A microtomographic and histopathological evaluation of dental cements as late-stage peri-implant complication in a rat model.

Cement mediated peri-implantitis accounts for 1.9-75% of dental implant failures associated with peri-implant diseases. This study evaluated the biological impact of dental cements on osseointegrated implants using Lewis rats. Twenty-two rats were distributed into 6 groups: negative control (NC) soft diet (SD), and hard diet (HD); positive control SD and HD (n = 3); Implant + bio-ceramic Cement (BC) SD and HD which included contralateral Sham sites (n = 5). Titanium implants were placed on either side of the maxillae and allowed to heal for 14 days. Later, both sides of experimental groups underwent a re-entry surgery to simulate clinical cementation. The right side received 0.60 mg of BC. At 14 days post cement application, maxillae were harvested for clinical, microtomographic, and histological evaluations. Clinical and microtomographic evaluations indicated evidence of extensive inflammation and circumferential bone resorption around BC implants in comparison to NC. Histology revealed cement particles surrounded by inflammatory infiltrate in the implant area accompanied by biofilm for SD groups. Both sides of BC indicated intensive bone resorption accompanied by signs of osteolysis when compared to NC. Cemented groups depicted significantly lower bone to implant contact when compared to NC. In conclusion, residual cement extravasation negatively impacted osseointegrated implants after re-entry surgeries.

Evaluating the Safety of the Intragastric Balloon: Spanish Multicenter Experience in 20,680 Cases and with 12 Different Balloon Models.

INTRODUCTION: Intragastric balloon (IGB) is a minimally invasive and reversible option for obesity treatment. There is a worldwide growing number of different IGB models. The efficacy and safety profile for each model must be demonstrated. We aim to evaluate IGB safety profile according to the experience of the Spanish Bariatric Endoscopy Group (GETTEMO). METHODS: A survey of 37 IGBs safety-related questions was sent to all GETTEMO members, to retrospectively collect a multicenter Spanish registry. Incidence, causes, and resolution of both major and minor complications and adverse events (AEs), including legal consequences, differentiated for each balloon model were evaluated. Secondary outcome was weight loss data to confirm efficacy. RESULTS: Twenty-one Spanish hospitals experienced in IGBs responded. The overall data encompassed 20,680 IGBs, including 12 different models. Mean %TBWL of 17.66 ± 2.5% was observed. Early removal rate due to intolerance was 3.62%. Mean major complications rate was 0.70% (> 1% in Spatz2, HB, and Spatz3 models), mainly complicated gastric ulcer. Minor AEs rate was 6.37%, mainly esophagitis. Nine cases (0.04%) required surgery. A single case of mortality (0.0048%) occurred. Seven lawsuits (0.0034%) were received, all with favorable resolution. CONCLUSIONS: In the Spanish experience accumulating 20,680 IGBs and including 12 different balloon models, a low incidence rate of major complications and minor AEs are observed (0.70% and 6.37%, respectively), mostly resolved with medical/endoscopic management. IGB shows good tolerance and efficacy profile. These safety data are within the accepted quality standards.

DISPEL: A Python Framework for Developing Measures From Digital Health Technologies.

Goal: This paper introduces DISPEL, a Python framework to facilitate development of sensor-derived measures (SDMs) from data collected with digital health technologies in the context of therapeutic development for neurodegenerative diseases. Methods: Modularity, integrability and flexibility were achieved adopting an object-oriented architecture for data modelling and SDM extraction, which also allowed standardizing SDM generation, naming, storage, and documentation. Additionally, a functionality was designed to implement systematic flagging of missing data and unexpected user behaviors, both frequent in unsupervised monitoring. Results: DISPEL is available under MIT license. It already supports formats from different data providers and allows traceable end-to-end processing from raw data collected with wearables and smartphones to structured SDM datasets. Novel and literature-based signal processing approaches currently allow to extract SDMs from 16 structured tests (including six questionnaires), assessing overall disability and quality of life, and measuring performance outcomes of cognition, manual dexterity, and mobility. Conclusion: DISPEL supports SDM development for clinical trials by providing a production-grade Python framework and a large set of already implemented SDMs. While the framework has already been refined based on clinical trials' data, ad-hoc validation of the provided algorithms in their specific context of use is recommended to the users.

