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In preclinical studies, we investigated a novel mechanism of in situ vaccination in lymphoma. Radiation therapy (RT) can induce abscopal responses in lymphoma models, but this has not translated into clinical efficacy. We hypothesized that immune stimulation with cytosine guanine dinucleotide (CpG) deoxynucleotides could enhance abscopal effects induced by RT or photothermal therapy (PTT), which has been shown to have an immune stimulatory effect in solid tumors but has not been studied in lymphoma. We designed a branched gold nanoparticle (NP) platform to carry CpG deoxynucleotides while maintaining PTT function and compared the immunologic profile of the tumor microenvironment after PTT or RT in a dual-flank lymphoma model. One flank was treated with CpG deoxynucleotides with RT or PTT, and the other tumor was left untreated. We found that the CpG deoxynucleotide/PTT group had significant reduction in growth in both treated (primary) and untreated (secondary) tumors, suggesting an improved abscopal response, with a concomitant increase in CD8/CD4 and cytotoxic T-cell/regulatory T-cell ratios in both primary and secondary tumors compared with CpG deoxynucleotides/RT. Dendritic cells in primary and secondary draining lymph nodes had increased maturation markers in the CpG deoxynucleotide/PTT group, and the effector memory T cells (both CD4 and CD8) in the secondary tumor and spleen were increased, suggesting a systemic vaccination effect. These data suggest that in a lymphoma model, PTT using a CpG deoxynucleotide NP platform resulted in enhanced in situ vaccination and abscopal response compared with RT.

Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT.PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/mBetween July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70-78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1-18·0). 49 (80% [95% CI 68-89]; p0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths.These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended.Juno Therapeutics, a Bristol-Myers Squibb company.

Forty-five percent of deaths among children under 5 years of age are associated with undernutrition. Globally, almost 200 million children exhibit the two major forms of undernutrition-wasting (low weight-for-height) or stunting (low height-for-age), with many affected by both. Undernutrition is not due to food insecurity alone. Growing evidence indicates that perturbed postnatal gut microbiome development contributes to its pathogenesis. This perspective focuses on defining and repairing these defects in gut microbiome development. We describe an approach that involves the analysis of well-phenotyped human cohorts, followed by preclinical studies using gnotobiotic animals colonized with microbiota from these cohorts. Additionally, these models can be used to identify therapeutic targets and candidates that can then be tested clinically. Furthermore, introducing pretreatment microbiota from trial participants into gnotobiotic animals and re-enacting trial conditions allow mechanisms to be dissected. We highlight these recent advances as well as gaps in existing knowledge that present opportunities for future research.

BACKGROUND: Human milk oligosaccharides (HMOs) are an abundant class of compounds found in human milk and have been linked to the development of the infant, and specifically the brain, immune system, and gut microbiome. OBJECTIVES: Advanced analytical methods were used to obtain relative quantitation of many structures in approximately 2000 samples from over 1000 mothers in urban, semirural, and rural sites across geographically diverse countries. METHODS: LC-MS−based analytical methods were used to profile the compounds with broad structural coverage and quantitative information. The profiles revealed their structural heterogeneity and their potential biological roles. Comparisons of HMO compositions were made between mothers of different age groups, lactation periods, infant sexes, and residing geographical locations. RESULTS: A common behavior found among all sites was a decrease in HMO abundances during lactation until approximately postnatal month 6, where they remained relatively constant. The greatest variations in structural abundances were associated with the presence of α(1,2)-fucosylated species. Genomic analyses of the mothers were not performed; instead, milk was phenotyped according to the abundances of α(1,2)-fucosylated structures. Mothers from the South American sites tended to have higher proportions of phenotypic secretors [mothers with relatively high concentrations of α(1,2)-fucosylated structures] in their populations compared to the rest of the globe, with Bolivia at ∼100% secretors, Peru at ∼97%, Brazil at ∼90%, and Argentina at ∼85%. Conversely, the cohort sampled in Africa manifested the lowest proportion of secretors (South Africa ∼ 63%, the Gambia ∼ 64%, and Malawi ∼ 75%). Furthermore, we compared total abundances of HMOs in secretors compared with nonsecretors and found that nonsecretors have lower abundances of HMOs compared to secretors, regardless of geographical location. We also observed compositional differences of the 50+ most abundant HMOs between milk types and geographical locations. CONCLUSIONS: This study represents the largest structural HMO study to date and reveals the general behavior of HMOs during lactation among different populations.

BACKGROUND: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor.METHODS: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.RESULTS: A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; PCONCLUSIONS: Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).

The continuing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with decreased susceptibility to neutralizing antibodies is of clinical importance. Several spike mutations associated with immune escape have evolved independently in association with different variants of concern (VOCs). How and when these mutations arise is still unclear. We hypothesized that such mutations might arise in the context of persistent viral replication in immunosuppressed hosts.Nasopharyngeal specimens were collected longitudinally from two immunosuppressed patients with persistent SARS-CoV-2 infection. Plasma was collected from these same patients late in disease course. SARS-CoV-2 whole genome sequencing was performed to assess the emergence and frequency of mutations over time. Select Spike mutations were assessed for their impact on viral entry and antibody neutralization in vitro.Our sequencing results revealed the intrahost emergence of spike mutations that are associated with circulating VOCs in both immunosuppressed patients (del241-243 and E484Q in one patient, and E484K in the other). These mutations decreased antibody-mediated neutralization of pseudotyped virus particles in cell culture, but also decreased efficiency of spike-mediated cell entry.These observations demonstrate the de novo emergence of SARS-CoV-2 spike mutations with enhanced immune evasion in immunosuppressed patients with persistent infection. These data suggest one potential mechanism for the evolution of VOCs and emphasize the importance of continued efforts to develop antiviral drugs for suppression of viral replication in hospitalized settings.

Non-Hodgkin lymphoma (NHL) is the seventh most common type of malignancy worldwide, with approximately 544,000 cases diagnosed in 2020.[1-3] The vast majority of NHLs are derived from B cells. The more than 80 subtypes of B-cell NHL are categorized according to their typical clinical course: indolent or aggressive.[4] Aggressive B-cell NHLs that are refractory to first-line therapy or that relapse following initial treatment are historically associated with a poor prognosis, despite the use of salvage chemotherapy and autologous stem cell transplant.[5] The advent of chimeric antigen receptor (CAR) T-cell therapy has changed the treatment paradigm for patients who have relapsed/refractory aggressive B-cell NHL, with impressive response rates and the possibility for a durable remission in those whose disease has progressed despite multiple prior treatments.[6-8] This review outlines current indications for CAR T-cell therapy, major toxicities, novel CARs under investigation, and future directions.

