Search

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.

Disrupted development of the gut microbiota is a contributing cause of childhood malnutrition. Bifidobacterium longum subspecies infantis is a prominent early colonizer of the infant gut that consumes human milk oligosaccharides (HMOs). We found that the absolute abundance of Bifidobacterium infantis is lower in 3- to 24-month-old Bangladeshi infants with severe acute malnutrition (SAM) compared to their healthy age-matched counterparts. A single-blind, placebo-controlled trial (SYNERGIE) was conducted in 2- to 6-month-old Bangladeshi infants with SAM. A commercial U.S. donor–derived B. infantis strain (EVC001) was administered daily with or without the HMO lacto- N -neotetraose for 28 days. This intervention increased fecal B. infantis abundance in infants with SAM, although to levels still 10- to 100-fold lower than in untreated healthy controls. EVC001 treatment promoted weight gain that was associated with reduced intestinal inflammation markers in infants with SAM. We cultured fecal B. infantis strains from Bangladeshi infants and colonized gnotobiotic mice with these cultured strains. The gnotobiotic mice were fed a diet representative of that consumed by 6-month-old Bangladeshi infants, with or without HMO supplementation. One B. infantis strain, Bg_2D9, expressing two gene clusters involved in uptake and utilization of N -glycans and plant-derived polysaccharides, exhibited superior fitness over EVC001. The fitness advantage of Bg_2D9 was confirmed in a gnotobiotic mouse model of mother-to-infant gut microbiota transmission where dams received a pretreatment fecal community from a SAM infant in the SYNERGIE trial. Whether Bg_2D9 is superior to EVC001 for treating malnourished infants who consume a diet with limited breastmilk requires further clinical testing.

Background: The rapid global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains the international public health concern of the decade. Early clinical data suggest that patients (pts) with hematologic malignancies are vulnerable to severe forms of SARS-CoV-2 and have higher mortality rates than the general population. Greater understanding of risk factors and outcomes associated with SARS-CoV-2 in pts with hematologic malignancies is crucial in order to develop individualized risk-benefit analyses to guide care. Herein, we report a cohort study from a Comprehensive Cancer Center evaluating outcomes in pts with hematologic malignancies who developed SARS-CoV-2. Methods: Adult pts at Northwestern Memorial Hospital with a current/prior hematologic malignancy and laboratory-confirmed SARS-CoV-2 infection confirmed by quantitative RT-PCR from nasopharyngeal swabs between March-July, 2020 were identified using electronic health records. Data were collected and analyzed based on epidemiologic, laboratory, and clinical characteristics. Severity of illness was defined by level of care (ambulatory, inpatient), need for advanced respiratory support (high flow nasal cannula, BiPAP, mechanical ventilation), incidence of thrombotic events, incidence of acute kidney injury (AKI), and/or death. Statistical analyses of risk factors, severity, and outcomes were performed. Subgroup analyses based on antineoplastic treatment status and receipt of SARS-CoV-2 -directed therapy were made. Active cancer treatment was defined as antineoplastic therapy within 12 months of SARS-CoV-2 diagnosis. Results: Demographic (Table 1) and clinical (Table 2) data were recorded from 73 SARS-CoV-2 infected pts. Sixty (80%) pts had lymphoid and 15 (20%) had myeloid neoplasms, 2 with concurrent lymphoid and myeloid neoplasms. Thirty-seven (51%) pts were undergoing active treatment for their malignancy. Twenty-one pts (29%) were managed in the ambulatory setting while 52 (71%) required hospital admission. Twenty-five (34%) pts required advanced respiratory support including 14 (19%) who required mechanical ventilation. Four pts (6%) had thrombotic events and 31 (42%) received SARS-CoV-2-directed therapies. Sixteen pts (22%) died during the study period. Pts on active cancer treatment had higher rates of hospital admission (81% v 60%; p=0.05) and AKI (51% v 29%; p=0.04) but similar rates of death compared with pts not on active treatment (24% v 20%; p=0.66) (Table 3). Comparing pts who received SARS-CoV-2 -directed therapy versus no therapy: pts on therapy had longer median lengths of stay (11 v 7 days; p=0.04) and higher rates of hospital admission (94% v 55%; p=0.0003) but similar rates of death (23% v 21%; p=0.91); pts in the ICU on SARS-COV-2 -directed therapy had lower rates of death (38% v 88% p=0.02) than pts who did not receive such therapy (Table 4). Twenty-six pts (36%) were tested for viral clearance, defined as two serial negative swabs ≥24 hours apart. Of these, 17 (65%) achieved clearance with a median time of 51 days (range 15-119 days). Thirteen pts (18%) had antibody (Ab) testing. Ten (77%) had detectable Abs: 8 were positive for IgG, 1 for IgG and IgM, and 1 had unspecified positivity. Notably, all 3 pts with undetectable Abs were on active cancer treatment. Conclusion: We demonstrate that pts with hematologic malignancies are exceptionally vulnerable to severe forms of SARS-CoV-2 with high mortality rates. The incidence of thrombotic events was low, an unexpected finding in the setting of a hyperinflammatory syndrome. Prolonged time to viral clearance was observed, a finding which may cause potential delays in the resumption of cancer-directed therapies. Notably, the majority of pts who received antibody testing had detectable antibodies suggesting that pts with hematologic malignancies may be able to mount an immune response to early vaccination. Accordingly, close monitoring, aggressive therapy, and early vaccination, when available, may be warranted for this population. Larger studies are needed to confirm our findings and help guide management of pts with hematologic malignancies during the SARS-CoV-2 pandemic. Disclosures Altman: Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; Syros: Consultancy; Genentech: Research Funding; Novartis: Consultancy; Amphivena: Research Funding; Amgen: Research Funding; Aprea: Research Funding; ImmunoGen: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; Fujifilm: Research Funding; Kartos: Research Funding; AbbVie: Other: advisory board, Research Funding; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Theradex: Other: Advisory Board; ASH: Consultancy; Cancer Expert Now: Consultancy; France Foundation: Consultancy; PeerView: Consultancy; PrIME Oncology: Consultancy. Winter:Delta Fly Pharma: Consultancy; Amgen: Consultancy; Epizyme: Other: DSMB; CVS/Caremark: Consultancy; Ariad/Takeda: Consultancy; Norvartis: Consultancy, Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Pro:Verastem Oncology: Research Funding. Ma:TG Therapeutics: Research Funding; Juno: Research Funding; Novartis: Research Funding; Kite: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Karmali:BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Takeda: Research Funding; Karyopharm: Honoraria; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau.

