect of effort-reward imbalance on brain structure and resting-state functional connectivity in individuals with high levels of schizotypal traits.

INTRODUCTION: Effort-reward imbalance (ERI) is a typical psychosocial stress. Schizotypal traits are attenuated features of schizophrenia in the general population. According to the diathesis-stress model, schizotypal traits and psychosocial stress contribute to the onset of schizophrenia. However, few studies examined the effects of these factors on brain alterations. This study aimed to examine relationships between ERI, schizotypal traits and brain structures and functions. METHODS: We recruited 37 (13 male, 24 female) participants with high levels of schizotypal traits and 36 (12 male, 24 female) participants with low levels of schizotypal traits by the Schizotypal Personality Questionnaire (SPQ). The Chinese school version of the effort-reward imbalance questionnaire (C-ERI-S) was used to measure ERI. We conducted the voxel-based morphometry (VBM) and whole brain resting-state functional connectivity (rsFC) analysis using reward or stress-related regions as seeds. RESULTS: Participants with high levels of schizotypal traits were more likely to perceive ERI. The severity of ERI was correlated with grey matter volume (GMV) reduction of the left pallidum and altered rsFC among the prefrontal, striatum and cerebellum in participants with high levels of schizotypal traits. CONCLUSION: ERI is associated with GMV reduction and altered rsFC in individuals with high levels of schizotypal traits.

Entropy and Fractal Dimension Study of the TDP-43 Protein Low Complexity Domain Sequence in ALS Disease Severity and SARS-CoV-2 Gene Sequences in Virulence Variability.

The low complexity domain (LCD) sequence has been defined in terms of entropy using a 12 amino acid sliding window along a protein sequence in the study of disease-related genes. The amyotrophic lateral sclerosis (ALS)-related TDP-43 protein sequence with intra-LCD structural information based on cryo-EM data was published recently. An application of entropy and Higuchi fractal dimension calculations was described using the Znf521 and HAR1 sequences. A computational analysis of the intra-LCD sequence entropy and Higuchi fractal dimension values at the amino acid level and at the ATCG nucleotide level were conducted without the sliding window requirement. The computational results were consistent in predicting the intermediate entropy/fractal dimension value produced when two subsequences at two different entropy/fractal dimension values were combined. The computational method without the application of a sliding-window was extended to an analysis of the recently reported virulent genes-Orf6, Nsp6, and Orf7a-in SARS-CoV-2. The relationship between the virulence functionality and entropy values was found to have correlation coefficients between 0.84 and 0.99, using a 5% uncertainty on the cell viability data. The analysis found that the most virulent Orf6 gene sequence had the lowest nucleotide entropy and the highest protein fractal dimension, in line with extreme value theory. The Orf6 codon usage bias in relation to vaccine design was discussed.

Generalizability of machine learning for classification of schizophrenia based on resting-state functional MRI data.

Machine learning has increasingly been applied to classification of schizophrenia in neuroimaging research. However, direct replication studies and studies seeking to investigate generalizability are scarce. To address these issues, we assessed within-site and between-site generalizability of a machine learning classification framework which achieved excellent performance in a previous study using two independent resting-state functional magnetic resonance imaging data sets collected from different sites and scanners. We established within-site generalizability of the classification framework in the main data set using cross-validation. Then, we trained a model in the main data set and investigated between-site generalization in the validated data set using external validation. Finally, recognizing the poor between-site generalization performance, we updated the unsupervised algorithm to investigate if transfer learning using additional unlabeled data were able to improve between-site classification performance. Cross-validation showed that the published classification procedure achieved an accuracy of 0.73 using majority voting across all selected components. External validation found a classification accuracy of 0.55 (not significant) and 0.70 (significant) using the direct and transfer learning procedures, respectively. The failure of direct generalization from one site to another demonstrates the limitation of within-site cross-validation and points toward the need to incorporate efforts to facilitate application of machine learning across multiple data sets. The improvement in performance with transfer learning highlights the importance of taking into account the properties of data when constructing predictive models across samples and sites. Our findings suggest that machine learning classification result based on a single study should be interpreted cautiously.

Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline chemotherapy. Achievement of complete remission (CR) with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT. This phase 1/2 study evaluated the combination of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory HL. A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled. Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m2) on days 1 and 2 of a 21-day cycle for up to 6 cycles. Patients could undergo ASCT any time after cycle 2. Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy. After a median of 2 cycles of combination therapy (range, 1-6), the objective response rate among 53 efficacy-evaluable patients was 92.5%, with 39 patients (73.6%) achieving CR. Forty patients underwent ASCT. Thirty-one patients (25 of whom underwent ASCT) received BV monotherapy (median, 10 cycles; range, 1-14). After a median of 20.9 months of follow-up, the estimated 2-year progression-free survival was 69.8% and 62.6% for patients who received ASCT and all patients, respectively. Thirty-one patients (56.4%) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy. A protocol amendment requiring premedication reduced IRR severity. BV plus bendamustine as first salvage therapy in relapsed/refractory HL is highly active with a manageable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT01874054.