Molecular diagnosis of primary CNS lymphoma in 2024 using MYD88Leu265Pro and IL-10.

Early diagnosis is crucial for the successful treatment of primary CNS lymphoma (PCNSL), a rapidly progressing tumour. Suspicion raised on brain MRI must be confirmed by a histopathological diagnosis of a tumour specimen collected by stereotactic biopsy. In rare cases, cerebrospinal fluid (CSF) or vitreous humour might aid in providing a cytological diagnosis. Several disease-related, patient-related, and treatment-related factors affect the timing and accuracy of diagnosis and patient outcome. Some molecules detected in CSF, aqueous and vitreous humour, and peripheral blood were proposed as diagnostic biomarkers for PCNSL; however, detection methods for most of these molecules are not yet standardised, have a long turnaround time, are expensive, and have little reproducibility among labs. By contrast, the MYD88Leu265Pro somatic hotspot mutation, revealed by PCR-based assay, is currently and reliably used during the diagnosis of some lymphomas, and IL-10, measured by enzyme-linked immunosorbent assay, is routinely used to diagnose and monitor different common metabolic and immunological diseases. Several independent studies have shown that MYD88Leu265Pro and IL-10 can be easily assessed in peripheral blood, plasma, aqueous and vitreous humour, and CSF of patients with PCNSL with substantial sensitivity and specificity, especially when evaluated in combination. In this Viewpoint, evidence supporting the routine use of MYD88Leu265Pro and IL-10 in diagnosing PCNSL is considered, and some examples of the frequent difficulties found in the diagnosis of PCNSL are provided, highlighting the role and indications of these two biomarkers to improve the timely recognition of this aggressive tumour.

Immune checkpoint inhibitors-associated thrombosis in patients with head and neck cancer: a study of the Spanish society of medical oncology (SEOM) thrombosis and cancer group.

PURPOSE: Both venous and arterial thrombotic events (VTE/AT) can be associated with Immune Checkpoint Inhibitors (ICI). However, there is a paucity of information apropos patients in routine clinical practice. METHODS: /Patients. This retrospective, multicenter study was promoted by the Thrombosis and Cancer Section of the Spanish Society of Medical Oncology (SEOM). Individuals with head and neck cancer who initiated ICI between 01/01/2015 and 31/12/2021 were recruited. Minimum follow-up was 6 months (except in cases of demise). The primary objective was to calculate the incidence of ICI-associated VTE/AT, with secondary objectives including the analysis of their impact on survival and the identification of variables predictive of VTE/AT. RESULTS: A total of 143 patients with head and neck cancer were enrolled. The incidence of VTE/AT during follow-up (median 8.6 months) was 2.8%. Survival analysis showed no significant differences (p = 0.644) between the group that developed VTE/AT (median 7.13 months, 95% CI 0-22.9) and the group that did not (median 9.86 months, 95% CI 6.3-13.4). The presence of liver metastases was predictive of VTE/AT (p < 0.05). CONCLUSIONS: Thromboembolic disease associated with immunotherapy in patients with head and neck neoplasia does not significantly impact survival. The presence of liver metastases can predict these events.

Impact of Prior Biologic or Janus Kinase Inhibitor Therapy on Efficacy and Safety of Etrasimod in the ELEVATE UC 52 and ELEVATE UC 12 Trials.

BACKGROUND AND AIMS: Etrasimod is an oral, once daily, selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12. METHODS: Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism. RESULTS: In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission (p<0.05) in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p=0.033; experienced: 18.9% vs 13.2%, p=0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [N=90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p=0.030], but not clinical remission [9.8% vs 3.4%, p=0.248], with etrasimod vs placebo. CONCLUSIONS: Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo.

Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial.

BACKGROUND: The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. METHODS: This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. FINDINGS: Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. INTERPRETATION: Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. FUNDING: AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.

