The study included patients diagnosed with pediatric Hodgkin lymphoma at a tertiary referral center in Iran from 2014 through 2024. Eligible participants had baseline positron emission tomography/computed tomography staging and complete outcome data; three additional patients without baseline staging were excluded. The analysis covered demographic, clinical, histopathological, laboratory, treatment and outcome information extracted from medical records. Treatment failure was defined as relapse following complete remission or primary refractory disease. Associations with failure were examined using univariate analyses, rather than a multivariable predictive model.

The cohort included 54 males, or 65.1%, and 29 females, or 34.9%), and the mean age at diagnosis was 10.72 ± 3.86 years. Stage III disease was the predominant presentation, accounting for 66.3% of patients. Younger age at diagnosis was associated with relapse: relapsing patients had a mean age of 8.29 ± 3.73 years, compared with 11.22 ± 3.72 years among those who did not relapse (p = 0.015). Elevated erythrocyte sedimentation rate, defined as ESR above 50 mm/hr, was also associated with relapse, occurring in 42.9% of relapsing patients and 11.6% of patients without relapse (p = 0.010).

Fever and night sweats at diagnosis were associated with primary refractory disease. Fever was present in 45.5% of patients with refractory disease, compared with 8.3% of those without it (p = 0.005), while night sweats were present in 36.4% and 8.3%, respectively (p = 0.024). Histological subtype, whether classical Hodgkin lymphoma or nodular lymphocyte-predominant Hodgkin lymphoma, disease stage and the first-line chemotherapy regimen were not significantly associated with treatment failure. Among patients who experienced failure, ESHAP was the most frequently used salvage regimen, while 14 patients, or 16.9% of the full cohort, received brentuximab vedotin or nivolumab.

The findings are limited by the retrospective design, small single-center population, exclusion of three patients without baseline PET/CT staging and use of univariate associations. The results therefore identify features associated with relapse or refractory disease in this cohort but do not establish independent predictors or demonstrate that the reported factors caused treatment failure. The authors called for larger prospective studies to assess whether these associations can support risk stratification and inform treatment strategies.

Subject of Research: Factors associated with relapse and primary refractory disease in a retrospective cohort of 83 children with Hodgkin lymphoma in Iran

Article Title: Treatment failure and associated factors in pediatric Hodgkin lymphoma: a decade of institutional experience from a middle-income country

Article References: Farokhmanesh, S., Ghanbari, P., Karimzadeh, A., Zekavat, O. R., Bordbar, M., Shahriari, M., Zareifar, S., & Mottaghipisheh, H. (2026). Treatment failure and associated factors in pediatric Hodgkin lymphoma: a decade of institutional experience from a middle-income country. BMC Cancer. https://doi.org/10.1186/s12885-026-17031-w

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17031-w

Keywords: pediatric Hodgkin lymphoma, treatment failure, relapse, primary refractory disease, retrospective cohort, Iran, prognostic factors, PET/CT staging, salvage therapy, Treatment, failure, associated

The technological core of this shift lies in the ability to measure behavior and neural activity with unprecedented temporal, chemical, and spatial resolution. Genetically encoded biosensors can now report the release of neuropeptides such as opioids in living tissue, a capability highlighted in a 2024 Nature Neuroscience study that the editorial cites as emblematic of the new toolkit. Fiber photometry systems, paired with open-source analysis software such as the Python library Pyfiber, allow researchers to integrate operant behavior with real-time fluorescence signals, linking moment-to-moment neural dynamics to the choices animals make. Optogenetic approaches have matured to the point where researchers can mimic aspects of drug action in defined circuits, dissecting the dopamine-dependent core of addiction with cell-type specificity. Automated behavioral tracking and computational analyses complete the picture, replacing coarse endpoints such as total drug consumed with rich, continuous streams of data that capture how brain activity and behavior shape one another over time.

That temporal dimension matters because, as the editors emphasize, addiction is not a static state. It is a dynamic sequence of processes, including drug use, seeking, withdrawal, craving, and relapse, each shaped by internal states and external cues and expressed in environments full of competing rewards. Conventional experimental designs, which typically sample behavior at isolated time points, can miss exactly the transitions that matter most clinically: the moment a cue triggers craving, the slow emergence of social withdrawal during abstinence, or the drift from controlled use to compulsive consumption. Continuous monitoring and increasingly sophisticated behavioral models offer a way to capture those processes. Within the Research Topic, Mathis and colleagues introduce a novel, automated, and unbiased approach to characterizing the emergence of social deficits during morphine abstinence in mice. By providing long-term longitudinal and quantitative assessment of social behavior, the work reveals dimensions of withdrawal that conventional assays simply do not register, illustrating how better phenotyping can expose previously invisible features of the addicted state.

Human studies in the collection follow the same logic of dynamic, quantified measurement. Yilmazer and colleagues investigate whether new neurophysiological biomarkers can track gambling disorder, focusing specifically on theta cordance, an electroencephalographic measure. Their approach exemplifies how analytical methods such as Granger Causality, which tests whether activity in one brain region predictively influences activity in another, can be leveraged to move diagnosis beyond self-report and toward objective, physiology-based indicators. The editors suggest that such biomarkers could eventually improve diagnosis and guide the implementation of treatment, a prospect that resonates far beyond gambling. If neural signatures can index the severity and trajectory of a behavioral addiction, the same logic may apply across the spectrum of substance use disorders, where clinicians currently lack reliable tools for predicting who will relapse and when.

Yet the editors are careful to temper enthusiasm with a caution: methodological innovation and basic discovery alone will not revolutionize clinical practice. More detailed behavioral phenotyping does not automatically yield mechanistic understanding, and identifying patterns of neural circuit activity that correlate with addictive states does not reveal the core cognitive disruptions that seed maladaptive behavior. The central challenge, they argue, is determining which measurements meaningfully explain the emergence and persistence of maladaptive behaviors, and translating that understanding into new diagnostic and prognostic tools. Correlation is not explanation, and a flood of high-resolution data is only as valuable as the questions it is used to answer. This framing sets the intellectual agenda for the rest of the collection, which repeatedly asks not just what the brain is doing during addiction, but which of those measurements actually matter.

Several contributions point toward a redefinition of addiction itself, shifting from substance-centered categories to shared mechanisms. Insalaco and colleagues examined longitudinal changes in physiological and mental-health functioning among individuals receiving treatment for substance use disorders, underscoring the importance of tracking addiction-related outcomes over time. Their findings offer insight into the dynamics of substance use disorder as a clinical condition and could be used to tailor therapeutic interventions at different points in its trajectory, rather than applying the same strategy regardless of stage. Allache and colleagues go further, proposing craving as a potential transdiagnostic marker for both substance and behavioral addictions. The implication is provocative: instead of defining addiction by the substance or behavior involved, clinicians and researchers might orient diagnosis around core mechanisms shared across different forms of pathological behavior, unifying disorders that the current diagnostic framework keeps separate.

The reach of addiction biology may extend even beyond the brain. Tyrode and colleagues suggest that gut microbiota signatures could be predictive of both cocaine use and binge eating disorder, a viewpoint that pushes addiction research into peripheral biological systems and reinforces the idea that seemingly distinct disorders may share biological fingerprints. The gut-brain axis has become one of the most active frontiers in neuroscience, and its appearance in addiction research signals how far the field has traveled from a purely dopaminergic account of reward. Alongside this, a review by O’Connor revisits the controversial concept of food addiction in the context of GLP-1-based obesity pharmacotherapy, the class of drugs that has transformed treatment of metabolic disease. By examining the overlap between neural pathways regulating feeding and those implicated in substance use, the review illustrates both the value and the limitations of identifying shared reward mechanisms across disorders. Crucially, it also demonstrates how societal motives must be considered in the evolution of the addiction concept, a reminder that scientific categories are shaped as much by culture as by data.

What emerges from the collection as a whole is a convergence, despite contributions spanning animal and human research, experimental and clinical investigations, and multiple subtypes of addiction-like behavior, on a single message: understanding addiction requires studying the dynamic interactions between biological mechanisms, behavior, and context. The editors highlight three complementary shifts now reshaping the field, moving from static measures to dynamic trajectories, from isolated brain circuits to interacting biological systems, and from substance-centered definitions to mechanistically informed models of maladaptive behavior. They also stress nuance: food and drugs engage overlapping motivational systems, but feeding is embedded within metabolic regulation and physiological homeostasis, so problematic eating necessarily manifests with both overlapping and unique underpinnings relative to psychoactive drugs. Not every reward-based behavior leads to addiction, and true progress will require acknowledging the complex interplay of environmental, cognitive, neurochemical, and genetic predispositions that seed addiction in certain individuals rather than in others.