Increases in snack consumption associated with Westernized lifestyles provide an opportunity to introduce nutritious foods into poor diets. We describe two 10-wk-long open label, single group assignment human studies that measured the effects of two snack prototypes containing fiber preparations from two sustainable and scalable sources; the byproducts remaining after isolation of protein from the endosperm of peas and the vesicular pulp remaining after processing oranges for the manufacture of juices. The normal diets of study participants were supplemented with either a pea- or orange fiber-containing snack. We focused our analysis on quantifying the abundances of genes encoding carbohydrate-active enzymes (CAZymes) (glycoside hydrolases and polysaccharide lyases) in the fecal microbiome, mass spectrometric measurements of glycan structures (glycosidic linkages) in feces, plus aptamer-based assessment of levels of 1,300 plasma proteins reflecting a broad range of physiological functions. Computational methods for feature selection identified treatment-discriminatory changes in CAZyme genes that correlated with alterations in levels of fiber-associated glycosidic linkages; these changes in turn correlated with levels of plasma proteins representing diverse biological functions, including transforming growth factor type β/bone morphogenetic protein-mediated fibrosis, vascular endothelial growth factor-related angiogenesis, P38/MAPK-associated immune cell signaling, and obesity-associated hormonal regulators. The approach used represents a way to connect changes in consumer microbiomes produced by specific fiber types with host responses in the context of varying background diets.

Background Childhood undernutrition is a major public health concern that needs special attention to achieve 2025 global nutrition targets. Moderate acute malnutrition (MAM), manifest as wasting (low weight-for-height), affects 33 million children under 5, yet there are currently no global guidelines for its treatment. We recently performed a randomized-controlled clinical study of a microbiota-directed complementary food formulation (MDCF-2) in 12-18-month-old Bangladeshi children with MAM. The results revealed that MDCF-2, freshly prepared each day, produced a significantly greater improvement in ponderal growth than a standard ready-to-use supplementary food (RUSF), an effect that is associated with repair of the disrupted gut microbial community development that occurs in children with MAM. To test the generalizability of these results in acutely malnourished children at other sites, there is a pressing need for a packaged, shelf-stable, organoleptically-acceptable formulation that is bioequivalent to MDCF-2. This report describes the protocol for a clinical study to evaluate candidate formulations designed to meet these criteria. Methods A randomized single-blind study will be conducted in 8-12-month-old Bangladeshi children with MAM to compare the efficacy of alternative shelf-stable MDCF prototypes versus the current MDCF-2 formulation that is produced fresh each day. V4-16S rDNA amplicon and shotgun sequencing datasets will be generated from faecal DNA samples collected from each child enrolled in each group prior to, during, and after treatment to determine the abundances of MDCF-2-responsive bacterial taxa. Efficacy will be assessed by quantifying the change in representation of MDCF-2-responsive gut bacterial taxa after 4-weeks of treatment with freshly prepared MDCF-2 compared to their changes in abundance after treatment with the prototype MDCFs. Equivalence will be defined as the absence of a statistically significant difference, after 4-weeks of treatment, in the representation of faecal bacterial taxa associated with the response to MDCF-2 in participants receiving a test MDCF. Discussion This trial aims to establish acceptability and equivalence with respect to microbiota repair, of scalable, shelf-stable formulations of MDCF-2 in 8-12-month-old Bangladeshi children with moderate acute malnutrition. Trial registration ClinicalTrials.gov (NCT05094024). The trial has been registered before starting enrolment on 23 October 2021.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Significance Postnatal development of the human gut microbiota is linked to healthy growth. Because the number of potential interactions between community components is vast, an unanswered question is what mechanisms determine the form of community assembly (succession). We created a simplified, manipulable in vivo model where bacterial strains cultured from an infant were divided into consortia, representing earlier and later periods in assembly, and introduced in different order into germ-free mice fed infant formula. Measuring strain abundances, bacterial gene expression and levels of gut nutrients, and applying computational tools to deduce interacting features, we identify genomic and metabolic correlates of how strains establish and maintain themselves. This approach may facilitate discoveries of how communities respond to various perturbations and microbiota-directed therapeutics., Human gut microbiota development has been associated with healthy growth but understanding the determinants of community assembly and composition is a formidable challenge. We cultured bacteria from serially collected fecal samples from a healthy infant; 34 sequenced strains containing 103,102 genes were divided into two consortia representing earlier and later stages in community assembly during the first six postnatal months. The two consortia were introduced alone (singly), or sequentially in different order, or simultaneously into young germ-free mice fed human infant formula. The pattern of fitness of bacterial strains observed across the different colonization conditions indicated that later-phase strains substantially outcompete earlier-phase strains, although four early-phase members persist. Persistence was not determined by order of introduction, suggesting that priority effects are not prominent in this model. To characterize succession in the context of the metabolic potential of consortium members, we performed in silico reconstructions of metabolic pathways involved in carbohydrate utilization and amino acid and B-vitamin biosynthesis, then quantified the fitness (abundance) of strains in serially collected fecal samples and their transcriptional responses to different histories of colonization. Applying feature-reduction methods disclosed a set of metabolic pathways whose presence and/or expression correlates with strain fitness and that enable early-stage colonizers to survive during introduction of later colonizers. The approach described can be used to test the magnitude of the contribution of identified metabolic pathways to fitness in different community contexts, study various ecological processes thought to govern community assembly, and facilitate development of microbiota-directed therapeutics.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody-drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1-mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

Treatment strategies for post-transplant lymphoproliferative disorders (PTLD) consist of response-adapted risk-stratified methods using immunosuppression reduction, immunotherapy, and chemotherapy. We investigated the efficacy of Brentuximab vedotin given concurrently with Rituximab (BV + R) once weekly for four weeks, followed by optional consolidation, and up to one year of maintenance. Among 20 assessable patients, BV + R therapy resulted in an overall response rate of 75% (95% CI 51 to 91, p = 0.044) with 60% achieving a complete response. Median time to best response was 28 days. Two-year progression-free survival and overall survival rates were 75 and 90%, respectively. Most common severe grade 3/4 treatment-related toxicities included neutropenia (40%), hypertension (30%), infection (25%), and peripheral neuropathy (15%). BV + R is a novel and effective therapeutic strategy that achieved rapid and durable remissions in previously untreated PTLD patients; however, this treatment platform requires further modification due to the high rates of treatment-related toxicity.Key pointsBrentuximab vedotin + Rituximab showed ORR and CR rates of 75 and 60% in patients with immunosuppression-associated lymphoid malignanciesHigh rates of treatment delay were attributed to treatment-related toxicity; further dosing optimization of this regimen is required.

