Epstein-Barr virus-associated lymphomas decoded.

Epstein-Barr virus (EBV)-associated lymphomas cover a range of histological B- and T-cell non-Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B-cell malignant pathogenesis and its impact on the tumour microenvironment are intriguing but incompletely understood. Both the International Consensus Classification (ICC) and 5th Edition of the World Health Organization (WHO-HAEM5) proposals give prominence to the distinct clinical, prognostic, genetic and tumour microenvironmental features of EBV in lymphoproliferative disorders. There have been major advances in our biological understanding, in how to harness features of EBV and its host immune response for targeted therapy, and in using EBV as a method to monitor disease response. In this article, we showcase the latest developments and how they may be integrated to stimulate new and innovative approaches for further lines of investigation and therapy.

Diagnosis, management and follow-up of follicular lymphoma: a consensus practice statement from the Australasian Lymphoma Alliance.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma subtype, accounting for 15-20% of all lymphoma diagnoses. Although typically slow-growing and responsive to frontline therapies, advanced-stage FL remains incurable with current treatments and typically follows a chronic relapsing/remitting course with increasingly shorter responses to subsequent lines of therapy. Outcomes are highly variable; some patients experience prolonged first remissions that may approximate a 'functional cure'. By contrast, a significant minority of patients experience disease progression shortly after frontline treatment resulting in high rates of lymphoma-related mortality. Reflecting on the heterogeneous natural history of FL, clinical practice varies widely, particularly in controversial areas, including appropriate disease staging, selection of management strategies and duration of clinical follow-up. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice.

Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma.

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

Influenza Suppresses Neutrophil Recruitment to the Lung and Exacerbates Secondary Invasive Pulmonary Aspergillosis.

Aspergillus fumigatus is an environmental fungus that can cause invasive pulmonary aspergillosis when spores are inhaled into the respiratory tract and invade airway or lung tissue. Influenza is a common respiratory virus that can cause severe respiratory disease, and postinfluenza invasive pulmonary aspergillosis, which is becoming a well-recognized clinical problem, typically occurs in critically ill patients. Mice challenged with influenza A PR/8/34 H1N1 and subsequently challenged with A. fumigatus had increased fungal burden, viral burden, inflammation, and mortality compared with single infected mice. Neutrophil recruitment in the lung of superinfected mice was decreased; however, mice were not neutropenic, and there was no difference in absolute blood neutrophils between groups. Additionally, CXCL1 and CXCL2 were decreased in lungs of superinfected mice compared with controls. IFN levels were increased in mice that received influenza, and deletion of STAT1 resulted in decreased fungal burden, increased airway and lung neutrophils, and increased CXCL1 compared with wild-type mice, whereas deletion of STAT2 did not change fungal burden or airway neutrophilia compared with wild-type mice. These data demonstrate a mechanism by which influenza A-induced STAT1 signaling inhibits neutrophil recruitment and increases susceptibility to postinfluenza invasive pulmonary aspergillosis.

Diagnosis, management and follow up of peripheral T-cell lymphomas: a consensus practice statement from the Australasian Lymphoma Alliance.

Peripheral T-cell lymphomas (PTCL) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared with aggressive B-cell lymphomas. However, such outcomes are heavily dependent on subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone remain the standard first-line treatment for most aggressive PTCL, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to understand better the pathogenesis of PTCL to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice.

Successful treatment of Epstein-Barr virus-associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein-Barr virus-specific T cells.

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).

Efficacy of galcanezumab in patients with migraine who did not benefit from commonly prescribed preventive treatments.