The editorial closes with a formulation that may define the next decade of the field. The future of addiction research, the authors write, will not be defined solely by the ability to measure more molecules, record more neurons, or quantify more behavioral dimensions; progress will depend on using those technologies to ask better questions and to improve analysis and interpretation. Rethinking addiction, they suggest, does not necessarily mean expanding its definition. It may instead mean refining it: identifying when, why, and for whom a behavior becomes persistent, maladaptive, and difficult to control. That conceptual refinement, supported by increasingly sophisticated technologies and integrative approaches spanning brain, body, and environment, may ultimately provide a stronger foundation for more precise diagnosis, prevention, and treatment, turning a period of methodological exuberance into a period of genuine clinical advance.

Subject of Research: Technological and conceptual advances in addiction neuroscience and the re-evaluation of substance use disorders

Article Title: Editorial: Rethinking addiction: technological advances, mechanistic insights, and the re-evaluation of substance use disorders

Article References: Darcq, E., Howe, W. M., Nicolas, C., & Mathis, V. P. (2026). Editorial: Rethinking addiction: technological advances, mechanistic insights, and the re-evaluation of substance use disorders. Frontiers in Behavioral Neuroscience, 20, Article 2009605. https://doi.org/10.3389/fnbeh.2026.2009605

Image Credits: AI Generated

DOI: 10.3389/fnbeh.2026.2009605

Keywords: addiction, substance use disorders, behavioral neuroscience, biosensors, craving, gambling disorder, gut microbiota, food addiction, GLP-1, neural circuits, biomarkers, relapse

The paper, written by Daniel Kretchman of Infinity Behavioral Health in North Las Vegas, begins with a striking acknowledgment of how little formal research underpins this ubiquitous tool. A Google search for the terms HALT and recovery conducted in May 2025 returned more than 30 million results in a quarter of a second, yet searches across academic databases including EBSCOhost, APA PsycNet, and ProQuest failed to identify who first coined the acronym or when. The concepts embedded in HALT — the recognition that physical and emotional states shape relapse risk — have circulated in recovery discussions since the early days of Alcoholics Anonymous, appearing in workshops and recovery literature from the 1980s and 1990s onward. A retired recovery counselor quoted in the paper classified HALT simply as AA folk wisdom. Notably, foundational texts like the Big Book and Twelve Steps and Twelve Traditions never explicitly cite the acronym, even though the underlying principles appear in classic relapse prevention scholarship such as Marlatt and Gordon’s 1985 work, which detailed the same components without ever naming them.

The clinical logic of the original HALT is straightforward. When a craving strikes, a person in recovery can run through the checklist and identify a factor within their control. Hunger may reflect low blood sugar or dehydration; anger may be a secondary emotion masking hurt or fear; loneliness may signal an unmet need for connection; tiredness may indicate inadequate rest or poor sleep. Addressing the identified state — eating, reaching out, relaxing — can defuse the urge before it escalates into use. The author frames this as short-term relapse prevention, but also points toward tertiary prevention: the same states, managed habitually, reduce vulnerability over time. This dual application aligns closely with Dialectical Behavior Therapy’s emotion regulation skills, and the connection is supported by a 2023 systematic review and meta-analysis in Addiction that documented emotion regulation difficulties in people with substance use disorders, along with evidence that DBT skills training benefits recovery from alcohol use disorder.

What makes the new paper theoretically interesting is its rationale for expansion, which draws on Vygotskian psychology. Vygotsky’s perspective, dating to before 1934, holds that a full understanding of mental processes requires attention to the sociocultural context in which they occur. In recovery, this insight is already embedded in practice: 12-step programs and SMART Recovery meetings are group-based precisely because social supports and influences are integral to maintenance from compulsive behaviors. The empirical case is compelling. In one study cited by Kretchman, rats that learned to self-administer alcohol in a specific environment stopped seeking it when sensory characteristics of the setting changed — olfactory, visual, and tactile cues — but resumed alcohol-seeking behavior immediately upon return to the original setting. In a human cohort study, living situation and socioeconomic status emerged as risk factors for relapse after a first alcohol-related hospitalization. As Donovan and Chaney wrote in 1985, considering person and situational variables simultaneously explains more variance in human behavior than either does independently.

From this foundation, Kretchman proposes four new contextual domains, each chosen for being easily applied and easily recalled. The first is Free — as in free availability. Marketing research has long shown that free samples are an effective technique for changing behavior, which is exactly why industries from supermarkets to pharmaceutical companies deploy them. Old behavioral habits and neural circuitry, combined with free opportunities such as drinks at a party or reward money for gambling, can present a direct pathway back to past compulsive habits. Prevention strategies range from basic risk identification to sophisticated skills: recognizing the hazard of free offers, identifying individuals who may place a person at risk, learning to decline through role play, and rehearsing alternative behaviors.

The second domain is environment and culture, and it carries one of the paper’s most counterintuitive findings. Markose and colleagues reported that 88 percent of their study participants relapsed due to pleasurable events — joyful celebrations, not misfortune. The concept generalizes to physical environments, such as a work gathering with alcohol, and to social-cultural events like holidays, celebrations, and funerals. Social occasions carry connections associated with past compulsive behaviors, offer rule-bending opportunities, and can involve encounters with people who create stress or expectations that increase vulnerability. The recovery community has absorbed this risk informally; commercial and nonprofit recovery websites routinely publish articles specifically addressing relapse around the holiday season.

The third domain is sick or physical health, including pain. Poor health presents a dual challenge for abstinence: prescribed or unprescribed substances can offer relief but also present re-exposure that can restart old behavioral habits and trigger the same neural circuitry. Illness may further contribute to poor self-perception, limited access to resources, and isolation. The significance of physical health as a protective measure is visible in DBT’s PLEASE skill, which emphasizes attending to physical wellbeing. Preventative measures include developing strategies to maintain health and identifying resources for times of illness before they are needed.

The fourth domain is transitions and stressors, and the paper draws a technically useful distinction between the two. Transitions are changes across life domains — health, ability, relationships, employment, relocation, legal issues, living situation, or loss — and are more objective, which may make them easier for individuals to recognize and address. Stressors may be short-term, like an upcoming exam, or long-term, like the end of a relationship. Critically, research by Tate and colleagues found that severe long-term stressors increased the risk of relapse after treatment, while short-term stressors did not. Positive changes can be just as difficult as negative ones; the euphoria from a work promotion is cited alongside more obvious challenges. The updated Social Readjustment Rating Scale, modernized in 2023, provides quantification of life events and may allow identification of unrecognized challenges. Prevention skills include reframing situations, preparing for known transitions, and learning to separate emotions from facts.

The paper is candid about the limitations of its evidence base. Despite widespread community use, there is scant research of HALT itself in the scientific literature, though individual components — nutrition, fatigue, emotional regulation, relationships — have been studied and are consistent with established treatment approaches such as DBT and Lazarus’s Multimodal Therapy. The author suggests that evaluating the entire expanded skill set, or exploring its effectiveness as part of a comprehensive program similar to how DBT is assessed, may be more practical than assessing each component in isolation. Future research avenues include measuring the impact of the expanded framework on both short-term relapse prevention and long-term resilience building, and applying it to other mental health conditions beyond substance and behavioral compulsions — the author and others, including Siegel and Payne Bryson in their work on parenting, have recognized applications for reducing vulnerability to depression and anxiety and improving parenting skills.

The proposed result is a new acronym: HALT FEST, standing for Hungry, Angry, Lonely, Tired, Free, Environment/culture, Sick/health, and Transitions/stressors. The author’s reasoning for building on the existing tool rather than inventing a new one is itself a lesson in clinical design. As Melemis noted in commenting on Gorski’s breakdown of relapse into eleven phases, that level of detail is helpful to clinicians but can sometimes be overwhelming to clients. Tools that must be accessible under duress need brevity. HALT FEST preserves the simplicity that makes the original acronym easy to apply in real time while adding the contextual domains that research shows matter enormously. The author also emphasizes that in real life the components rarely appear in isolation — free alcohol at a celebration is the interaction of two risk factors at once — so the framework is meant to be taught as an integrated whole, whether in groups or individual treatment. Whether HALT FEST survives empirical testing remains to be seen, but the paper makes a persuasive case that the most viral tool in recovery history was always pointing at something bigger than four states of being: the entire context of a person’s life.