Changing food preferences brought about by westernization that have deleterious health effects1,2—combined with myriad forces that are contributing to increased food insecurity—are catalysing efforts to identify more nutritious and affordable foods3. Consumption of dietary fibre can help to prevent cardiovascular disease, type 2 diabetes and obesity4–6. A substantial number of reports have explored the effects of dietary fibre on the gut microbial community7–9. However, the microbiome is complex, dynamic and exhibits considerable intra- and interpersonal variation in its composition and functions. The large number of potential interactions between the components of the microbiome makes it challenging to define the mechanisms by which food ingredients affect community properties. Here we address the question of how foods containing different fibre preparations can be designed to alter functions associated with specific components of the microbiome. Because a marked increase in snack consumption is associated with westernization, we formulated snack prototypes using plant fibres from different sustainable sources that targeted distinct features of the gut microbiomes of individuals with obesity when transplanted into gnotobiotic mice. We used these snacks to supplement controlled diets that were consumed by adult individuals with obesity or who were overweight. Fibre-specific changes in their microbiomes were linked to changes in their plasma proteomes indicative of an altered physiological state. Fibre snacks that target distinct features of the microbiomes of donors with obesity transplanted into gnotobiotic mice also lead to fibre-specific changes in the microbiome and physiology when used in controlled-diet human studies.

Background Campylobacter infection is associated with impaired growth of children, even in the absence of symptoms. To examine the underlying mechanisms, we evaluated associations between Campylobacter infection, linear growth, and fecal microbial community features in a prospective birth cohort of 271 children with a high burden of diarrhea and stunting in the Amazonian lowlands of Peru. Methods Campylobacter was identified using a broadly reactive, genus-specific enzyme-linked immunosorbent assay. 16S rRNA-based analyses were used to identify bacterial taxa in fecal samples at ages 6, 12, 18, and 24 months (N = 928). Associations between infection, growth, and gut microbial community composition were investigated using multiple linear regression adjusting for within-child correlations, age, and breastfeeding. Indicator species analyses identified taxa specifically associated with Campylobacter burden. Results Ninety-three percent (251) of children had Campylobacter present in asymptomatic fecal samples during the follow-up period. A 10% increase in the proportion of stools infected was associated with mean reductions of 0.02 length-for-age z scores (LAZ) at 3, 6, and 9 months thereafter (P < .01). We identified 13 bacterial taxa indicative of cumulative Campylobacter burden and 14 taxa significantly associated with high or low burden of enteroaggregative Escherichia coli, norovirus, or Giardia. Conclusions Campylobacter infection is common in this cohort and associated with changes in microbial community composition. These results support the notion that disruptions to the fecal microbiota may help explain the observed effects of asymptomatic infections on growth in early life., In this longitudinal cohort study, we demonstrate a high prevalence of asymptomatic Campylobacter infection among children aged 0–24 months, describe the effects of Campylobacter on gut microbial community composition, and link alterations in community composition to deficits in linear growth in early life.

Diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma (FL) (tDLBCL) has been traditionally associated with an aggressive course, but more recent studies have shown longer survivals. The clinical significance of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) is less clear. We compared outcomes of tDLBCL, cDLBCL/FL, and

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin’s lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.

Transposable elements (TEs) are an abundant and rich genetic resource of regulatory sequences1–3. Cryptic regulatory elements within TEs can be epigenetically reactivated in cancer to influence oncogenesis in a process termed onco-exaptation4. However, the prevalence and impact of TE onco-exaptation events across cancer types are poorly characterized. Here, we analyzed 7,769 tumors and 625 normal datasets from 15 cancer types, identifying 129 TE cryptic promoter activation events involving 106 oncogenes across 3,864 tumors. Furthermore, we interrogated the AluJb-LIN28B candidate: the genetic deletion of the TE eliminated oncogene expression, while dynamic DNA methylation modulated promoter activity, illustrating the necessity and sufficiency of a TE for oncogene activation. Collectively, our results characterize the global profile of TE onco-exaptation and highlight this prevalent phenomenon as an important mechanism for promiscuous oncogene activation and ultimately tumorigenesis.

Purpose: To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA). Patients and Methods: ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. Results: The NA subgroup consisted of 497 subjects in the A+AVD (n = 250) and ABVD (n = 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint [modified progression-free survival (PFS) per independent review] demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60; P = 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50; P = 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD. Conclusions: The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.

Plant fibers in byproduct streams produced by non-harsh food processing methods represent biorepositories of diverse, naturally occurring, and physiologically active biomolecules. To demonstrate one approach for their characterization, mass spectrometry of intestinal contents from gnotobiotic mice, plus in vitro studies, revealed liberation of N-methylserotonin from orange fibers by human gut microbiota members including Bacteroides ovatus. Functional genomic analyses of B. ovatus strains grown under permissive and non-permissive N-methylserotonin “mining” conditions revealed polysaccharide utilization loci that target pectins whose expression correlate with strain-specific liberation of this compound. N-methylserotonin, orally administered to germ-free mice, reduced adiposity, altered liver glycogenesis, shortened gut transit time, and changed expression of genes that regulate circadian rhythm in the liver and colon. In human studies, dose-dependent, orange-fiber-specific fecal accumulation of N-methylserotonin positively correlated with levels of microbiome genes encoding enzymes that digest pectic glycans. Identifying this type of microbial mining activity has potential therapeutic implications.

This review provides a contemporary overview of current studies outlining the incidence and characteristics of CAR T-cell cardiotoxicity in an effort to identify future directions for research and potential opportunities for prevention and intervention.Cardiovascular events occurred in anywhere between 10 and 36% of patients in CAR T-cell clinical trials, ranging from tachycardia, hypotension, arrhythmia, decreased left ventricular systolic function to cardiogenic shock and death. Cardiac events are more often associated higher grades (2) of cytokine release syndrome and frequently proceeded by an elevated troponin. There is a growing recognition of cardiotoxicities of CAR T-cell therapy but has a limited study in this area. The mechanism of left ventricular dysfunction due to CAR T-cell therapy is also unknown. As CAR T-cell use expands, it becomes imperative to truly understand the mechanism behind cardiac injury and to assess long-term follow-up data as this will allow for surveillance, early intervention, and potentially prevention of cardiotoxicity.

Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell’s palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

Perturbed gut microbiome development has been linked to childhood malnutrition. Here, we characterize bacterial Toll/interleukin-1 receptor (TIR) protein domains that metabolize nicotinamide adenine dinucleotide (NAD), a co-enzyme with far-reaching effects on human physiology. A consortium of 26 human gut bacterial strains, representing the diversity of TIRs observed in the microbiome and the NAD hydrolase (NADase) activities of a subset of 152 bacterial TIRs assayed in vitro, was introduced into germ-free mice. Integrating mass spectrometry and microbial RNA sequencing (RNA-seq) with consortium membership manipulation disclosed that a variant of cyclic-ADPR (v-cADPR-x) is a specific product of TIR NADase activity and a prominent, colonization-discriminatory, taxon-specific metabolite. Guided by bioinformatic analyses of biochemically validated TIRs, we find that acute malnutrition is associated with decreased fecal levels of genes encoding TIRs known or predicted to generate v-cADPR-x, as well as decreased levels of the metabolite itself. These results underscore the need to consider microbiome TIR NADases when evaluating NAD metabolism in the human holobiont.

Normal human cells can either synthesize cholesterol or take it up from lipoproteins to meet their metabolic requirements. In some malignant cells, de novo cholesterol synthesis genes are transcriptionally silent or mutated, meaning that cholesterol uptake from lipoproteins is required for survival. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also subject to ferroptosis, an oxygen- and iron-dependent cell death mechanism triggered by accumulation of oxidized lipids in cell membranes unless the lipid hydroperoxidase, glutathione peroxidase 4 (GPX4), reduces these toxic lipid species. To study mechanisms linking cholesterol uptake with ferroptosis and determine the potential role of the high-density lipoprotein (HDL) receptor as a target for cholesterol depleting therapy, we treated lymphoma cell lines known to be sensitive to the reduction of cholesterol uptake with HDL-like nanoparticles (HDL NPs). HDL NPs are a cholesterol-poor ligand that binds to the receptor for cholesterol-rich HDLs, scavenger receptor type B1 (SCARB1). Our data reveal that HDL NP treatment activates a compensatory metabolic response in treated cells toward increased de novo cholesterol synthesis, which is accompanied by nearly complete reduction in expression of GPX4. As a result, oxidized membrane lipids accumulate, leading to cell death through a mechanism consistent with ferroptosis. We obtained similar results in vivo after systemic administration of HDL NPs in mouse lymphoma xenografts and in primary samples obtained from patients with lymphoma. In summary, targeting SCARB1 with HDL NPs in cholesterol uptake–addicted lymphoma cells abolishes GPX4, resulting in cancer cell death by a mechanism consistent with ferroptosis.

Purpose: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. Patients and Methods: Patients received continuous, once-daily oral TAK-659, 60–120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. Results: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (Tmax ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60–120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). Conclusions: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

Background Tumor necrosis factor (TNF) inhibitors are widely used in pediatric patients with inflammatory bowel disease, as well as psoriasis. However, there is growing evidence that these medications can also paradoxically induce a psoriasiform skin reaction in a subset of patients. Goals We seek to share our experience in treating severe TNF inhibitor-induced psoriasis in a pediatric patient with Crohnrs disease. Study We report a case of a 10-year-old female with Crohnrs disease, who developed psoriasis after twelve months of infliximab therapy. Her skin disease was recalcitrant to topical therapies, methotrexate, and phototherapy. Results The patient was transitioned to ustekinumab with significant improvement in her symptoms and maintenance of remission of her bowel disease. Conclusion This is the first reported case of a school-age pediatric patient with TNF inhibitor-induced psoriasis treated with ustekinumab. Controlled trials are warranted to fully assess the safety and efficacy of ustekinumab for treating TNF inhibitor-induced psoriasis in the pediatric population.J Drugs Dermatol. 2020;19(3): doi:10.36849/JDD.2020.2106.

Summary Background Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas. Methods We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044. Findings Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1–8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0–19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8–78·0) patients and a complete response by 136 (53%, 46·8–59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells. Interpretation Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. Funding Juno Therapeutics, a Bristol-Myers Squibb Company.

Undernourished children in low-income countries often exhibit poor responses to oral vaccination. Perturbed microbiota development is linked to undernutrition but whether and how microbiota changes affect vaccine responsiveness remain unclear. Here, we show that gnotobiotic mice colonized with microbiota from undernourished Bangladeshi children and fed a Bangladeshi diet exhibited microbiota-dependent differences in mucosal IgA responses to oral vaccination with cholera toxin (CT). Supplementation with a nutrient-rich diet consisting of spirulina, amaranth, flaxseed and micronutrients augmented CT-IgA production. Mice initially colonized with a microbiota associated with poor CT responses exhibited improved immunogenicity upon invasion of bacterial taxa from cagemates colonized with a more ‘responsive’ microbiota. Additionally, a consortium of five cultured bacterial invaders conferred augmented CT-IgA responses in mice fed the supplemented diet and colonized with the ‘hypo-responsive’ community. These results provide preclinical proof-of-concept that diet and microbiota influence mucosal immune responses to CT vaccination and identify a candidate synbiotic formulation.

Breastmilk research holds important opportunities to improve maternal-child health

Pain is a serious adverse event which frequently accompanies hematopoietic stem cell transplantation (HSCT). The safety and efficacy of NSAIDS during HSCT is currently unknown. Salsalate is a platelet-sparing NSAID with a favorable toxicity profile compared with other NSAIDS. We report the safety and efficacy of salsalate for different types of pain during SCT.We conducted a retrospective study of SCT recipients empirically treated with salsalate for 48 h. Pain scores were assessed using the verbal rating scale for pain. A subset analysis of patients who received 7 days of salsalate during periods of pancytopenia, mucositis, and other end-organ toxicities is included.Sixty-four patients, 42 auto- and 22 allografts, were identified. Reason for use: vertebral-related pain (30%), musculoskeletal (30%), and cytokine inflammatory pain syndromes (24%). Median dose 1500 mg/day, number of treatment days = 5, started on day+5 post-HSCT. Pain resolved/improved to pain score 4 in 76% and stable in 15%. Forty-four patients (28-auto and 16 allografts) received 7-day salsalate. Median WBC and platelet nadir were 0.1 and 10,000 cells/ml respectively.pain was improved or eradicated in 64% and stable in 32%.LFT elevation (n = 2), elevated serum creatinine (n = 2), and minor bleed (n = 5-nose, gums, and urine). Salsalate discontinuation (n = 6): ineffective (n = 1), the liver (n = 1), the kidney (n = 1), 5 platelet transfusions (n = 1), and vomiting (n = 2). There was no treatment related mortality. Salsalate was well tolerated, safe, and beneficial for several different types of pain during HSCT.

Aggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B/P-MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi-institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B/P-MCL, using next generation sequencing and SNP-array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C-MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B/P-MCL cases showed loss of CDKN2A/B (6 biallelic and 6 monoallelic losses); while only one C-MCL showed monoallelic CDKN2A/B loss. In B/P-MCL, TP53 was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored TP53 mutations. Other recurrent mutations in B/P-MCL included ATM (7, 53%), CCND1 (5, 38%), NOTCH1 (2, 18%), NOTCH2, and BIRC3 (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of CDKN2A/B and TP53 alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B/P-MCL may be an indicator of clinically aggressive MCL. In addition, frequent CDKN2A deletion and high genomic instability may provide potential targets for alternative treatment.

Background Childhood undernutrition remains a significant global health challenge accounting for over half of all under 5 child mortality. Moderate acute malnutrition (MAM), which leads to wasting [weight-for-length z-scores (WLZ) between − 2 and − 3], affects 33 million children under 5 globally and more than 2 million in Bangladesh alone. We have previously reported that acute malnutrition in this population is associated with gut microbiota immaturity, and in a small, 1-month pre-proof-of-concept (POC) study demonstrated that a microbiota-directed complementary food formulation (MDCF-2) was able to repair this immaturity, promote weight gain and increase plasma biomarkers and mediators of healthy growth. Here we describe the design controlled feeding study that tests whether MDCF-2 exhibits superior efficacy (ponderal growth, host biomarkers of a biological state) than a conventional Ready-to-use Supplementary Food (RUSF) in children with MAM over intervention period of 3 months. Methods Two separate cohorts of 12–18-month-old children will be enrolled: 124 with primary MAM, and 124 with MAM after having been treated for severe acute malnutrition (post-SAM MAM). We have established several field sites in an urban slum located in the Mirpur district of Dhaka, Bangladesh and at a rural site, Kurigram in the north of Bangladesh. The two groups of children receiving MDCF-2 and RUSF will be compared at baseline (pre-intervention), after 1 month, at the end of intervention (3 months), 1 month after cessation of intervention, and every 6 months thereafter for 4 years. Discussion This study will determine whether daily, controlled administration of MDCF-2 for 3 months provides superior improvements in weight gain, microbiota repair, and elevated levels of key plasma biomarkers/mediators of healthy growth compared to the control RUSF formulation. The pathogenesis of MAM is poorly defined and there are currently no WHO-approved treatments; results from the current study of children with primary MAM and post-SAM MAM will shed light on the effects of the gut microbiota on childhood growth/development and will provide a knowledge base that may help improve complementary feeding practices. Trial registration The primary MAM and post-SAM MAM trials are registered in Clintrials.gov (NCT04015999 and NCT04015986, registered on July 11, 2019, retrospectively registered).

Metagenomic sequencing of bacterial samples has become the gold standard for profiling microbial populations, but 16S rRNA profiling remains widely used due to advantages in sample throughput, cost, and sensitivity even though the approach is hampered by primer bias and lack of specificity. We hypothesized that a hybrid approach, that combined targeted PCR amplification with high-throughput sequencing of multiple regions of the genome, would capture many of the advantages of both approaches. We developed a method that identifies and quantifies members of bacterial communities through simultaneous analysis of multiple variable regions of the bacterial 16S rRNA gene. The method combines high-throughput microfluidics for PCR amplification, short read DNA sequencing, and a custom algorithm named MVRSION (Multiple 16S Variable Region Species-Level IdentificatiON) for optimizing taxonomic assignment. MVRSION performance was compared to single variable region analyses (V3 or V4) of five synthetic mixtures of human gut bacterial strains using existing software (QIIME), and the results of community profiling by shotgun sequencing (COPRO-Seq) of fecal DNA samples collected from gnotobiotic mice colonized with a defined, phylogenetically diverse consortium of human gut bacterial strains. Positive predictive values for MVRSION ranged from 65%-91% versus 44%-61% for single region QIIME analyses (p < .01, p < .001), while the abundance estimate r2 for MVRSION compared to COPRO-Seq was 0.77 vs. 0.46 and 0.45 for V3-QIIME and V4-QIIME, respectively. MVRSION represents a generally applicable tool for taxonomic classification that is superior to single-region 16S rRNA methods, resource efficient, highly scalable for assessing the microbial composition of up to thousands of samples concurrently, with multiple applications ranging from whole community profiling to targeted tracking of organisms of interest in diverse habitats as a function of specified variables/perturbations.

Purpose To improve the curability of older patients with newly diagnosed Hodgkin lymphoma. Patients and Methods We conducted a multicenter phase II study that administered brentuximab vedotin (Bv) sequentially before and after standard doxorubicin, vinblastine, and dacarbazine (AVD) for untreated patients with Hodgkin lymphoma age 60 years or older. After two lead-in doses of single-agent Bv (1.8 mg/kg once every 3 weeks), patients received six cycles of AVD chemotherapy followed by four consolidative doses of Bv in responding patients. Results Patient characteristics included median age of 69 years (range, 60 to 88 years), 63% male, median Eastern Cooperative Oncology Group performance status 1, 81% stage III to IV disease, 60% International Prognostic Score 3 to 7, median Cumulative Illness Rating Scale-Geriatric comorbidity score of 7 (52% grade 3 to 4); and 12% had loss of instrumental activities of daily living at diagnosis. Thirty-seven (77%) of 48 patients completed six cycles of AVD, and 35 patients (73%) received at least one Bv consolidation. Overall response and complete remission rates after initial Bv lead-in dose were 18 (82%) of 22 and 8 (36%) of 22, respectively, and 40 (95%) of 42 and 34 (90%) of 42, respectively, after six cycles of AVD among 42 response-evaluable patients. Twenty (42%) of 48 patients experienced a grade 3 to 4 adverse event, most commonly neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%); 33% had grade 2 peripheral neuropathy, which was reversible in a majority of patients. By intent-to-treat, the 2-year event-free survival, progression-free survival, and overall survival rates were 80%, 84%, and 93%, respectively. Furthermore, 2-year progression-free survival rates for patients with a Cumulative Illness Rating Scale-Geriatric comorbidity score of ≥ 10 versus < 10 were 45% versus 100%, respectively ( P < .001), and with baseline loss versus no loss of instrumental activities of daily living were 25% versus 94% ( P < .001), respectively, the latter persisting on multivariable analyses. Conclusion Altogether, sequential Bv-AVD was well tolerated and was associated with robust outcomes. Furthermore, geriatric-based measures were strongly associated with patient survival.