BACKGROUND: Galcanezumab is a calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) indicated for the preventive treatment of migraine. While galcanezumab has demonstrated efficacy in patients who did not respond to prior preventive medications in general, its efficacy in patients who did not benefit from individual, commonly prescribed preventive treatments due to inadequate efficacy or safety/tolerability remains unknown. METHODS: CONQUER was a 3-month, randomized, double-blind, placebo-controlled, phase 3b study that enrolled patients with episodic or chronic migraine who had 2 to 4 migraine preventive medication category failures in the past 10 years. Patients were randomly assigned 1:1 to receive placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). Post hoc analyses were conducted to determine the efficacy of galcanezumab in patients who had not benefited from six of the most commonly prescribed migraine preventive medications. The mean change from baseline in monthly migraine headache days and ≥ 50 % response rates were assessed over months 1-3. Improvement in Migraine-Specific Questionnaire Role Function-Restrictive (MSQ-RFR) scores were assessed at month 3. The endpoints were estimated via mixed model with repeated measures. RESULTS: The most common treatment failures due to inadequate efficacy or safety/tolerability, which at least 20 % of patients reported trying without benefit, included topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and metoprolol. Patients who had not previously benefited from these treatments had a greater mean reduction in monthly migraine headache days across months 1-3 in the galcanezumab group compared to placebo (all p < 0.01). More patients treated with galcanezumab experienced a ≥ 50 % reduction from baseline in monthly migraine headache days across months 1-3 compared to placebo (all p < 0.05). Galcanezumab-treated patients had a greater improvement in mean MSQ-RFR scores at month 3 compared to placebo (all p < 0.01). CONCLUSIONS: In this population, galcanezumab was effective in reducing monthly migraine headache days, improving response rates, and enhancing quality of life in patients who had not previously benefited from topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and/or metoprolol due to inadequate efficacy or safety/tolerability. TRIAL REGISTRATION: ClinicalTrials.gov NCT03559257 (CONQUER).

Lasmiditan for the acute treatment of migraine: Subgroup analyses by prior response to triptans.

BACKGROUND: Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve. METHODS: Subgroups of patients reporting an overall response of "good" or "poor/none" to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient). RESULTS: Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients. CONCLUSIONS: Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine. TRIAL REGISTRATION: SAMURAI (NCT02439320); SPARTAN (NCT02605174).

The tumour microenvironment is immuno-tolerogenic and a principal determinant of patient outcome in EBV-positive diffuse large B-cell lymphoma.

OBJECTIVE: Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV-pos DLBCL) is a recently identified entity. Data regarding outcome to frontline immuno-chemotherapy are conflicting. Although the prognostic impact of the tumour microenvironment (TME) in EBV-neg DLBCL is well-established, it remains untested whether the TME influences survival in EBV-pos DLBCL. There are no data with new digital gene expression technologies that simultaneously interrogate the virus, B cells and the tumour microenvironment (TME). METHODS: We used the NanoString™ platform in a population-based cohort of 433 patients to establish if the technology could detect EBV in the tumour biopsies and to investigate the influence that EBV has on the complex tumour microenvironment of DLBCL. RESULTS: Incidence of EBV-pos DLBCL was 6.9% with 5-year survival of 65% vs 82% in EBV-neg DLBCL (P = 0.018). EBV-pos tissues had similar expression of T-cell genes compared to EBV-neg DLBCL but higher levels of the antigen-presenting molecule B2M. This was countered by elevated PD-L1, PD-L2, LAG3 and TIM3 immune checkpoints and a higher CD163/CD68 "M2" macrophage score. CONCLUSION: In EBV-pos DLBCL, the TME is immuno-tolerogenic and may explain the poor outcomes seen in this subtype of DLBCL.

The Ryder Cognitive Aid Checklist for Trauma Anesthesia.

Despite mixed results regarding the clinical utility of checklists, the anesthesia community is increasingly interested in advancing research around this important topic. Although several checklists have been developed to address routine perioperative care, few checklists in the anesthesia literature specifically target the management of trauma patients. We adapted a recently published "trauma and emergency checklist" for the initial phase of resuscitation and anesthesia of critically ill trauma patients into an applicable perioperative cognitive aid in the form of a pictogram that can be downloaded by the medical community. The Ryder Cognitive Aid Checklist for Trauma Anesthesia is a letter-sized, full-color document consisting of 2 pages and 5 sections. This cognitive aid describes the essential steps to be performed: before patient arrival to the hospital, on patient arrival to the hospital, during the initial assessment and management, during the resuscitation phase, and for postoperative care. A brief online survey is also presented to obtain feedback for improvement of this tool. The variability in utility of cognitive aids may be because of the specific clinical task being performed, the skill level of the individuals using the cognitive aid, overall quality of the cognitive aid, or organizational challenges. Once optimized, future research should be focused at ensuring successful implementation and customization of this tool.

Factor concentrates in trauma.