Gelatin maleimide microgels for hematopoietic progenitor cell encapsulation.

Hematopoietic stem cells (HSCs) are the apical cells of the hematopoietic system, giving rise to cells of the blood and lymph lineages. HSCs reside primarily within bone marrow niches that contain matrix and cell-derived signals that help inform stem cell fate. Aspects of the bone marrow microenvironment have been captured in vitro by encapsulating cells within hydrogel matrices that mimic native mechanical and biochemical properties. Hydrogel microparticles, or microgels, are increasingly being used to assemble granular biomaterials for cell culture and noninvasive delivery applications. Here, we report the optimization of a gelatin maleimide hydrogel system to create monodisperse gelatin microgels via a flow-focusing microfluidic process. We report characteristic hydrogel stiffness, stability, and swelling characteristics as well as encapsulation of murine hematopoietic stem and progenitor cells, and mesenchymal stem cells within microgels. Microgels support cell viability, confirming compatibility of the microfluidic encapsulation process with these sensitive bone marrow cell populations. Overall, this work presents a microgel-based gelatin maleimide hydrogel as a foundation for future development of a multicellular artificial bone marrow culture system.

Modeling epithelial homeostasis and perturbation in three-dimensional human esophageal organoids.

Background: Esophageal organoids from a variety of pathologies including cancer are grown in Advanced Dulbecco's Modified Eagle Medium-Nutrient Mixture F12 (hereafter ADF). However, the currently available ADF-based formulations are suboptimal for normal human esophageal organoids, limiting the ability to compare normal esophageal organoids with those representing a given disease state. Methods: We have utilized immortalized normal human esophageal epithelial cell (keratinocyte) lines EPC1 and EPC2 and endoscopic normal esophageal biopsies to generate three-dimensional (3D) organoids. To optimize ADF-based medium, we evaluated the requirement of exogenous epidermal growth factor (EGF) and inhibition of transforming growth factor-(TGF)-ß receptor-mediated signaling, both key regulators of proliferation of human esophageal keratinocytes. We have modeled human esophageal epithelial pathology by stimulating esophageal 3D organoids with interleukin (IL)-13, an inflammatory cytokine, or UAB30, a novel pharmacological activator of retinoic acid signaling. Results: The formation of normal human esophageal 3D organoids was limited by excessive EGF and intrinsic TGFß receptor-mediated signaling. In optimized HOME0, normal human esophageal organoid formation was improved, whereas IL-13 and UAB30 induced epithelial changes reminiscent of basal cell hyperplasia, a common histopathologic feature in broad esophageal disease conditions including eosinophilic esophagitis. Conclusions: HOME0 allows modeling of the homeostatic differentiation gradient and perturbation of the human esophageal epithelium while permitting a comparison of organoids from mice and other organs grown in ADF-based media.

Biomaterial-Based Therapeutic Delivery of Immune Cells.

Immune cell therapy (ICT) is a transformative approach used to treat a wide range of diseases including type 1 diabetes, sickle cell disease, disorders of the hematopoietic system, and certain forms of cancers. Despite excellent clinical successes, the scope of adoptively transferred immune cells is limited because of toxicities like cytokine release syndrome and immune effector cell-associated neurotoxicity in patients. Furthermore, reports suggest that such treatment can impact major organ systems including cardiac, renal, pulmonary, and hepatic systems in the long term. Additionally, adoptively transferred immune cells cannot achieve significant penetration into solid tissues, thus limiting their therapeutic potential. Recent studies suggest that biomaterial-assisted delivery of immune cells can address these challenges by reducing toxicity, improving localization, and maintaining desired phenotypes to eventually regain tissue function. In this review, recent efforts in the field of biomaterial-based immune cell delivery for the treatment of diseases, their pros and cons, and where these approaches stand in terms of clinical treatment are highlighted.

Predictive Factors of Non-Inflammatory Small Bowel Obstruction After Bowel Resection in Crohn's Patients.