Immune-based treatment strategies, such as checkpoint inhibition and chimeric antigen receptor (CAR) T cells, have started a new frontier for treatment in non-Hodgkin lymphoma (NHL). Checkpoint inhibition has been most successful in Hodgkin lymphoma, where higher expression of PD-L1 is correlated with better overall response rate. Combinations of checkpoint inhibition with various chemotherapy or biologics are in clinical trials, with initially promising results and manageable safety profiles. CAR T-cell therapies that target CD19 are a promising and attractive therapy for B-cell NHLs, with a product approved by the US Food and Drug Administration in 2017. Changes in the target, hinge, or costimulatory domain can dramatically alter the persistence and efficacy of the CAR T cells. The ZUMA trials from Kite used CD19-(CD28z) CAR T cells, whereas the TRANSCEND studies from Juno and the JULIET studies from Novartis used CD19-(4-1BBz) CARs. Despite the recent successes with CAR T-cell clinical trials, major concerns associated with this therapy include cytokine release syndrome, potential neurotoxicities, B-cell aplasia, loss of tumor antigen leading to relapse, and cost and accessibility of the treatment. Although first-generation CAR T-cell therapies have failed in solid malignancies, newer second- and third-generation CAR T cells that target antigens other than CD19 (such as mesothelin or B-cell maturation antigen) are being studied in clinical trials for treatment of lung cancer or multiple myeloma. Overall, immune-based treatment strategies have given oncologists and patients hope when there used to be none, as well as a new basket of tools yet to come with further research and development.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

Background With the introduction of the anti-CD20 antibody rituximab, the outcome of patients with follicular lymphoma (FL) has greatly improved over the last two decades. First-line prolonged rituximab monotherapy is effective, achieving long-term remission and prolonged failure-free survival in some patients. Additionally, rituximab has been shown to synergize with chemotherapeutic and novel targeted agents alike with measurable gains in duration of response. As such, rituximab has made its mark in the treatment of FL and remains a valid agent despite the availability of newer monoclonal antibodies. This review summarizes the evolving role of rituximab as the first available anti-CD20 monoclonal antibody, emphasizing its clear activity as a single agent and in combination with chemotherapy or molecular targeted agents, and setting the standard for the development of new anti-CD20 monoclonal antibodies. Conclusion We provide data that support the ongoing use of rituximab as a therapeutic partner for novel agents in future clinical trials exploring chemotherapy-free alternatives.

Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1). As we previously reported, GC DLBCL are exquisitely sensitive to HDL NP as monotherapy, while ABC DLBCL are less sensitive. Herein, we report that enhanced BCR signaling and resultant de novo cholesterol synthesis in ABC DLBCL drastically reduces the ability of HDL NPs to reduce cellular cholesterol and induce cell death. Therefore, we combined HDL NP with the BCR signaling inhibitor ibrutinib and the SYK inhibitor R406. By targeting both cellular cholesterol uptake and BCR-associated de novo cholesterol synthesis, we achieved cellular cholesterol reduction and induced apoptosis in otherwise resistant ABC DLBCL cell lines. These results in lymphoma demonstrate that reduction of cellular cholesterol is a powerful mechanism to induce apoptosis. Cells rich in cholesterol require HDL NP therapy to reduce uptake and molecularly targeted agents that inhibit upstream pathways that stimulate de novo cholesterol synthesis, thus, providing a new paradigm for rationally targeting cholesterol metabolism as therapy for cancer.

This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

BACKGROUND Electrocardiographic (ECG) monitored outpatient cardiac rehabilitation (OP-CR) is routinely performed following a variety of cardiovascular procedures and conditions. OBJECTIVE The aim of this study is to determine if diagnostic-quality ECG monitoring in patients with coronary artery disease (CAD) during OP-CR is useful in identifying asymptomatic myocardial ischemia, resulting in change(s) in care or medical management. METHODS A retrospective analysis of ECG monitoring was done on all OP-CR patients diagnosed with CAD (n = 1213) from January 2000 through June 2013. RESULTS Nearly a quarter of the patients (24%; n = 288) displayed at least 1 mm of asymptomatic ST-segment depression at 80 milliseconds after the J-point during at least 1 session of OP-CR. Of these patients, 57% had medical management change(s) compared with 24% for those who did not show ECG changes suggesting ischemia (P < .0001). In patients with asymptomatic ischemia having medical management change(s), 84% resulted directly from OP-CR staff detection. Fewer patients diagnosed with myocardial infarction and coronary artery bypass graft surgery demonstrated ECG signs of ischemia, whereas more patients diagnosed with stable angina and percutaneous coronary interventions demonstrated ECG signs of ischemia. CONCLUSION This study demonstrates that most patients with CAD showing asymptomatic ECG signs suggesting ischemia undergo medical management change(s) as a result of the finding. Diagnostic-quality ECG monitoring during OP-CR appears warranted in this population.