PURPOSE OF REVIEW: Recent advances in the understanding of transfusion practices during hemorrhagic shock in trauma have led to early administration of thawed plasma in increased ratios to packed red blood cells and have improved survival in the most severely injured patients. As an appreciation for the sequelae of massive transfusion continues to mature, it is becoming apparent that a more targeted approach to coagulation deficiencies may offer an advantage. RECENT FINDINGS: Factor concentrate therapy offers the advantage of smaller volumes of resuscitative fluids directed at specific phases of coagulation identified by alternative laboratory assays (e.g., viscoelastic testing). Case reports, animal studies, and retrospective reviews offer encouraging data on the ability of factor concentrates to reverse coagulopathy and reduce blood product usage. SUMMARY: The use of factor concentrates to target specific phases of coagulation may offer benefit over blood product ratio-driven transfusion. The outcome benefit of factor concentrates, however, has not yet been demonstrated in well powered prospective trials.

Developing a trauma curriculum for anesthesiology residents and fellows.

PURPOSE OF REVIEW: The board certification process for qualification by the American Board of Anesthesiology is undergoing significant review. A basic sciences examination has been added to the process and the traditional oral examination is evolving into a combined oral interview and practical skills assessment. These recent developments, as well as the growing body of evidence regarding the resuscitation of trauma patients, call for a revision in the curriculum beyond the documentation of participation in the anesthetics of 20 trauma patients. RECENT FINDINGS: The implications of the 80-h work week are beginning to be appreciated. The development of a new trauma curriculum must take this significant change in residency training into account while incorporating modern educational theory (e.g. simulation) and new data on the resuscitation of trauma patients. SUMMARY: Currently, the curriculum for trauma anesthesia requires only that residents participate in the anesthetics of 20 trauma patients. There is no plan for, and little literature regarding, a more extensive educational program. This offers a unique opportunity to innovate a novel curriculum in the anesthesiology residency. The American Society of Anesthesiologists Committee on Trauma and Emergency Preparedness has designed a curriculum that can serve as a template for this important step forward in anesthesiology education.

A Theoretical Analysis of Density Peaks Clustering and the Component-Wise Peak-Finding Algorithm.

Density peaks clustering detects modes as points with high density and large distance to points of higher density. Each non-mode point is assigned to the same cluster as its nearest neighbor of higher density. Density peaks clustering has proved capable in applications, yet little work has been done to understand its theoretical properties or the characteristics of the clusterings it produces. Here, we prove that it consistently estimates the modes of the underlying density and correctly clusters the data with high probability. However, noise in the density estimates can lead to erroneous modes and incoherent cluster assignments. A novel clustering algorithm, Component-wise Peak-Finding (CPF), is proposed to remedy these issues. The improvements are twofold: 1) the assignment methodology is improved by applying the density peaks methodology within level sets of the estimated density; 2) the algorithm is not affected by spurious maxima of the density and hence is competent at automatically deciding the correct number of clusters. We present novel theoretical results, proving the consistency of CPF, as well as extensive experimental results demonstrating its exceptional performance. Finally, a semi-supervised version of CPF is presented, integrating clustering constraints to achieve excellent performance for an important problem in computer vision.

PTPN2 deficiency: Amping up JAK/STAT.

Identification of monogenic causes of immune dysregulation provides insight into human immune response and signaling pathways associated with autoimmunity. Here, Jeanpierre et al. (https://doi.org/10.1084/jem.20232337) identify new germline variants in the gene encoding PTPN2 associated with loss of regulatory function, enhanced JAK/STAT signaling, and early-onset autoimmunity.

Artificial intelligence and machine learning: Definition of terms and current concepts in critical care research.

With increasing computing power, artificial intelligence (AI) and machine learning (ML) have prospered, which facilitate the analysis of large datasets, especially those found in critical care. It is important to define these terminologies, to inform a standardized approach to critical care research. This manuscript hopes to clarify these terms with examples from medical literature. Three major components that are required for a successful ML implementation: (i) reliable dataset, (ii) ML algorithm, and (iii) unbiased model evaluation, are discussed. A reliable dataset can be structured or unstructured with limited noise, outliers, and missing values. ML, a subset of AI, is typically focused on supervised or unsupervised learning tasks in which the output is based on inputs and derived from iterative pattern recognition algorithms, while AI is the overall ability of a machine to "think" or mimic human behavior; and to analyze data free from human influence. Even with successful implementation, advanced AI and ML algorithms have faced challenges in adoption into practice, mainly due to their lack of interpretability, which hinders trust, buy-in, and engagement from clinicians. Consequently, traditional algorithms, such as linear and logistic regression, that may have reduced predictive power but are highly interpretable, continue to be widely used.

Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.

Prehospital Critical Care Blood Product Administration: Quantifying Clinical Benefit.

BACKGROUND: Prehospital blood transfusion has been widely practiced in the military and is drawing renewed scrutiny after many years of civilian use. OBJECTIVE: The objective of this article is to quantify the benefit derived from prehospital transfusion of blood products. METHODS: Deidentified data were extracted retrospectively from the flight records of a critical care transportation program between April 2018 and January 2020. Patients who were transported before a prehospital blood transfusion protocol were compared with patients after initiation of the blood transfusion protocol. Demographic data, vital signs, laboratory analytics, and other outcome measures were analyzed. RESULTS: Nine scene transport patients who met the transfusion criteria before a blood transfusion protocol were compared with 11 patients transported after initiation of the protocol. Identical outcome measures were analyzed. Patients who received prehospital blood transfusions had a statistically significantly longer hospital length of stay (16.5 vs 3.7 days, P = .03) and were more often taken directly to the operating room (80% vs 28%, P = .04). No statistically significant difference was identified when comparing mean arterial pressure, heart rate, respiratory rate, hemoglobin, hematocrit, or survival to hospital discharge. CONCLUSIONS: Trauma patients who received prehospital blood transfusion had a longer hospital length of stay and were more often taken directly to the operating room, but without improvement in survival.

Diffuse large B-cell lymphoma and red cell autoimmunity: clinical role and pathogenesis.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of B-cell non-Hodgkin lymphoma (B-NHL) with significant morbidity and mortality despite advancements in treatment. Lymphoma and autoimmune disease both result from breakdowns in normal cell regulatory pathways, and epidemiological studies have confirmed both that B-NHL is more likely to develop in the setting of autoimmune diseases and vice versa. Red cell immunity, as evidenced by direct antiglobulin test (DAT) positivity, has been linked to DLBCL and more recently the pathogenic causes of this association have begun to be better understood using molecular techniques. This project aimed to explore the relationship between red cell autoimmunity and DLBCL. DAT positivity was more common in DLBCL as compared to healthy controls (20.4% vs 3.7%, p=0.0005). Univariate analysis found a non-significant trend towards poorer overall survival in the DAT positive (DAT+) compared to the DAT negative (DAT-) groups (p=0.087). High throughput sequencing was used to compare mutations in DLBCL from DAT+ and DAT- patients. The most frequently mutated genes in 15 patient samples were KMT2D (n=13), MYOM2 (n=9), EP300 (n=8), SPEN (n=7), and ADAMTSL3 (n=7), which were mutated in both DAT+ and DAT- groups. BIRC3 (n=3), FOXO1 (n=3) and CARD11 (n=2) were found to be mutated only in samples from the DAT+ group. These gene mutations may be involved in disease development and progression, and potentially represent targets for future therapy. The immunoglobulin genotype IGHV4-34 is seen more frequently in DLBCL clones than in normal B cells and has intrinsic autoreactivity to self-antigens on red cells, which is largely mediated by two motifs within the first framework region (FR1); Q6W7 and A24V25Y.26 These motifs form a hydrophobic patch which determines red cell antigen binding and are frequently mutated away from self-reactivity in normal B cells. If this does not occur this may provide constant B cell receptor signalling which encourages lymphoma development, a theory known as antigen driven lymphomagenesis. As with previous studies, IGHV4-34 was over-represented (15.6%) in our DLBCL cohort. Furthermore, of 6 IGHV4-34-expressing DLBCL samples five had unmutated hydrophobic patch mutations providing further evidence for antigen-driven lymphomagenesis. Mutation analysis of these five samples demonstrated high frequency of mutations in several genes, including CREBBP and NCOR2. Further research could explore if mutations in CREBBP and NCOR2 work in conjunction with the preserved QW and AVY motifs to promote lymphomagenesis in IGHV4-34-expressing B cells, and if so, could guide future targeted therapy.