Ibrutinib, a known Burton's tyrosine kinase (BTK) and interleukin‐2 inducible T‐cell kinase (ITK) inhibitor, is used for the treatment of B‐cell disorders (chronic lymphocytic leukemia [CLL] and various other lymphomas) and chronic graft versus host disease following allogeneic hematopoietic cell transplantation. Because it is considered an immunosuppressant, continuation of ibrutinib is often debated when patients have an active infection, and this becomes an especially difficult decision in the setting of coronavirus disease 2019 (COVID‐19). Here, we describe a patient with CLL who was on ibrutinib then developed severe COVID‐19 infection requiring mechanical ventilation. We elected to continue ibrutinib the same day he was intubated, reasoning that BTK inhibition in myeloid immune cells has been shown to reduce or even reverse influenza‐mediated acute lung injury and that ITK inhibition in T cells has correlated with reduction in viral replication, and therefore may have an advantage in this setting. Ibrutinib also has been shown to block Src family kinases, which potentially could result in reduction of viral entry and the inflammatory cytokine response in the lungs. The patient was extubated after 9 days with a complex hospital course and eventually discharged on room air. The only way to rationally inform these decisions and explore similar potentially promising leads in this pandemic is to conduct carefully done clinical trials.

Various computing subdisciplines, such as computer science and software engineering, each have their own curricular guidelines. They can be very difficult to understand and compare for people such as prospective students, industry personnel, and even faculty members. This is compounded by a lack of information surrounding undergraduate computing curricular topics via visual methods. This paper describes two experimental activities where the objective is to explore the possibility of obtaining quantitative data sets necessary for visualization, one based on competencies and the other based on knowledge areas. Both activities were based on surveys. The results from the first activity showed that a consensus interpretation could be obtained for the knowledge, skills, and dispositions implied by the competency descriptions, although not as strongly for dispositions. The second activity resulted in a table of knowledge areas with minimum and maximum weights for six computing subdisciplines. Finally, this paper also shows two examples of how users can explore the various curricular guidelines through visualization.