Subject of Research: HALT: Relapse prevention to resilience

Article Title: HALT: Relapse prevention to resilience

Article References: Kretchman, D. (2026). HALT: Relapse prevention to resilience. Advances in Drug and Alcohol Research, 5, Article 15477. https://doi.org/10.3389/adar.2025.15477

Image Credits: AI Generated

DOI: 10.3389/adar.2025.15477

Keywords: HALT, Relapse, prevention, resilience, scientific research, peer-reviewed research

The therapy works by harvesting a patient’s own T cells and engineering them to express a synthetic receptor that recognizes CD19, a surface protein found on B cells. Nearly all approved CD19 CAR-T products use a binding domain derived from the FMC63 antibody, which recognizes an epitope encoded by exons 3 and 4 of the CD19 gene. When cancer cells lose or alter the CD19 antigen, the engineered T cells have nothing to latch onto, and the malignancy escapes immune destruction. Previous work has shown that a splice variant called CD19Δexon2, in which exon 2 is skipped during RNA processing, is linked to therapy resistance and relapse. What has been missing is a reliable way to identify, before treatment ever begins, which patients carry this risk.

The research team, led by Søren Helweg Dam, Giorgia Moranzoni and Lars Rønn Olsen of the University of Copenhagen, together with colleagues at the Technical University of Denmark, Rigshospitalet and Odense University Hospital, took a computational approach. They mined publicly available RNA-sequencing data from four B-ALL patients treated with CD19 CAR-T therapy—one complete responder, one non-responder, and two who relapsed after an initial response. For each patient, they quantified the percent spliced in (PSI) of CD19 exon 2, a metric that estimates how much of the CD19 messenger RNA retains exon 2 versus skipping it. A lower PSI means a higher abundance of the CD19Δexon2 variant.

The pattern was striking. The patient who relapsed earliest—just 1.5 months after infusion—had the lowest pre-treatment exon 2 PSI, with 21 RNA reads spanning the exon 1–3 junction, a direct signature of exon 2 skipping. The non-responder showed 13 such reads, the slow relapser only one, and the complete responder none at all. After treatment, CD19 read coverage dropped sharply in all patients who initially responded, consistent with effective B-cell depletion, while the non-responder retained substantial CD19 expression and continued exon 1–3 junction usage. Although the cohort is far too small for statistical inference, the qualitative concordance between exon 2 inclusion and clinical outcome suggests that reduced exon 2 retention may be associated with CAR-T therapy failure.

To understand why skipping exon 2 might undermine the therapy, the researchers turned to structural modeling. They retrieved the experimentally resolved structure of canonical CD19 from the AlphaFold Database and predicted the structure of the Δexon2 variant de novo using AlphaFold3. In the canonical protein, the two discontinuous segments of the FMC63 epitope fold into close spatial proximity, forming a contiguous binding surface. Exon 2 skipping disrupts this arrangement, separating the epitope elements and likely impairing antibody accessibility. The finding provides a plausible mechanistic explanation for the experimentally observed reduction in FMC63 binding affinity to the variant protein, positioning exon 2 as a stabilizing element of the functional epitope.

Experimental studies add weight to this model. CD19 isoforms lacking exon 2 exhibit defective folding, abnormal glycosylation, and impaired interaction with the CD81 chaperone complex, causing the misfolded protein to be retained in the endoplasmic reticulum rather than trafficked to the cell surface. Only a small fraction of the variant escapes quality control and reaches the membrane, and that population appears unstable and poorly recognized by CD19-directed antibodies. Reduced CAR recognition of CD19Δexon2 therefore arises from both impaired trafficking and altered surface conformation, leading to markedly diminished antigen density.

Perhaps the most provocative finding is that exon 2 skipping is not exclusively a therapy-induced phenomenon. The team analyzed larger RNA-sequencing datasets from treatment-naïve B-ALL (75 samples from the iCOPE/STAGING study), newly diagnosed DLBCL (553 samples from the GOYA trial), and healthy tissues from the GTEx project (1,048 blood and 255 spleen samples). Exon 2 inclusion was uniformly high in B-ALL and healthy tissues, with median PSI values of 96.3 percent, 96.9 percent and 97.7 percent respectively, and roughly 96 to 97 percent of samples in these groups showed near-complete exon retention. DLBCL, by contrast, displayed marked heterogeneity: the median PSI was 91.6 percent, only 59.5 percent of samples met the 90 percent inclusion threshold, and 86.8 percent showed measurable skipping, including one patient with a PSI as low as 22.8 percent.

These results suggest that CD19Δexon2 is a naturally occurring, low-frequency splice variant present in both malignant and normal B cells, rather than a strictly disease-specific or therapy-induced transcript. Under the selective pressure of CD19-directed CAR-T therapy, malignant cells already expressing the variant may gain a survival advantage and expand, producing the apparent enrichment of the isoform in relapsed disease. This reframes the biology: the variant is not created by the treatment but unmasked by it, which is precisely what makes pre-treatment detection potentially valuable.

The translational implications are considerable. Because bulk RNA sequencing of leukemic cells is increasingly performed as part of the diagnostic workup for B-ALL, exon 2 PSI could be computed as an additional feature at no extra experimental cost. Alternatively, quantitative PCR assays targeting the exon 1–3 junction could provide a rapid and inexpensive test to stratify relapse risk or monitor splicing changes during follow-up. The epitope connection may extend even further: the parental antibody of blinatumomab, a bispecific T-cell engager now moving into front-line B-ALL therapy, competes with FMC63 for CD19 binding, suggesting that structural disruption caused by exon 2 skipping could also compromise blinatumomab-mediated cytotoxicity—though this remains to be formally tested.

The authors are careful to emphasize the limitations. The CAR-T cohort contains only four patients, precluding statistical analysis and any claim of causality or predictive value. Post-treatment samples had sparse read coverage, bulk RNA-seq cannot resolve whether the variant is co-expressed with canonical CD19 in the same cells or confined to distinct subclones, and pre-treatment tumor burden may confound PSI measurements, since normal B cells express predominantly canonical CD19. Protein-level consequences remain to be verified experimentally, and the structural analyses rely on computational modeling. Still, the consistency between structural predictions, patient-level RNA patterns and baseline tissue distributions strengthens the biological plausibility of the findings, and larger prospective studies using targeted long-read sequencing or isoform-specific qPCR could determine whether CD19 exon 2 skipping is merely a correlate of poor response or a functional determinant of resistance. Either outcome would sharpen the understanding of CD19 biology and help clinicians decide which patients might benefit most from multi-target CAR strategies directed against CD19 together with CD20 or CD22.

Subject of Research: CD19 exon 2 alternative splicing as a potential prognostic biomarker for relapse after anti-CD19 CAR-T cell therapy in B-cell malignancies

Article Title: CD19 exon 2 skipping is a potential prognostic correlate of anti-CD19 CAR-T therapy relapse

Article References: Dam, S. H., Moranzoni, G., Høie, M. H., Modvig, S., Wadt, K. A. W., Als-Nielsen, B., Schmiegelow, K., Vitting-Seerup, K., Barnkob, M. B., & Olsen, L. R. (2026). CD19 exon 2 skipping is a potential prognostic correlate of anti-CD19 CAR-T therapy relapse. Frontiers in Molecular Medicine, 6, Article 1763390. https://doi.org/10.3389/fmmed.2026.1763390

Image Credits: AI Generated

DOI: 10.3389/fmmed.2026.1763390

Keywords: CAR-T therapy, CD19, alternative splicing, exon 2 skipping, B-cell acute lymphoblastic leukemia, DLBCL, relapse, biomarker, antigen escape, FMC63 epitope, RNA sequencing, immunotherapy resistance

Hairy cell leukemia is a rare hematological malignancy that affects the blood, bone marrow, spleen, and other organs. First described in the late 1950s, the disease is characterized by the overgrowth of abnormal white blood cells, which crowds out the production of normal blood cells and leaves patients vulnerable to infection, anemia, and bleeding complications. The cancer takes its name from a striking microscopic feature: the malignant cells carry short, thin, hair-like projections on their surface, giving them an unmistakable appearance under the microscope. Approximately 1,200 Americans receive a diagnosis each year, and for reasons that remain unknown, men are affected four times more often than women.