Background: The aim of the study was to investigate the risk factors associated with the development of small bowel obstruction (SBO) in Crohn's disease (CD) after small bowel resection (SBR) that are not due to active/recurrent inflammation. Methods: We conducted a retrospective cohort study of patients who had SBR for active or complicated CD. Abstracted data included demographics, phenotype, therapies for CD, endoscopic disease recurrence, and several surgical variables. The primary outcome was the development of non-inflammatory SBO (NI-SBO) within 5 years after SBR. Results: A total of 335 patients were included. The cumulative rates of NI-SBO at 6 months, 1 year, and 5 years were 5 (1.5%), 8 (2.4%), and 29 (8.9%), respectively. Variables associated with the development of NI-SBO were active macroscopic or microscopic inflammation in the surgical margins (13 (56%) vs. 65 (27%), P = 0.004), open resection (vs. laparoscopic resection) (12 (41.4%) vs. 60 (19.5%), P = 0.0006) and a higher median number of previous resections (2 (interquartile range (IQR) 2 - 3) vs. 1 (IQR 1 - 2), P = 0.0002). Only 21% of patients who developed NI-SBO required surgical intervention. Conclusions: The incidence of NI-SBO after SBR in CD is low and associated with inflammation at the margins of the resected bowel, previous bowel resections, and an open laparotomy approach. Most NI-SBOs resolve with medical management.

Netrin G1 Ligand is a new stromal immunomodulator that promotes pancreatic cancer.

Understanding pancreatic cancer biology is fundamental for identifying new targets and for developing more effective therapies. In particular, the contribution of the stromal microenvironment to pancreatic cancer tumorigenesis requires further exploration. Here, we report the stromal roles of the synaptic protein Netrin G1 Ligand (NGL-1) in pancreatic cancer, uncovering its pro-tumor functions in cancer-associated fibroblasts and in immune cells. We observed that the stromal expression of NGL-1 inversely correlated with patients' overall survival. Moreover, germline knockout (KO) mice for NGL-1 presented decreased tumor burden, with a microenvironment that is less supportive of tumor growth. Of note, tumors from NGL-1 KO mice produced less immunosuppressive cytokines and displayed an increased percentage of CD8 + T cells than those from control mice, while preserving the physical structure of the tumor microenvironment. These effects were shown to be mediated by NGL-1 in both immune cells and in the local stroma, in a TGF-ß-dependent manner. While myeloid cells lacking NGL-1 decreased the production of immunosuppressive cytokines, NGL-1 KO T cells showed increased proliferation rates and overall polyfunctionality compared to control T cells. CAFs lacking NGL-1 were less immunosuppressive than controls, with overall decreased production of pro-tumor cytokines and compromised ability to inhibit CD8 + T cells activation. Mechanistically, these CAFs downregulated components of the TGF-ß pathway, AP-1 and NFAT transcription factor families, resulting in a less tumor-supportive phenotype. Finally, targeting NGL-1 genetically or using a functionally antagonistic small peptide phenocopied the effects of chemotherapy, while modulating the immunosuppressive tumor microenvironment (TME), rather than eliminating it. We propose NGL-1 as a new local stroma and immunomodulatory molecule, with pro-tumor roles in pancreatic cancer. Statement of Significance: Here we uncovered the pro-tumor roles of the synaptic protein NGL-1 in the tumor microenvironment of pancreatic cancer, defining a new target that simultaneously modulates tumor cell, fibroblast, and immune cell functions. This study reports a new pathway where NGL-1 controls TGF-ß, AP-1 transcription factor members and NFAT1, modulating the immunosuppressive microenvironment in pancreatic cancer. Our findings highlight NGL-1 as a new stromal immunomodulator in pancreatic cancer.

General Direct Anticancer Effects of Deer Growing Antler Extract in Several Tumour Cell Lines, and Immune System-Mediated Effects in Xenograft Glioblastoma.