There is a saying, “Everything changes, but nothing changes.” We are realizing a rapid technological revolution in the development, deployment, and application of computing technologies within every discipline and every sector of society. Yet, our ability to respond to the well-documented need for a large, diverse, computationally literate workforce remains a challenge. We summarize our 35 years of lessons learned for preparing the workforce that can inform efforts to address this challenge. We have pursued a multiprong approach to reach instructors, researchers, professionals, and students on a national scale. Our efforts in scaling up and sustaining activities range from teaching computational thinking through imparting HPC skills. We have been able to scale up these activities through community efforts to share, cooperate, and collaborate. The potential for providing life-long learning to everyone wishing to expand their computational knowledge and skills is greater than any organization can achieve on its own.

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.

Patients with a history of malignancy have been shown to be at an increased risk of COVID-19-related morbidity and mortality. Poorer clinical outcomes in that patient population are likely due to the underlying systemic illness, comorbidities, and the cytotoxic and immunosuppressive anti-tumor treatments they are subjected to. We identified 416 cancer patients with SARS-CoV-2 infection being managed for their malignancy at Northwestern Medicine in Chicago, Illinois, between March and July of 2020. Seventy-five (18.0%) patients died due to COVID-related complications. Older age (>60), male gender, and current treatment with immunotherapy were associated with shorter overall survival. Laboratory findings showed that higher platelet counts, ALC, and hemoglobin were protective against critical illness and death from COVID-19. Conversely, elevated inflammatory markers such as ferritin, d-dimer, procalcitonin, CRP, and LDH led to worse clinical outcomes. Our findings suggest that a thorough clinical and laboratory assessment of infected patients with cancer might help identify a more vulnerable population and implement more aggressive proactive strategies.

Classical Hodgkin lymphoma is biologically different than other lymphomas. The cancer cells only occupy a small amount of the lymph node and evade the immune system by amplification of PD-L1 and PD-L2. Therefore, checkpoint inhibitors are a logical treatment option for Hodgkin lymphoma patients to unlock the immune system. Checkpoint inhibitors have shown high response rates in clinical trials in advanced-stage Hodgkin lymphoma. The two most commonly used checkpoint inhibitors are pembrolizumab and nivolumab, both FDA approved as third-line therapy. There is increasing interest in the use of checkpoint inhibitors with combination chemotherapy or with other targeted agents in the second-line or even frontline setting. In this review, we will highlight the clinical trials that led to approvals of checkpoint inhibitors for Hodgkin lymphoma.

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.

Background Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Targeted therapy is available in the form of recombinant human leptin (metreleptin). We previously reported baseline characteristics of one of the first cases of CLD diagnosed in the United States, a patient with a comorbid diagnosis of Hodgkin lymphoma prior to initiation of therapy. Metreleptin has a black box warning for risk of T-cell lymphoma, which has been reported in acquired generalized lipodystrophy patients, both treated and untreated with metreleptin. Clinical Case A 20 yr old female (Pt B) was referred for evaluation of obesity (BMI 45.0 kg/m2) with a history of hyperphagia and excessive weight gain by three months of life. Pt B is of Pakistani origin with a family history of consanguinity. She was treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. At the time of her initial evaluation, serum leptin levels were undetectable. Pt B was homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. On MR elastography performed for hepatic steatosis, she had an incidental finding of axillary lymphadenopathy. Surgical biopsy and staging work-up confirmed diagnosis of nodular lymphocyte predominant Hodgkin lymphoma, Stage II disease. She was treated with 2 cycles of R-ABVD followed by adjuvant radiation (2000 cGy) to the right supraclavicular and axillary region, achieving clinical remission. Pt B was then treated with 3.75-5 mg metreleptin once daily in an observational treatment protocol for 18 months. With therapy, pt B lost 39.1 kg or 33% of initial body weight. Clinically significant improvements in related parameters were observed, including percent body fat (-18%), estimated visceral adipose tissue (-53%), HOMA2 IR (-80%), ALT (-91%), total cholesterol (-10%), triglycerides (-26%), HDL (+6%), LDL (-19%), and high-sensitivity C-reactive protein (-84%). In addition, prediabetes (with abnormal 2 hour OGTT) resolved, hepatic steatosis improved, bone mineral density increased (+0.6 SD), and pt B developed spontaneous regular menses. She tolerated metreleptin well without serious adverse effects and her lymphoma remained in remission throughout the study. Conclusion To our knowledge, this is the first report of lymphoma in a patient with CLD, occurring prior to treatment with metreleptin. Pt B achieved clinical remission prior to initiation of therapy with metreleptin, with no recurrence on 18 months of therapy. She experienced substantial weight loss and marked improvements in body composition, glucose metabolism, insulin sensitivity, lipid metabolism, liver and reproductive health. Untreated CLD has been associated with impaired lymphocyte production and function. The risk for lymphoma associated with metreleptin may relate to preexisting autoimmunity or immunologic abnormalities related to leptin deficiency rather than medication adverse effect. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Cellular phenotypes emerge from a hierarchy of molecular interactions: proteins interact to form complexes, pathways, and phenotypes. We show that hierarchical networks of protein interactions can be extracted from the statistical pattern of proteome variation as measured across thousands of bacteria and that these hierarchies reflect the emergence of complex bacterial phenotypes. We describe the mathematics underlying our statistical approach and validate our results through gene-set enrichment analysis and comparison to existing experimentally-derived hierarchical databases. We demonstrate the biological utility of our unbiased hierarchical models by creating a model of motility in Pseudomonas aeruginosa and using it to discover a previously unappreciated genetic effector of twitch-based motility. Overall, our approach, SCALES (Spectral Correlation Analysis of Layered Evolutionary Signals), predicts hierarchies of protein interaction networks describing emergent biological function using only the statistical pattern of bacterial proteome variation.