One of the most important conceptual advances in recent years has been the recognition that hairy cell leukemia is not a single disease but two distinct entities: classic hairy cell leukemia and hairy cell leukemia variant. Classic disease is by far the more common form, accounting for up to 90 percent of cases. Thanks to current treatments, most patients with classic hairy cell leukemia remain in remission for five to 15 years or more, a remarkable achievement for a blood cancer that once carried a grim prognosis. Variant disease, by contrast, is far more aggressive. Roughly 10 to 15 percent of patients have the variant form, which tends to respond less well to therapy, relapses more quickly, and carries a poor survival rate. Patients with classic disease who relapse also face a much worse outlook. Closing this gap between the success achieved in classic disease and the unmet needs of variant and relapsed patients is the central focus of the latest round of grants.

The six new awards zero in on a range of aspects of the disease, supporting patients from initial diagnosis and throughout their treatment. At The Ohio State University, Christopher Oakes, Ph.D., is working to advance understanding and classification of hairy cell leukemia in individual patients. Precise classification is the essential first step in ensuring that each patient receives the right treatment, particularly in a rare cancer where expertise is concentrated at a limited number of centers. At Dana-Farber Cancer Institute in Boston, Gregory Abel, M.D., M.P.H., is examining quality of life, decision-making, and outcomes for patients, acknowledging that survival is only one measure of success in a chronic disease that can require repeated courses of therapy.

At Stanford University in California, Gerlinde Wernig, M.D., is focused on finding new methods to improve disease prognosis, including understanding the factors that lead to relapse and to the development of variant disease. Her work addresses one of the deepest questions in the field: why some patients respond beautifully to treatment while others progress to more aggressive forms. At Case Western Reserve University in Cleveland, Reshmi Parameswaran, Ph.D., is examining how hairy cell leukemia becomes resistant to treatment and developing new therapeutic strategies for the variant form. Drug resistance is a central mechanism behind relapse, and unraveling it at the molecular level could open the door to treatments that overcome or prevent it.

Two of the grants support clinical trials testing combination therapies in Europe. Enrico Tiacci, M.D., at the University of Perugia in Italy, will be testing an all-oral combination treatment for patients whose hairy cell leukemia has relapsed. Tiacci’s involvement in this partnership is not new: his groundbreaking earlier work, also supported by research funds from this collaboration, established the drug vemurafenib as an alternative to the chemotherapy-based standard of care. Vemurafenib targets the BRAF mutation that drives the vast majority of classic hairy cell leukemia cases, and its success transformed the treatment landscape for relapsed patients who had exhausted conventional options.

Across the Atlantic, Francesco Forconi, M.D., Ph.D., at the University of Southampton in the United Kingdom, is testing whether a combination of two drugs that inhibit different proteins involved in hairy cell leukemia can produce deep, long-lasting remissions. The ambition behind his trial is a fixed-duration treatment paradigm: patients would stop therapy after a defined period and remain in remission, rather than having to take treatment indefinitely. For a rare cancer where patients may live for decades with their disease, the difference between lifelong therapy and a finite course with durable remission is profound, both medically and in terms of quality of life.

The scale and coordination of the HCL2030 program reflect a deliberate strategy for a rare disease. Because hairy cell leukemia affects relatively few patients, no single institution sees enough cases to drive major advances alone. Lore Gruenbaum, Ph.D., chief scientific officer at Blood Cancer United, emphasized this point, noting that medical research is not a solo sport. Even though researchers are working at different locations across two continents, she said, they are all very much on the same team, and that cooperation is particularly important for rare diseases such as hairy cell leukemia. It takes cooperation, time, and money, she added, to find the advances that will make a real difference for patients.

Anna Lambertson, executive director of the Hairy Cell Leukemia Foundation, framed the grants as the direct result of patient and family commitment to the cause. For patients with classic hairy cell leukemia, she noted, the field has achieved years and often decades of remission. Patients with variant disease, and those who relapse, deserve treatments that work just as well, she said, describing the grants as the way to close that gap. The Hairy Cell Leukemia Foundation, founded in 1984, is the only United States nonprofit solely focused on the disease. Founded and governed by patients, it funds innovative research, advances education, and provides peer support worldwide, and its patient-led mission has helped drive major treatment advances over four decades.

Blood Cancer United, the largest global nonprofit focused on blood cancer patient support, research, and advocacy, has served people affected by more than 100 types of blood cancer since its founding in 1949. The organization funds innovative research, offers free resources and personalized support, and advocates for more accessible and affordable healthcare for all patients. Together, the two organizations have turned the HCL2030 program into a coordinated engine for progress in a cancer that receives little attention relative to its impact on those it affects. With nearly $7 million in new investment now flowing to laboratories and clinics in the United States and Europe, the next five years promise advances in classification, prognosis, drug resistance, and treatment duration that could reshape the outlook for every hairy cell leukemia patient, particularly those with variant disease or relapse who have waited longest for options equal to those enjoyed by the majority.

Subject of Research: New research funding for hairy cell leukemia diagnosis, prognosis, and therapy development

Article Title: Nearly $7 million in new funding accelerates hairy cell leukemia research

Article References: Nearly $7 million in new funding accelerates hairy cell leukemia research. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: hairy cell leukemia, Blood Cancer United, Hairy Cell Leukemia Foundation, HCL2030, blood cancer research grants, variant hairy cell leukemia, vemurafenib, drug resistance, relapse, rare disease funding, combination therapy, all-oral treatment

The study enrolled fourteen patients with B-cell acute lymphoblastic leukemia that had relapsed after allogeneic stem-cell transplantation. Eight of the fourteen carried extramedullary disease, the most difficult manifestation to treat. Rather than harvesting each patient’s own T cells for engineering—a standard approach in autologous CAR-T therapy—the team used allogeneic CAR-T cells, meaning the engineered immune cells were derived from donor sources. This distinction matters enormously in the post-transplant setting. Patients who have already undergone a stem-cell transplant often have depleted, dysfunctional T cells after years of chemotherapy, immunosuppression, and marrow failure, making it difficult or impossible to manufacture a potent autologous product. Allogeneic products sidestep that problem, but they introduce their own hazards: the infused donor cells can attack the recipient’s healthy tissues, and the recipient’s immune system can reject the therapeutic cells before they do their work.

The results, with a median follow-up of 13.8 months and individual follow-ups extending to nearly four and a half years, were striking. Thirteen of the fourteen patients—92.9 percent—achieved a complete remission, and the median duration of remission reached 12.7 months, with the longest remission lasting more than fifty months. Among the eight patients with extramedullary disease, seven achieved complete remission, a rate of 87.5 percent, with a median duration of remission of 14.7 months. Remarkably, the patients with disease outside the marrow did not fare worse than the cohort as a whole; their remissions were, if anything, slightly more durable on average. Neither median overall survival nor median event-free survival had been reached in either the overall cohort or the extramedullary subgroup at the time of analysis, meaning that more than half of the patients in both groups were still alive and free of events when the data were cut.

The technical logic behind targeting CD19 is central to understanding why this approach works. CD19 is a surface protein expressed on virtually all B-lineage cells, including the malignant lymphoblasts of B-ALL, but it is absent from nearly all other tissues, making it an attractive bullseye. CAR-T cells are engineered with a chimeric antigen receptor—a synthetic molecule combining an antibody-derived single-chain variable fragment that recognizes CD19 with intracellular signaling domains that activate the T cell upon binding. When the engineered cells encounter CD19 on a leukemia cell, they are triggered to kill it and to proliferate, amplifying the attack. In this study, the researchers tracked the kinetics of the infused cells in patients’ blood, finding that the CAR-T cells persisted in vivo for a median of 5.9 months, with persistence ranging from 1.2 to 51.6 months. That sustained presence is thought to underpin the durability of the remissions, as the cells continue to patrol for any leukemia cells that escape initial clearance.