Cancer cachexia is defined as a state of involuntary weight loss, attributed to altered body composition with muscle mass loss and/or loss of adiposity. Identifying the association between cancer cachexia and outcomes may pave the way for novel agents that target the cancer cachexia process. Clinical parameters for measurement of cancer cachexia are needed. We conducted a single-institution retrospective analysis that included 86 NHL patients with the aim of identifying an association between cancer cachexia and outcomes in aggressive lymphomas using the cachexia index (CXI) suggested by Jafri et al. (Clin Med Insights Oncol 9:87–93, 15). Impact of cachexia factors on progression-free survival (PFS) and overall survival (OS) were assessed using log-rank test and Cox proportional hazards regression. Patients were dichotomized around the median CXI into “non-cachectic” (CXI ≥49.8, n = 41) and “cachectic” (CXI

// Kaylin M. McMahon 1, * , Cristina Scielzo 2, 3, * , Nicholas L. Angeloni 1 , Elad Deiss-Yehiely 1 , Lydia Scarfo 2, 3 , Pamela Ranghetti 2, 3 , Shuo Ma 4 , Jason Kaplan 4, 5 , Federica Barbaglio 3 , Leo I. Gordon 4 , Francis J. Giles 4, 5 , C. Shad Thaxton 1, 4, 6, 7 , Paolo Ghia 2, 3 1 Department of Urology, Feinberg School of Medicine, Northwestern University, Tarry, Chicago, IL, USA 2 Universita Vita-Salute San Raffaele, Milan, Italy 3 Strategic Research Program On CLL and Unit of B cell Neoplasia, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy 4 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 5 Developmental Therapeutics Program of The Division of Hematology Oncology, Feinberg School of Medicine, Chicago, IL, USA 6 Simpson Querrey Institute (SQI) for BioNanotechnology, Chicago, IL, USA 7 International Institute for Nanotechnology, Evanston, IL, USA * These authors equally contributed to this work Correspondence to: C. Shad Thaxton, email: cthaxton003@md.northwestern.edu Paolo Ghia, email: ghia.paolo@hsr.it Keywords: lipoprotein, leukemia, scavenger receptor type B-I, nanoparticle, biomaterials Received: June 29, 2016 Accepted: December 26, 2016 Published: January 04, 2017 ABSTRACT Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new drugs. Therapies targeting receptors and pathways active specifically in malignant B cells might provide better treatment options. For instance, in B cell lymphoma, our group has previously shown that scavenger receptor type B-1 (SR-B1), the high-affinity receptor for cholesterol-rich high-density lipoproteins (HDL), is a therapeutic target. As evidence suggests that targeting cholesterol metabolism in CLL cells may have therapeutic benefit, we examined SR-B1 expression in primary CLL cells from patients. Unlike normal B cells that do not express SR-B1, CLL cells express the receptor. As a result, we evaluated cholesterol-poor synthetic HDL nanoparticles (HDL NP), known for targeting SR-B1, as a therapy for CLL. HDL NPs potently and selectively induce apoptotic cell death in primary CLL cells. HDL NPs had no effect on normal peripheral blood mononuclear cells from healthy individuals or patients with CLL. These data implicate SR-B1 as a target in CLL and HDL NPs as targeted monotherapy for CLL.

Glucocorticoids are widely used for therapy of hematologic malignancies. Unfortunately, chronic treatment with glucocorticoids commonly leads to adverse effects including skin and muscle atrophy and osteoporosis. We found recently that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. Here, we tested whether REDD1 suppression makes glucocorticoid-based therapy of blood cancer safer. Unexpectedly, approximately 50% of top putative REDD1 inhibitors selected by bioinformatics screening of Library of Integrated Network-Based Cellular Signatures database (LINCS) were PI3K/Akt/mTOR inhibitors. We selected Wortmannin, LY294002, and AZD8055 for our studies and showed that they blocked basal and glucocorticoid-induced REDD1 expression. Moreover, all PI3K/mTOR/Akt inhibitors modified glucocorticoid receptor function shifting it toward therapeutically important transrepression. PI3K/Akt/mTOR inhibitors enhanced anti-lymphoma effects of Dexamethasone in vitro and in vivo, in lymphoma xenograft model. The therapeutic effects of PI3K inhibitor+Dexamethasone combinations ranged from cooperative to synergistic, especially in case of LY294002 and Rapamycin, used as a previously characterized reference REDD1 inhibitor. We found that coadministration of LY294002 or Rapamycin with Dexamethasone protected skin against Dexamethasone-induced atrophy, and normalized RANKL/OPG ratio indicating a reduction of Dexamethasone-induced osteoporosis. Together, our results provide foundation for further development of safer and more effective glucocorticoid-based combination therapy of hematologic malignancies using PI3K/Akt/mTOR inhibitors.

Development of microbiota-directed foods (MDFs) that selectively increase the abundance of beneficial human gut microbes, and their expressed functions, requires knowledge of both the bioactive components of MDFs and the mechanisms underlying microbe-microbe interactions. Here, gnotobiotic mice were colonized with a defined consortium of human-gut-derived bacterial strains and fed different combinations of 34 food-grade fibers added to a representative low-fiber diet consumed in the United States. Bioactive carbohydrates in fiber preparations targeting particular Bacteroides species were identified using community-wide quantitative proteomic analyses of bacterial gene expression coupled with forward genetic screens. Deliberate manipulation of community membership combined with administration of retrievable artificial food particles, consisting of paramagnetic microscopic beads coated with dietary polysaccharides, disclosed the contributions of targeted species to fiber degradation. Our approach, including the use of bead-based biosensors, defines nutrient-harvesting strategies that underlie, as well as alleviate, competition between Bacteroides and control the selectivity of MDF components.

To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF that changes the abundances of targeted bacteria and increases plasma biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function in children with MAM. INTRODUCTION There is a dimension to post-natal human development that involves assembly of microbial communities in different body habitats, including the gut. Children with acute malnutrition have impaired development of their gut microbiota, leaving them with communities that appear younger (more immature) than those of chronologically age-matched healthy individuals. Current therapeutic foods given to children with acute malnutrition have not been formulated based on knowledge of how they affect the developmental biology of the gut microbiota. Moreover, they are largely ineffective in ameliorating the long-term sequelae of malnutrition that include persistent stunting, neurodevelopmental abnormalities, and immune dysfunction. RATIONALE Repairing microbiota immaturity and determining the degree to which such repair restores healthy growth requires identification of microbial targets that are not only biomarkers of community assembly but also mediators of various aspects of growth. Identifying ingredients in complementary foods, consumed during the transition from exclusive milk feeding to a fully weaned state, that increase the representation and expressed beneficial functions of growth-promoting bacterial taxa in the developing microbiota could provide an effective, affordable, culturally acceptable, and sustainable approach to treatment. RESULTS Metabolomic and proteomic analyses of serially collected plasma samples were combined with metagenomic analyses of serially collected fecal samples from Bangladeshi children with severe acute malnutrition (SAM) treated with standard therapy. The results provided a readout of their biological features as they transitioned from SAM to a state of persistent moderate acute malnutrition (MAM) with accompanying persistent microbiota immaturity. Significant correlations were identified between levels of plasma proteins, anthropometry, plasma metabolites, and the representation of bacteria in their microbiota. Gnotobiotic mice were subsequently colonized with a defined consortium of bacterial strains that represent various phases of microbiota development in healthy Bangladeshi children. Administration of different combinations of Bangladeshi complementary food ingredients to colonized mice and germ-free controls revealed diet-dependent increases in the abundance and changes in the metabolic activities of targeted weaning-phase strains as well as diet- and colonization-dependent augmentation of growth-promoting host signaling pathways. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes were subsequently examined in gnotobiotic mice colonized with immature microbiota from children with post-SAM MAM and in gnotobiotic piglets colonized with a defined consortium of targeted age- and growth-discriminatory taxa. A randomized, double-blind study of standard therapy versus various MDCF prototypes emerging from these preclinical models, conducted in Bangladeshi children with MAM, identified a lead MDCF that increased levels of biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function toward a state resembling healthy children. Using an approach inspired by statistical methods applied to financial markets, we show in the accompanying paper by Raman et al. that this lead MDCF was most effective in repairing the microbiota. CONCLUSION These findings demonstrate the translatability of results obtained from pre-clinical gnotobiotic animal models to humans, directly support the hypothesis that healthy microbiota development is causally linked to healthy growth, illustrate an approach for treating childhood undernutrition, and with the capacity to deliberately reconfigure immature microbiota, suggest a means to decipher how elements of the gut microbial community operate to regulate various host systems involved in healthy growth. Overview of therapeutic food discovery and testing. The approach used for integrating preclinical gnotobiotic animal models with human studies to understand the contributions of perturbed gut microbiota development to childhood malnutrition and to identify MDCFs.