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 Detrimental effects of diarrhea on child growth and survival are well documented, but details of the underlying mechanisms remain poorly understood. Recent evidence demonstrates that perturbations to normal development of the gut microbiota in early life may contribute to growth faltering and susceptibility to related childhood diseases. We assessed associations between diarrhea, gut microbiota configuration, and childhood growth in the Peruvian Amazon. Methods Growth, diarrhea incidence, illness, pathogen infection, and antibiotic exposure were assessed monthly in a birth cohort of 271 children aged 0–24 months. Gut bacterial diversity and abundances of specific bacterial taxa were quantified by sequencing 16S rRNA genes in fecal samples collected at 6, 12, 18, and 24 months. Linear and generalized linear models were used to determine whether diarrhea was associated with altered microbiota and, in turn, if features of the microbiota were associated with the subsequent risk of diarrhea. Results Diarrheal frequency, duration, and severity were negatively associated with bacterial diversity and richness (P < .05). Children born stunted (length-for-age z-score [LAZ] ≤ −2) who were also severely stunted (LAZ ≤ −3) at the time of sampling exhibited the greatest degree of diarrhea-associated reductions in bacterial diversity and the slowest recovery of bacterial diversity after episodes of diarrhea. Increased bacterial diversity was predictive of reduced subsequent diarrhea from age 6 to 18 months. Conclusions Persistent, severe growth faltering may reduce the gut microbiota's resistance and resilience to diarrhea, leading to greater losses of diversity and longer recovery times. This phenotype, in turn, denotes an increased risk of future diarrheal disease and growth faltering.

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.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14) chromosomal translocation. This translocation most often results in overexpression of cyclin D1. MCL is clinically heterogeneous, outcomes are generally poor, and no standard treatment has been established. The recent approvals of ibrutinib and acalabrutinib have provided an additional therapeutic option; however, resistance has emerged as a significant issue and presents the need for more detailed studies of resistance mechanisms. Recent clinical trials have provided new perspectives on the relative efficacy and safety of various approaches for both transplant-eligible and transplant-ineligible patients. Multiple novel strategies are being evaluated in the treatment of MCL, including both targeted agents and cellular immunotherapies. At the Lymphoma Research Foundation's 13th MCL Workshop, researchers gathered to discuss research findings, clinical trial results, and future directions related to MCL, its biology, and its treatment. This report, which includes a summary of each presentation, aims to review recent findings in MCL research and highlight potential areas for future study.

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.