Extramedullary disease has historically been a weak point for CAR-T therapy of any kind. Solid tumor deposits outside the marrow and blood present a different microenvironment, one that may suppress T-cell infiltration and function, and leukemia cells sequestered in such sanctuaries can evade surveillance. The finding that seven of eight patients with extramedullary disease achieved complete remission challenges the assumption that this population should be excluded from CAR-T strategies or expected to respond poorly. The authors suggest that allogeneic CAR-T therapy could serve as an effective backbone onto which tailored combination strategies can be built—for example, pairing the cellular therapy with targeted drugs in patients whose leukemia carries specific driver mutations.

That combination concept is not hypothetical in this cohort. Four of the eight patients with extramedullary disease had Philadelphia chromosome-positive leukemia, an aggressive subtype defined by the BCR-ABL fusion gene, and they received maintenance therapy with tyrosine kinase inhibitors after their CAR-T infusions. One patient received dasatinib, two received ponatinib, and one received olverembatinib, a newer third-generation inhibitor developed in China specifically for resistant Philadelphia-positive leukemias. The rationale is straightforward: CAR-T cells clear CD19-expressing leukemia cells rapidly, while tyrosine kinase inhibitors suppress the oncogenic signaling that drove the leukemia in the first place, attacking the disease through a complementary mechanism and potentially preventing outgrowth of CD19-negative escape variants. Whether this sequencing improves long-term outcomes will require larger controlled studies, but the durable remissions observed in these patients provide a proof of concept.

Safety is where allogeneic CAR-T therapy has historically stumbled, and the toxicities observed here deserve close attention. One patient experienced grade 3 cytokine release syndrome, the systemic inflammatory storm caused by massive immune activation, and grade 4 immune effector cell-associated neurotoxicity syndrome, a potentially life-threatening neurological complication of CAR-T therapy. Both grades represent the severe end of the toxicity spectrum, though such events are generally manageable with intensive supportive care, the interleukin-6 blocker tocilizumab, and corticosteroids. In addition, one patient developed acute graft-versus-host disease affecting the gastrointestinal tract, followed by chronic graft-versus-host disease involving the skin and lungs—a reminder that donor-derived immune cells can turn against host tissues, the very risk that makes allogeneic products controversial. The authors characterize the overall safety profile as manageable, and notably, graft-versus-host disease occurred in only one of fourteen patients, suggesting that the product design or the post-transplant immune context may mitigate this risk compared with earlier allogeneic platforms.

The engineering details of allogeneic CAR-T products are critical to those safety outcomes. Because donor T cells carry their own T-cell receptors, they can recognize recipient tissues as foreign and initiate graft-versus-host disease. Strategies to prevent this include knocking out or disrupting the endogenous T-cell receptor, using short hairpin RNA or gene-editing techniques to silence the molecules responsible, and selecting donor sources that minimize alloreactivity. The study’s product, manufactured by Shanghai Unicar-Therapy Bio-Medicine Technology, was used under a clinical trial registered with the Chinese Clinical Trial Registry in August 2020. Two of the study’s authors are employees of the manufacturing company; the remaining authors declared no conflicts of interest, and the work was funded by the National Natural Science Foundation of China and other national and provincial research programs. The study was approved by the institutional review board of The Third Xiangya Hospital, and all patients provided written informed consent.

The broader significance of the work lies in its positioning within the CAR-T treatment landscape. Autologous anti-CD19 CAR-T therapy has transformed the management of relapsed and refractory B-cell malignancies, but its application after allogeneic transplant has been constrained by manufacturing failures, poor T-cell quality, and concerns about exacerbating graft-versus-host disease. Demonstrating that a donor-derived product can achieve a 92.9 percent complete remission rate with controllable toxicity in precisely this population reframes the calculus. It suggests that patients who relapse after transplant need not be relegated to palliative care or high-risk salvage chemotherapy; they may be candidates for a second, engineered immune attack using cells that are themselves of donor origin, effectively recruiting a fresh immunological army against the leukemia.

Caveats remain, and the authors are careful not to overstate them away. Fourteen patients constitute a small, single-center cohort, and the trial was retrospectively registered, limitations that temper the strength of any conclusion. Median survival figures that have not been reached are encouraging but reflect a relatively short median follow-up of under fourteen months. Longer observation will be needed to determine how many remissions endure and whether late relapses, CD19 loss, or delayed toxicities emerge. Still, for a disease setting in which historical survival is measured in months, the combination of near-universal remission induction, multi-year remissions in some patients, and tolerable toxicity represents a genuine advance. The study points toward a future in which allogeneic CAR-T cells, deployed as a rapid and repeatable platform and combined rationally with targeted agents, become a standard salvage strategy for the hardest-to-treat relapses of childhood and adult acute lymphoblastic leukemia.

Subject of Research: Allogeneic anti-CD19 CAR-T cell therapy for B-cell acute lymphoblastic leukemia relapsed after allogeneic stem-cell transplantation

Article Title: Allogeneic anti-CD19 CAR-T therapy demonstrates sustained efficacy and manageable safety in post-allo-HSCT relapsed B-ALL with extramedullary disease

Article References: Liu, R., Zhang, J., Li, Y., Wang, E., Xiao, H., Chen, X., Yan, Y., Wang, L., Tang, Y., Kang, L., Yu, L., Cheng, Q., & Li, X. (2026). Allogeneic anti-CD19 CAR-T therapy demonstrates sustained efficacy and manageable safety in post-allo-HSCT relapsed B-ALL with extramedullary disease. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04585-8

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04585-8

Keywords: CAR-T therapy, allogeneic CAR-T, B-cell acute lymphoblastic leukemia, CD19, extramedullary disease, allogeneic hematopoietic stem-cell transplantation, relapse, graft-versus-host disease, cytokine release syndrome, tyrosine kinase inhibitors, Philadelphia chromosome, immunotherapy

The rationale for immunomodulation is biologically plausible. In herpes simplex virus encephalitis, much of the neurological damage is attributed not only to direct viral cytolysis but also to the host immune response, including cytokine release, edema, and secondary inflammatory cascades that can extend injury well beyond infected neurons. Corticosteroids, by suppressing this inflammation, could in theory reduce swelling, limit tissue damage, and improve outcomes. The idea is not new; discussions of dexamethasone in herpes simplex encephalitis appeared in the medical literature as early as the 1970s, and the approach has been incorporated into some clinical guidelines as an option for patients with life-threatening cerebral edema. Yet the clinical evidence base has remained fragmented, small, and methodologically uneven.

To resolve the uncertainty, Zhang and colleagues searched PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from their inception through 4 July 2026, and also examined trial registries and reference lists of relevant publications. They included randomized controlled trials and comparative observational studies that evaluated systemic corticosteroids added to background antiviral therapy against the same antiviral therapy alone or with placebo. Acyclovir was the background antiviral agent in every study that specified the regimen, ensuring that the comparison isolated the effect of the steroid rather than differences in antiviral care. The co-primary outcomes were study-defined unfavorable global neurological or functional outcome and all-cause mortality, with secondary endpoints covering serious adverse events, seizures during follow-up, cognition, persistent herpes simplex virus DNA in cerebrospinal fluid, relapse, and functional independence measured by the Barthel Index.

The yield from more than five decades of literature was strikingly thin. Only four comparative studies, encompassing 209 patients, met the inclusion criteria: two randomized trials and two retrospective studies. The randomized trials were pooled using Mantel-Haenszel random-effects methods for risk ratios, while mean differences were combined with inverse-variance random-effects approaches. Because non-randomized treatment allocation introduces substantial clinical heterogeneity and confounding by indication, the observational evidence was analyzed and interpreted separately from the randomized data, a decision that reflects contemporary standards for evidence synthesis.

The pooled results from the randomized trials were uniformly inconclusive. For unfavorable global outcome, the pooled risk ratio was 1.00 with a 95 percent confidence interval of 0.68 to 1.47, a point estimate of exactly no effect flanked by intervals wide enough to accommodate both meaningful benefit and meaningful harm. Mortality showed a risk ratio of 0.92 (95 percent confidence interval 0.35 to 2.40), serious adverse events a risk ratio of 1.14 (95 percent confidence interval 0.54 to 2.44), and seizures during follow-up a risk ratio of 0.73 (95 percent confidence interval 0.33 to 1.62). None of these estimates approached conventional thresholds for statistical significance, and all were imprecise, reflecting the small number of patients contributing to each analysis.