Significance Identifying components of breast milk that influence postnatal development though their effects on the gut microbiota and immune system could provide new therapeutic approaches for childhood undernutrition, including heretofore treatment-refractory linear growth faltering (stunting). Plasma biomarkers of osteoclast-mediated bone resorption and osteoblast-driven bone formation in stunted Bangladeshi children provided evidence for elevated osteoclastic activity. Gnotobiotic mice, colonized with a stunted infant’s gut microbiota, exhibited decreased bone resorption when consuming diets supplemented with a purified bovine oligosaccharide mixture dominated by sialylated structures found in human breast milk. Supplementation decreased osteoclastogenesis while sparing osteoblast activity; the microbiota, intestinal cell populations, and immune mediators contribute to these responses. The influence of milk oligosaccharides on the gut microbiota–bone axis has diagnostic and therapeutic implications., Undernutrition in children is a pressing global health problem, manifested in part by impaired linear growth (stunting). Current nutritional interventions have been largely ineffective in overcoming stunting, emphasizing the need to obtain better understanding of its underlying causes. Treating Bangladeshi children with severe acute malnutrition with therapeutic foods reduced plasma levels of a biomarker of osteoclastic activity without affecting biomarkers of osteoblastic activity or improving their severe stunting. To characterize interactions among the gut microbiota, human milk oligosaccharides (HMOs), and osteoclast and osteoblast biology, young germ-free mice were colonized with cultured bacterial strains from a 6-mo-old stunted infant and fed a diet mimicking that consumed by the donor population. Adding purified bovine sialylated milk oligosaccharides (S-BMO) with structures similar to those in human milk to this diet increased femoral trabecular bone volume and cortical thickness, reduced osteoclasts and their bone marrow progenitors, and altered regulators of osteoclastogenesis and mediators of Th2 responses. Comparisons of germ-free and colonized mice revealed S-BMO-dependent and microbiota-dependent increases in cecal levels of succinate, increased numbers of small intestinal tuft cells, and evidence for activation of a succinate-induced tuft cell signaling pathway linked to Th2 immune responses. A prominent fucosylated HMO, 2′-fucosyllactose, failed to elicit these changes in bone biology, highlighting the structural specificity of the S-BMO effects. These results underscore the need to further characterize the balance between, and determinants of, osteoclastic and osteoblastic activity in stunted infants/children, and suggest that certain milk oligosaccharides may have therapeutic utility in this setting.

International audience; Greater understanding of the spatial relationships between members of the human gut microbiota and available nutrients is needed to gain deeper insights about community dynamics and expressed functions. Therefore, we generated a panel of artificial food particles with each type composed of microscopic paramagnetic beads coated with a fluorescent barcode and one of 60 different dietary or host glycan preparations. Analysis of 160 Bacteroides and Parabacteroides strains disclosed diverse strain-specific and glycan-specific binding phenotypes. We identified carbohydrate structures that correlated with binding by specific bacterial strains in vitro and noted strain-specific differences in the catabolism of glycans that mediate adhesion. Mixed in vitro cultures revealed that these adhesion phenotypes are maintained in more complex communities. Additionally, orally administering glycan beads to gnotobiotic mice confirmed specificity in glycan binding. This approach should facilitate analyses of how strains occupying the same physical niche interact, and it should advance the development of synbiotics, more nutritious foods, and microbiota-based diagnostics.

Purpose: Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N = 55) with single-agent abexinostat in relapsed/refractory lymphoma. Experimental Design: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m2 twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/refractory follicular lymphoma or mantle cell lymphoma. Results: The recommended phase II dose was 45 mg/m2 twice daily (90 mg/m2 total), 7 days/week given every other week. Of the 30 follicular lymphoma and mantle cell lymphoma patients enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell lymphoma) were response-evaluable. Tumor size was reduced in 86% of follicular lymphoma patients with an investigator-assessed ORR of 64.3% for evaluable patients [intent-to-treat (ITT) ORR 56.3%]. Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2–22.3+). Of responding follicular lymphoma patients, 89% were on study/drug >8 months. In mantle cell lymphoma, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1–11.5). Grade 3–4 treatment-related adverse events (phase II) with ≥10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths. Conclusions: The pan-HDACi, abexinostat, was overall well tolerated and had significant clinical activity in follicular lymphoma, including highly durable responses in this multiply relapsed patient population. Clin Cancer Res; 22(5); 1059–66. ©2015 AACR.

The advent of effective therapies has improved outcomes for those with newly diagnosed Hodgkin lymphoma (HL), with a resulting cure rate of at least 80%. However, with limited data on therapeutic options in the setting of advanced disease, individualized treatment is recommended, and potential long-term effects of therapy remain a key consideration. At the NCCN 22nd Annual Conference, Dr. Leo I. Gordon explored strategies for systemic therapy in the relapsed or refractory setting, focusing primarily on the standard of high-dose therapy/autologous stem cell rescue, the CD30-targeted antibody drug conjugate brentuximab vedotin, and checkpoint inhibition.