Deer antlers are the fastest growing tissue. Because they are based on proto-oncogenes, to avoid the risk of cancer, antlers evolved strong anticancer mechanisms, and thus their extract (DVA) is effective also against the few human tumours studied so far. We assessed whether DVA is a general anticancer compound by testing the direct effects in cells of different tumours: glioblastoma (GBM; lines U87MG and U251), colorectal (CRC; lines DLD-1, HT-29, SW480, and SW620), breast cancer (BRCA; lines MCF7, SKBR3, and PA00), and leukaemia (THP-1). DVA reduced the viability of tumours but not healthy cells (NHC; lines 293T and HaCaT). Mobility decreased at least for the longest test (72 h). Intraperitoneal/oral 200 mg DVA/kg administration in GBM xenograft mice for 28 d reduced tumour weight by 66.3% and 61.4% respectively, and it also reduced spleen weight (43.8%). In addition, tumours treated with DVA showed symptoms of liquefactive necrosis. Serum cytokines showed DVA up-regulated factors related to tumour fighting and down-regulated those related to inducing immune tolerance to the tumour. DVA shows general anticancer effects in the lines tested and, in GBM mice, also strong indirect effects apparently mediated by the immune system. DVA may contain a future anticancer medicine without secondary effects.

Abiotic Stress Tolerance Boosted by Genetic Diversity in Plants.

Plant breeding [...].

Etrasimod for the Treatment of Ulcerative Colitis: Analysis of Infection Events From the ELEVATE UC Clinical Program.

BACKGROUND AND AIMS: Infections are a safety concern in patients with ulcerative colitis (UC). Etrasimod is an oral, once-daily (QD), selective sphingosine 1phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. It leads to selective and reversible lymphocyte sequestration, and partial peripheral lymphocyte count decrease. We report infection events from the phase 3 ELEVATE program. METHODS: Proportions, incidence rates (IRs; per 100 patient-years) and descriptive analyses of all, serious, severe, herpes zoster, and opportunistic infections are reported in the Pivotal UC cohort (ELEVATE UC 52 and ELEVATE UC 12). Cox regression models evaluated potential baseline risk factors. RESULTS: In this analysis (n=787), proportions (IRs) of all infection events were similar for patients receiving etrasimod 2 mg QD (18.8% [41.1]) or placebo (17.7% [49.0]). Serious infections occurred in three (0.6%) and five (1.9%) patients receiving etrasimod and placebo, respectively. Two herpes zoster events were reported in each group (etrasimod: 0.4%; placebo: 0.8%); all localized and non-serious. One opportunistic infection event was reported in each group. No patient with an absolute lymphocyte count (ALC) <0.2 × 109/L reported serious/severe or opportunistic infections; no baseline risk factors were identified for such events. No deaths occurred. CONCLUSIONS: Patients receiving etrasimod demonstrated no increased risk of infection. The incidence of serious infections and herpes zoster was similar in each group. Among patients receiving etrasimod, no association between ALC <0.5 × 109/L and infection events was observed. Longer-term follow-up will further characterize the etrasimod safety profile.

Tissue mimicking materials and finger phantom design for pulse oximetry.

Pulse oximetry represents a ubiquitous clinical application of optics in modern medicine. Recent studies have raised concerns regarding the potential impact of confounders, such as variable skin pigmentation and perfusion, on blood oxygen saturation measurement accuracy in pulse oximeters. Tissue-mimicking phantom testing offers a low-cost, well-controlled solution for characterizing device performance and studying potential error sources, which may thus reduce the need for costly in vivo trials. The purpose of this study was to develop realistic phantom-based test methods for pulse oximetry. Material optical and mechanical properties were reviewed, selected, and tuned for optimal biological relevance, e.g., oxygenated tissue absorption and scattering, strength, elasticity, hardness, and other parameters representing the human finger's geometry and composition, such as blood vessel size and distribution, and perfusion. Relevant anatomical and physiological properties are summarized and implemented toward the creation of a preliminary finger phantom. To create a preliminary finger phantom, we synthesized a high-compliance silicone matrix with scatterers for embedding flexible tubing and investigated the addition of these scatterers to novel 3D printing resins for optical property control without altering mechanical stability, streamlining the production of phantoms with biologically relevant characteristics. Phantom utility was demonstrated by applying dynamic, pressure waveforms to produce tube volume change and resultant photoplethysmography (PPG) signals. 3D printed phantoms achieved more biologically relevant conditions compared to molded phantoms. These preliminary results indicate that the phantoms show strong potential to be developed into tools for evaluating pulse oximetry performance. Gaps, recommendations, and strategies are presented for continued phantom development.