Functional and cognitive endpoints fared no better. Barthel Index scores, a standard measure of activities of daily living, showed a mean difference of 3.05 points (95 percent confidence interval, minus 6.99 to 13.09) at approximately six months and 0.30 points (95 percent confidence interval, minus 13.84 to 14.45) at discharge or day 30, differences that are clinically negligible and statistically indistinguishable from zero. Cognitive findings across studies were not consistently favorable. In short, on every endpoint the meta-analysis examined, the randomized evidence could neither confirm benefit nor exclude harm, a pattern the authors attribute to the limited and imprecise nature of the underlying data rather than to demonstrated equivalence.

The observational studies added little clarity and, in some respects, raised concerns. Their estimates conflicted with one another and were judged to be seriously compromised by confounding, since clinicians tend to give steroids to the sickest patients, biasing any naive comparison. The randomized trials did, however, generate two signals worth noting. In the DexEnceph trial, a multicenter, observer-blind, phase 3 study of adjunct dexamethasone in adults with herpes simplex virus encephalitis conducted in the United Kingdom, herpes simplex virus DNA remained detectable in cerebrospinal fluid at approximately day 14 in 4 of 36 dexamethasone recipients compared with 9 of 43 controls, a numerical difference of uncertain significance. More strikingly, five relapses were reported among dexamethasone-treated patients and none among controls, although the authors caution that so few events do not permit a causal conclusion. The possibility that corticosteroid-induced immunosuppression might prolong viral clearance or provoke relapse has long been a theoretical worry, and these findings keep it alive without settling it.

The meta-analysis also highlights a critical gap. The one scenario in which corticosteroids are most often deployed in practice, life-threatening cerebral edema with impending herniation, was never specifically evaluated in any included study. The evidence is therefore insufficient to determine whether steroids help or harm this selected subgroup, leaving clinicians to make high-stakes decisions on physiological reasoning alone. The authors call for future adequately powered, multicenter randomized trials that use standardized treatment protocols and prespecify severity- and edema-defined subgroups, so that the question of immunomodulation can be answered separately for the broad population and for the narrow emergency indication.

For now, the practical message is one of restraint. With roughly 209 randomized and comparative patients studied across half a century, the field has generated data too sparse to justify routine adjunctive corticosteroids, yet too imprecise to close the door entirely. Clinicians managing herpes simplex virus encephalitis should continue to prioritize early acyclovir, the intervention with proven mortality benefit, and reserve corticosteroids for circumstances where cerebral edema threatens immediate deterioration, ideally within the framework of clinical trials or prospective registries. The new synthesis in the Journal of Neurology does not declare steroids useless; it declares the question still open, and in doing so it sets a clear agenda for the trials the field has, until now, failed to deliver.

Subject of Research: Adjunctive corticosteroid therapy for herpes simplex virus encephalitis

Article Title: Adjunctive corticosteroids in herpes simplex virus encephalitis: a meta-analysis of randomized and observational studies

Article References: Zhang, D., Yang, M., Huang, Y., Liang, M., Yao, L., Liang, J., Deng, M., & Shen, R. (2026). Adjunctive corticosteroids in herpes simplex virus encephalitis: a meta-analysis of randomized and observational studies. Journal of Neurology, 273(10), Article 567. https://doi.org/10.1007/s00415-026-14128-x

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DOI: 10.1007/s00415-026-14128-x

Keywords: herpes simplex virus encephalitis, corticosteroids, dexamethasone, acyclovir, meta-analysis, neurological outcome, cerebral edema, randomized controlled trials, Barthel Index, relapse, cerebrospinal fluid HSV DNA, Journal of Neurology

Primary thyroid lymphoma is a genuine medical rarity. The thyroid gland is packed with lymphatic tissue, particularly in people with chronic autoimmune inflammation such as Hashimoto’s thyroiditis, and on rare occasions a lymphoma can originate there directly rather than spreading from elsewhere in the body. Diffuse large B-cell lymphoma, or DLBCL, is the most common aggressive subtype of non-Hodgkin lymphoma overall, but when it presents as the first and only site of disease in the thyroid, it belongs to a small subset of so-called primary extranodal lymphomas. Because so few patients exist, no large randomized trials have ever defined a single standard of care. Treatment decisions are instead stitched together from small case series, registry data, and extrapolation from how DLBCL is managed at other anatomical sites. That evidence gap is precisely what the Hamburg team set out to address by pairing their patient’s story with a structured sweep of the published literature.

The clinical picture in 2017 was textbook for the disease in its most dangerous form. The patient’s enlarged thyroid was compressing her airway, explaining the dyspnoea and cough, while involvement of the recurrent laryngeal nerve that runs alongside the gland accounted for her hoarseness. Staging investigations placed her at Ann Arbor stage IE, meaning the lymphoma was confined to a single extranodal organ, and her International Prognostic Index score of 2 indicated intermediate risk. Histopathological analysis classified the tumor as the non-germinal-center B-cell-like, or non-GCB, subtype, a molecular categorization based on the cell of origin that carries prognostic weight in DLBCL generally. Establishing that classification reliably, the authors emphasize in their review, depends on obtaining an adequate tissue sample — ideally a core needle biopsy or a surgical biopsy — because fine-needle aspirates often cannot provide enough architectural and immunophenotypic detail to distinguish DLBCL from other thyroid malignancies or from inflammatory conditions.

First-line therapy followed the established chemoimmunotherapy playbook. The patient received R-CHOP, the workhorse regimen combining the anti-CD20 monoclonal antibody rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone, together with prophylactic treatment directed at the central nervous system. Rituximab’s arrival two decades ago transformed outcomes in DLBCL by targeting the CD20 surface protein found on malignant B cells, and the literature review confirms that rituximab-containing chemoimmunotherapy remains the backbone of first-line treatment for primary thyroid DLBCL as well, occasionally supplemented with radiotherapy to the thyroid bed. Surgery, by contrast, played essentially no therapeutic role: across the reviewed literature, operations were largely confined to obtaining diagnostic tissue rather than attempting resection, a notable departure from how many solid thyroid cancers are managed with near-total thyroidectomy.

The initial response was complete remission, and for six years the patient remained disease-free. Then came the twist that makes this case report valuable to practicing hematologists. Rather than recurring locally in the same gland or spreading to distant lymph nodes, the lymphoma re-emerged as an isolated relapse in the contralateral thyroid lobe — the opposite side of the gland from the original tumor. Isolated late relapses of primary thyroid DLBCL are vanishingly rare; the review notes that relapsed or refractory disease in general, and central nervous system involvement in particular, are uncommon events in this patient population. The contralateral pattern raises intriguing questions about clonal biology: whether the relapse represented re-seeding from an occult residual clone within the gland or a truly independent second primary lymphoma arising in the same chronically inflamed tissue environment.

Treating a relapse six years after the original diagnosis posed a practical dilemma. Because the patient had already received anthracycline-based chemotherapy and rituximab, the team chose an off-label regimen abbreviated Pola-R-miniCHP. The key ingredient is polatuzumab vedotin, an antibody-drug conjugate that ferries a potent cytotoxic payload, monomethyl auristatin E, directly to CD79b, a component of the B-cell receptor complex expressed on malignant cells. Polatuzumab-based combinations have reshaped the landscape of relapsed and refractory DLBCL since demonstrating survival benefits in randomized testing, and the miniaturized chemotherapy backbone in this regimen was designed to reduce cumulative toxicity in an elderly patient. The gamble worked: the contralateral relapse again melted into complete remission, giving the patient two separate cures from the same rare disease across nearly a decade.

The literature review that accompanies the case report assembles the fragmented evidence base into a coherent picture. Reported five-year overall survival rates for primary thyroid DLBCL span a wide range, from 57 percent to 88 percent, reflecting heterogeneity in patient age, stage, histological subtype, and treatment era across the small published series. The better end of that spectrum approaches outcomes for early-stage DLBCL at more conventional nodal sites, underscoring that when the disease is caught while confined to the thyroid and treated promptly with modern immunochemotherapy, long-term survival is a realistic expectation. The authors also highlight that central nervous system relapse, a feared complication of aggressive DLBCL, appears infrequently in this population, which has implications for how aggressively clinicians need to pursue CNS-directed prophylaxis at diagnosis.