Significance Employing an intergenerational model of diet restriction (DR) that reduces weight gain, we identify differences in carbohydrate metabolic enzyme gene content of DR versus full-fed (FF) pig gut microbiomes as animals experienced a phased-feeding program administered to farm-raised pigs during their growth cycle. Gnotobiotic mice harboring DR or FF pig microbiomes and fed a corn/soy-dominated pig diet disclosed that the DR microbiome has reduced capacity to produce butyrate, a key diet-derived energy source, and alters hepatic energy metabolism. Combining studies of farm animal microbiome development with functional assays of their microbiomes in gnotobiotic mice should help generate husbandry recommendations for promoting healthy growth of animals during this time of increasing food insecurity and mandates to eliminate subtherapeutic antibiotics for growth-promotion., The concept that gut microbiome-expressed functions regulate ponderal growth has important implications for infant and child health, as well as animal health. Using an intergenerational pig model of diet restriction (DR) that produces reduced weight gain, we developed a feature-selection algorithm to identify representative characteristics distinguishing DR fecal microbiomes from those of full-fed (FF) pigs as both groups consumed a common sequence of diets during their growth cycle. Gnotobiotic mice were then colonized with DR and FF microbiomes and subjected to controlled feeding with a pig diet. DR microbiomes have reduced representation of genes that degrade dominant components of late growth-phase diets, exhibit reduced production of butyrate, a key host-accessible energy source, and are causally linked to reduced hepatic fatty acid metabolism (β-oxidation) and the selection of alternative energy substrates. The approach described could aid in the development of guidelines for microbiome stewardship in diverse species, including farm animals, in order to support their healthy growth.

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.

7062 Background: Pts with R/R LBCL after first-line (1L) treatment (tx) who are unable to undergo high-dose chemotherapy (HDCT) and HSCT have poor outcomes and limited tx options. PILOT (NCT03483103) evaluated liso-cel, an autologous, CD19-directed chimeric antigen receptor (CAR) T cell product, as 2L tx in pts with R/R LBCL not intended for HSCT. Methods: Eligible pts were adults with R/R LBCL after 1L tx who were not deemed candidates for HDCT and HSCT by their physician and met ≥ 1 frailty criteria: age ≥ 70 yr, ECOG PS = 2, DLCO ≤ 60%, LVEF < 50%, CrCl < 60 mL/min, or ALT/AST > 2 × ULN. Bridging tx was allowed. Pts received lymphodepletion with cyclophosphamide and fludarabine, followed 2–7 days later by liso-cel at a target dose of 100 × 106 CAR+ T cells. Cytokine release syndrome (CRS) was graded per Lee 2014 criteria and neurological events (NE) per NCI CTCAE, version 4.03. Primary endpoint was ORR per independent review committee (IRC); all pts had ≥ 6 mo follow-up (f/u) from first response. Results: Of 74 pts leukapheresed, 61 received liso-cel and 1 received nonconforming product. Common reasons for pre-infusion dropout included death and loss of eligibility (5 each). For liso-cel–treated pts, median age was 74 yr (range, 53–84; 79% ≥ 70 yr) and 69%, 26%, and 5% met 1, 2, and 3 frailty criteria, respectively; 26% had ECOG PS = 2 and 44% had HCT-CI score ≥ 3. After 1L tx, 54% were chemotherapy refractory, 21% relapsed ≤ 12 mo, and 25% relapsed > 12 mo; 51% of pts received bridging chemotherapy. Median (range) on-study f/u was 12.3 mo (1.2–26.5). ORR and CR rate was 80% and 54%, respectively. Median DOR and PFS was 12.1 mo and 9.0 mo, respectively. Median OS has not been reached (Table). Most frequent tx-emergent AEs (TEAE) were neutropenia (51%), fatigue (39%), and CRS (38%), with grade (gr) 3 CRS in 1 pt (2%) and no gr 4/5 CRS. Any-grade NEs were seen in 31%, gr 3 in 5% (n = 3), and no gr 4/5 NEs; 7% received tocilizumab, 3% corticosteroids, and 20% both for tx of CRS/NEs. Overall, gr ≥ 3 TEAEs occurred in 79%, with gr 5 in 2 pts (both due to COVID-19). Two pts (3%) had gr 3/4 infections and 15 (25%) had gr ≥3 neutropenia at Day 29. Conclusions: In the PILOT study, liso-cel as 2L tx in pts with LBCL who met ≥ 1 frailty criteria and for whom HSCT was not intended demonstrated substantial and durable overall and complete responses, with no new safety concerns. Clinical trial information: NCT03483103. [Table: see text]