Marginal zone lymphoma international prognostic index: a unifying prognostic index for marginal zone lymphomas requiring systemic treatment.

Background: Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy. Methods: Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami. Findings: We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin <12 g/dL, absolute lymphocyte count <1 × 109/L, platelets <100 × 109/L, and MZL subtype (nodal or disseminated) were independently associated with inferior PFS. The proposed MZL International Prognostic index (MZL-IPI) combined these 5 factors, and we defined low (LRG, 0 factors, 27%), intermediate (IRG, 1-2 factors, 57%) and high (HRG, 3+ factors, 16%) risk groups with 5-y PFS of 85%, 66%, and 37%, respectively (c-Harrell = 0.64). Compared to the LRG, the IRG (Hazard Ratio [HR] = 2.30, 95% CI 1.39-3.80) and HRG (HR = 5.41, 95% CI 3.12-9.38) had inferior PFS. Applying the MZL-IPI to the pooled US cohort (N = 353), 94 (27%), 192 (54%), and 67 (19%) patients were classified as LRG, IRG, and HRG, respectively, and the model was validated for PFS (log-rank test p = 0.0018; c-Harrell = 0.578, 95% CI 0.54-0.62). The MZL-IPI was also prognostic for OS in both the training and the external validation sets. Interpretation: MZL-IPI is a new prognostic score for use in all patients with MZL considered for systemic treatment. Funding: The MER was supported by P50 CA97274 and U01 CA195568.

Targets and treatments in primary CNS lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive lymphoma entirely localized in the central nervous system or vitreoretinal space. PCNSL generally initially responds to methotrexate-containing chemotherapy regimens, but progressive or relapsing disease is common, and the prognosis is poor for relapsed or refractory (R/R) patients. PCNSL is often characterized by activation of nuclear factor kappa B (NF-κB) due to mutations in the B-cell receptor (BCR) or toll-like receptor (TLR) pathways, as well as immune evasion. Targeted treatments that inhibit key PCNSL mechanisms and pathways are being evaluated; inhibition of Bruton's tyrosine kinase (BTK) downstream of BCR activation has demonstrated promising results in treating R/R disease. This review will summarize the evidence and potential for targeted therapeutic agents to improve treatment outcomes in PCNSL. This includes immunotherapeutic and immunomodulatory approaches and inhibitors of the key pathways driving PCNSL, such as aberrant BCR and TLR signaling.

Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme.

BACKGROUND AND AIMS: Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, oncedaily, selective sphingosine 1phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. METHODS: Patients, including those with isolated proctitis (<10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. RESULTS: We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p<0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. CONCLUSIONS: Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52.

Liquid biopsy for improving diagnosis and monitoring of CNS lymphomas: A RANO review.

BACKGROUND: The utility of liquid biopsies is well documented in several extracranial and intracranial (brain/leptomeningeal metastases, gliomas) tumors. METHODS: The RANO (Response Assessment in Neuro-Oncology) group has set up a multidisciplinary Task Force to critically review the role of blood and cerebrospinal fluid (CSF)-liquid biopsy in CNS lymphomas, with a main focus on primary central nervous system lymphomas (PCNSL). RESULTS: Several clinical applications are suggested: diagnosis of PCNSL in critical settings (elderly or frail patients, deep locations, and steroid responsiveness), definition of minimal residual disease, early indication of tumor response or relapse following treatments, and prediction of outcome. CONCLUSIONS: Thus far, no clinically validated circulating biomarkers for managing both primary and secondary CNS lymphomas exist. There is need of standardization of biofluid collection, choice of analytes, and type of technique to perform the molecular analysis. The various assays should be evaluated through well-organized central testing within clinical trials.