What the review cannot yet deliver is a definitive, evidence-based treatment guideline, and the authors are candid about why. The rarity of primary thyroid DLBCL means that every published series is small, retrospective, and vulnerable to selection bias. Randomized trials enrolling patients with this specific presentation are practically impossible to mount. Their proposed way forward is registry-based research, particularly studies that group primary extranodal DLBCLs of various origins together to achieve analyzable patient numbers while still capturing the distinctive features of thyroid disease. Such registries could clarify outstanding controversies, including the optimal role of radiotherapy consolidation, the necessity and duration of CNS prophylaxis, the value of molecular risk stratification, and how best to manage the rare relapses like the one documented in this report.

For the broader oncology community, the case carries several practical lessons. First, a rapidly enlarging thyroid mass with compressive or neurological symptoms in an older patient, especially one with background autoimmune thyroid disease, should prompt consideration of lymphoma alongside the more common carcinomas — because the diagnostic and therapeutic pathways diverge sharply, and inappropriate upfront surgery can delay the correct treatment. Second, adequate tissue via core needle or surgical biopsy is not a formality but the linchpin of accurate subtyping. Third, relapsed primary thyroid DLBCL, while exceptionally uncommon, may be amenable to the same novel agents that have improved salvage therapy for DLBCL elsewhere, as the successful off-label use of a polatuzumab-based regimen here demonstrates. The report thus functions as both a caution and an encouragement: vigilance at first presentation and flexibility at relapse can yield complete remissions even in a disease so rare that no guideline exists to follow.

The Hamburg authors, writing from one of Germany’s major university cancer centers, published their work open access so that clinicians encountering their own rare cases can consult the full analysis. As targeted immunotherapies continue to migrate from relapsed settings into frontline treatment across the lymphoma spectrum, the experience documented in this single patient may foreshadow how primary thyroid DLBCL is managed in the coming decade — with antibody-drug conjugates and other precision agents potentially joining or even replacing legacy regimens, and with international registries finally assembling enough patients to turn anecdote into evidence.

Subject of Research: Primary thyroid diffuse large B-cell lymphoma: diagnosis, treatment, and relapse management

Article Title: Primary thyroid diffuse large B-cell lymphoma: a case report and focused review of the literature

Article References: Kirkgöz, K., Weisel, K., Bokemeyer, C., & von Kroge, S. (2026). Primary thyroid diffuse large B-cell lymphoma: a case report and focused review of the literature. Annals of Hematology. https://doi.org/10.1007/s00277-026-07303-7

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07303-7

Keywords: primary thyroid lymphoma, diffuse large B-cell lymphoma, DLBCL, rituximab, R-CHOP, polatuzumab vedotin, thyroid cancer, non-Hodgkin lymphoma, relapse, chemoimmunotherapy, extranodal lymphoma, Annals of Hematology

The team focused on a population they had previously identified, marked by the co-expression of the surface proteins CD34, CD123, CD25 and CD99. In their earlier work, these CD34/CD123/CD25/CD99-positive leukemic progenitor cells (LPCs) were seen to persist in patients after induction chemotherapy and to herald disease recurrence in FLT3-ITD-mutated AML. What remained unclear was whether these cells were merely passive survivors or genuine leukemia-initiating cells with stem-like capacity. The new study answers that question directly, providing what the authors describe as the first functional evidence that FLT3-ITD-mutated LPCs maintain stem cell potential in vivo.

The clinical part of the investigation began with a diagnostic twist that could change practice. Using multiparametric flow cytometry on prospective patient samples, the researchers showed that when the CD34/CD123/CD25/CD99-positive fraction exceeds 7.4 percent of the relevant cell compartment, the presence of an FLT3-ITD mutation can be predicted with 88.2 percent sensitivity and, remarkably, 100 percent specificity. In other words, an immunophenotypic signature visible on a standard flow cytometry panel can act as a surrogate flag for the mutation, and the same signature can be tracked over time as a form of measurable residual disease (MRD) monitoring that does not depend on molecular assays alone.

To test whether these cells truly behave like leukemia stem cells, the team purified LPCs by cell sorting and transplanted them into conditioned NSG mice, an immunodeficient strain widely used for human hematopoietic engraftment studies. The sorted LPCs engrafted efficiently and reinitiated leukemia in the recipient animals. Critically, when the resulting leukemic cells were harvested and transplanted into successive cohorts of mice, the LPC compartment expanded with each sequential passage. This serial transplantation behavior, with the progenitor pool growing rather than exhausting, is exactly what would be expected from a self-renewing disease reservoir capable of sustaining relapse.

With the functional identity of the LPCs established, the researchers turned to molecular profiling to understand what makes them tick. They performed transcriptomic analysis on 13 paired samples of LPCs and leukemic blasts from the same patients, allowing a direct comparison between the progenitor population and the bulk tumor cells. The most striking finding was an upregulation of genes encoding protein kinases in the LPCs, with the lymphocyte-specific protein tyrosine kinase, known as LCK, standing out as the dominant signal. LCK is classically associated with T-cell receptor signaling, so its prominence in myeloid leukemic progenitors was unexpected and immediately suggested a druggable vulnerability.

The LCK finding was not a one-off artifact of a small cohort. The team went on to confirm elevated LCK expression in 28 additional FLT3-ITD-mutated AML samples, consolidating the observation across an independent validation set. This reproducibility matters, because candidate therapeutic targets in AML have a long history of failing to survive independent validation. Here, the kinase overexpression pattern appeared consistently in the very cells that seed relapse, not just in the bulk blast population that most genomic studies interrogate.

On the therapeutic side, the researchers examined how the FLT3 inhibitor gilteritinib, already approved for relapsed or refractory FLT3-mutated AML, affects these progenitor cells. Gilteritinib reduced proliferation and dampened the FLT3-STAT5 signaling pathway, a canonical downstream axis of the mutant receptor, in both FLT3-ITD-mutated blasts and LPCs. That the drug reaches its canonical target even within the stem-like compartment is encouraging, but the experiments also revealed why single-agent inhibition is not enough: the LPCs retained survival capacity, pointing to parallel signaling routes that keep the cells alive when FLT3 itself is blocked.

That parallel route appears to run through LCK. When the investigators added LCK inhibition on top of gilteritinib, the effects were more than additive in key respects. Dual blockade further attenuated FLT3/STAT5 activity, disrupted the aberrant subcellular localization of the FLT3 receptor, and downregulated ABC transporter-associated multidrug resistance, the family of efflux pumps that chemotherapy and targeted agents alike must overcome. The combination of gilteritinib with LCK blockade enhanced the overall anti-leukemic activity, consistent with the idea that FLT3 and LCK cooperate to sustain FLT3-ITD-mutated leukemic progenitors and that hitting both pathways simultaneously collapses their support network.

The mechanistic detail about FLT3 localization deserves particular attention. The biosynthetic trafficking of FLT3-ITD has been implicated in the mutant receptor’s ability to transduce autonomous growth signals from intracellular compartments, and the finding that LCK inhibition corrects aberrant FLT3 localization suggests that LCK may help position the mutant receptor where it can signal most effectively. Meanwhile, the suppression of ABC transporter expression links the LCK axis to one of the classic mechanisms of chemoresistance in AML, offering a potential explanation for why LPCs survive induction chemotherapy in the first place.

Taken together, the study delivers three practical takeaways. First, a defined immunophenotypic signature above a 7.4 percent threshold provides a clinically actionable tool for identifying FLT3-ITD-mutated disease and monitoring residual leukemic progenitors by flow cytometry. Second, the in vivo engraftment and serial passage data cement LPCs as the functional reservoir of relapse, making them the logical target for eradication strategies aimed at long-term remission. Third, the LCK pathway emerges as a novel molecular vulnerability that can be attacked in combination with existing FLT3 inhibitors, a strategy the authors argue could selectively eliminate residual FLT3-ITD-mutated LPCs and improve long-term outcomes in a disease where relapsed and refractory cases remain a pressing unmet medical need. As gilteritinib-resistant relapses continue to challenge clinicians, the prospect of pairing FLT3 blockade with LCK-directed agents gives the field a concrete, mechanistically grounded next step.

Subject of Research: Functional and molecular characterization of FLT3-ITD-mutated leukemic progenitor cells in acute myeloid leukemia

Article Title: Characterization of FLT3-ITD-mutated leukemic stem cells: functional and clinical insights

Article References: Travaglini, S., Ottone, T., Antonelli, S., Serra, M., Silvestrini, G., Masciarelli, S., Sniegocka, M., Noguera, N. I., De Bardi, M., Lomi, M., Consalvo, M. A. I., Gurnari, C., Piazza, R., Divona, M., Marchesi, F., Fazi, F., Mattei, M., Buccisano, F., Battistini, L., … Voso, M. T. (2026). Characterization of FLT3-ITD-mutated leukemic stem cells: functional and clinical insights. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03319-0

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03319-0

Keywords: acute myeloid leukemia, FLT3-ITD, leukemic stem cells, leukemic progenitor cells, gilteritinib, LCK, STAT5 signaling, measurable residual disease, flow cytometry, NSG mice, drug resistance, relapse

The study, published in Annals of Clinical and Translational Neurology, drew on participants from DAYBREAK, a phase 3 open-label extension trial that followed adults with relapsing forms of multiple sclerosis who had previously completed earlier ozanimod trials. Across the parent trials and the extension, participants accumulated up to 117.2 months, nearly a decade, of cumulative exposure to the drug. Of the 2,494 people who entered DAYBREAK, nearly 80 percent completed the study. The researchers focused on 1,679 participants who had at least one day of post-treatment safety follow-up and who did not transition to commercial ozanimod within 14 days of stopping the study drug, creating a window in which any returning disease activity could be observed.

The headline finding is striking in its simplicity: only 55 participants, or 3.3 percent of the analysis population, experienced an objectively confirmed relapse after permanently discontinuing ozanimod. When suspected relapses that failed to meet strict objective criteria were included, the figure rose only slightly, to 4.1 percent. Given that multiple sclerosis is, by its nature, a relapsing disease in these patients, the question the investigators set out to answer was not merely whether relapses occurred, but whether they occurred at a rate and severity beyond what would be expected from the underlying disease simply reasserting itself.

The timing of the relapses tells a story written in pharmacology. Ozanimod works by selectively modulating sphingosine 1-phosphate receptors 1 and 5, trapping lymphocytes inside lymphoid tissues and preventing them from migrating into the central nervous system, where they drive the inflammatory attacks that characterize multiple sclerosis. The drug itself has an elimination half-life of about 21 hours, but its major active metabolite lingers far longer, with a half-life of approximately 11 days. After discontinuation, blood lymphocyte counts return to normal after a median of 30 days, with 80 to 90 percent of patients back in the normal range within three months. True to that pharmacokinetic profile, relapses clustered at two to three months after stopping the drug, with a median onset of 61 days and a range of 3 to 141 days.

The granular breakdown is equally informative. Only five participants, 0.3 percent, relapsed within the first 28 days after discontinuation. Another 22 relapsed between days 29 and 60, representing 1.7 percent of those followed that long, and 26 more relapsed between days 61 and 90, or 2.2 percent of participants with follow-up beyond 60 days. Just two participants relapsed after 90 days, one of whom fell within the protocol’s permitted 10-day follow-up window and the other of whom had been nonadherent to follow-up because of COVID-19 travel restrictions. The pattern mirrors the waning of the drug’s immunological grip rather than any paradoxical overshoot.

Severity is where the rebound question is truly decided, and here the data lean strongly toward reassurance. Nearly all post-treatment relapses were judged mild or moderate by the treating investigators: 20 were mild and 34 were moderate, while only a single participant, 1.8 percent, had a relapse classified as severe. Even that case, the investigators concluded, did not represent higher-than-expected disease activity. The participant, a 44-year-old woman with a heavy pre-treatment disease burden, including 70 T2 lesions on MRI and substantial prior relapse activity, had already experienced a severe relapse while still taking ozanimod roughly a year before the post-treatment episode. Her disability worsened from an Expanded Disability Status Scale score of 7.5 to 8.0, she was not hospitalized, and she achieved partial recovery within 36 days.

Recovery outcomes across the relapsing group were similarly encouraging. Among the 55 participants with confirmed post-treatment relapse, 76.4 percent had completely recovered by their last safety follow-up, 20 percent had partially recovered, and only two participants had not recovered. Median relapse duration was 22 days, and the median increase in EDSS score at relapse was just one point. Four of the seven participants whose EDSS scores rose by two or more points went on to make complete recoveries. Notably, no MRI scans were performed at the time of relapse, and no tumefactive demyelinating lesions, the dramatic, mass-like brain lesions sometimes seen after fingolimod cessation, were ever reported during or after ozanimod treatment in the entire trial program.

The investigators went further, stress-testing their data against definitions of rebound used in earlier studies. Applying the criteria from the fingolimod FREEDOMS trials, where higher-than-expected disease activity rates of 4.0 and 3.5 percent were recorded but were matched by 4.4 and 4.1 percent in placebo groups, 1.4 percent of the ozanimod analysis population met the threshold. Of the 24 participants qualifying, 14 were hospitalized during relapse, but 11 of those hospitalizations occurred in Eastern Europe, where intravenous steroid treatment for relapses is routinely delivered on an inpatient basis regardless of severity, a practice pattern that inflates hospitalization counts compared with settings like the United States. An informal comparison of EDSS changes during relapse against historical data from untreated patients found no statistically significant difference, further supporting the conclusion that these episodes reflect ordinary disease reactivation, not rebound.

Who relapsed matters as much as how many. Participants who experienced post-treatment relapse were younger, diagnosed with multiple sclerosis at a younger age, and carried greater clinical and radiological disease burden, with more gadolinium-enhancing and T2 lesions at baseline and more relapses both during the trials and in the year before discontinuation. A multivariable logistic regression model identified three nominally significant predictors: younger age at diagnosis, a higher number of relapses during the extension trial, and a higher T2 lesion count at parent-trial baseline. This aligns with a consistent theme in the literature, that patients with more active disease before or during treatment face greater risk of relapse after stopping any disease-modifying therapy, and with the well-documented observation that relapse rates in multiple sclerosis peak in the twenties and thirties before declining with age.

The study’s limitations deserve honest acknowledgment. DAYBREAK was not designed to assess post-treatment relapse, the analysis is exploratory and post hoc, and the reported P values are nominal rather than confirmatory. Roughly one-fifth of the overall population lacked safety follow-up and was excluded, though their characteristics resembled those analyzed. About a quarter of the analysis population had fewer than 29 days of follow-up, meaning some relapses may have occurred after observation ended, and the strict requirement for objective neurological worsening may have undercounted milder episodes. The absence of MRI data limits conclusions to clinical activity. Still, the authors’ conclusion stands on a large, systematically assessed dataset: no case showed a pattern suggestive of rebound, and the return of disease activity after stopping ozanimod appears milder and less frequent than that reported after discontinuing natalizumab, where rebound rates of 8 to 22 percent have been reported, or fingolimod, where observational studies have ranged as high as 42.8 percent under varying definitions. For clinicians and patients weighing discontinuation, whether for family planning, side effects, or waning benefit, the message is clear: relapses cluster two to three months after the last dose, are usually mild to moderate, and usually resolve completely, which argues for prompt switching to another therapy and careful monitoring rather than fear of a pharmacological storm.

Subject of Research: Relapse activity and rebound risk after discontinuation of the multiple sclerosis therapy ozanimod in the DAYBREAK open-label extension trial

Article Title: Multiple Sclerosis Relapse Activity After Ozanimod Discontinuation in DAYBREAK Trial Participants

Article References: Gold, R., Selmaj, K. W., Berkovich, R., Cohen, J. A., Comi, G., Havrdová, E. K., Sheffield, J. K., Desai, H., Cheng, C.-Y., Riolo, J. V., Thorpe, A., DeBoer, E., & Cree, B. A. C. (2026). Multiple Sclerosis Relapse Activity After Ozanimod Discontinuation in DAYBREAK Trial Participants. Annals of Clinical and Translational Neurology, 13(10), 2017-2026. https://doi.org/10.1002/acn3.70366

Image Credits: AI Generated

DOI: 10.1002/acn3.70366

Keywords: multiple sclerosis, ozanimod, DAYBREAK trial, rebound, disease-modifying therapy, S1P receptor modulator, relapse, fingolimod, natalizumab, lymphocytes, pharmacokinetics, neurology