45 year-old male with Becker muscular dystrophy (BMD), dilated cardiomyopathy (DCM) and reduced left ventricular ejection fraction (LVEF) developed ventricular tachycardia (VT), successfully treated with appropriate shocks from his cardioverter-defibrillator (ICD). Substrate ablation was planned, and although cardiac magnetic resonance (CMR) was performed, interpretation was impaired due to significative lead artifact. Epicardial access was obtained; electroanatomical (EA) mapping revealed a large area of low-amplitude, fractionated and delayed electrograms (EGMs) in left ventricular inferolateral wall. Coronary angiography and phrenic nerve (PN) stimulation were conducted to prevent damage to sensitive structures. Radiofrequency (RF) ablation was performed, achieving near-complete abolition of targeted potentials.

Background: The safety and cost of concomitant atrial fibrillation (AF) ablation and left atrial appendage occlusion (LAAO) procedure remain unknown. Objective: The study sought to determine real-world outcomes of AF patients who underwent LAAO with ablation. Methods: The National Inpatient Sample and International Classification of Diseases–Tenth Revision codes were used to identify patients who underwent LAAO with and without AF ablation during the years 2016-2022. The outcomes assessed included procedural complications and resource utilization. Results: LAAO with AF ablation was associated with a higher rate of overall complications (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.37-1.74), major complications (OR 1.38, 95% CI 1.18-1.60), non-home discharge (OR 1.55, 95% CI 1.23-1.96), prolonged length of stay >1 day (OR 3.21, 95% CI 2.92-3.52), and increased hospitalization costs as defined by median cost >$25,926 (OR 19.42, 95% CI 16.21-23.25) when compared to LAAO alone after adjustment for potential confounding variables. Patients who underwent LAAO with ablation were also more likely to receive pacemaker implantation (3.6 % vs 0.2%, P < 0.001) and experience acute kidney injury (3.9% vs 2.1%, P < 0.001) and non-ST elevation myocardial infarction (3.7% vs 1.5%, P < 0.001). Conclusion: In a large, contemporary, real-world study of LAAO procedures in the United States, concomitant AF ablation was associated with a higher rate of overall and major complications and an increased resource utilization.

Toddler cavotricuspid valve isthmus ablation for typical atrial flutter with cryoablationAuthors:Mohammad A Ebrahim | Department of Pediatrics, Kuwait University Faculty of Medicine, affiliated with Chest Diseases Hospital, Kuwait | mohammad.ebrahim@ku.edu.kwHasan Majid | Kuwait University Faculty of Medicine | Hassan.sgnote3@gmail.comMohamed A Abdelnaby | Department of Pediatric Cardiology, Chest Diseases Hospital, Ministry of Health, Kuwait | mohamedabass83@outlook.comJ. Philip Saul, MD | Professor of Pediatrics, West Virginia University School of Medicine | sauljp9@gmail.comCorresponding Author:Mohammad A Ebrahim, MDMohdi84@gmail.com or mohammad.ibrahim@hsc.edu.kwPhone: +965 90977894 ; + 965 25319486Address:Jabriya, Block 4, Street 102, Postal Office 46300Disclosures: NoneNo conflicts of interest

Extranodal lymphoplasmacytic lymphoma responding rapidly to Zanubrutinib: A Case SeriesAuthors[1] Mr. Samuel Brown, BA (Cantab.), University of Cambridge Clinical School of Medicinesb2382@cam.ac.ukORCID: 0009-0000-8484-5411[1] Miss Jillian Rusbridge, BA (Cantab.), University of Cambridge Clinical School of Medicinejillian.rusbridge@nhs.netORCID: 0009-0006-1678-1659[2] Professor Dr. George FollowsORCID: tbc[3] Dr Anna Santarsieri MA (Cantab.), MBBS, MRCP, FRCPath, MD,ORCID: 0000-0002-4449-2196.Author ContributionsMr SB and Miss JR wrote the initial manuscript with equal contribution, which has been reviewed and edited by Professor GF and Dr AS.Conflicts of InterestNo authors have any conflicts of interest to be declared.ConsentWritten informed consent was obtained from Patients A, B and C to publish this report in accordance with the journal’s patient consent policy.Key Clinical MessageManagement of recurrent or atypical Lymphoplasmacytic lymphoma poses a significant therapeutic challenge. Here we demonstrate a case series of three patients with atypical presentations of extranodal lymphoplasmacytic lymphoma that each show remarkable and timely responses to Zanubrutinib with limited side effect profile.Introduction Lymphoplasmacytic lymphomas (LPL) are a rare group of non-Hodgkin lymphoma, involving post-germinal centre B-cell lymphoproliferation with, usually, IgM monoclonal gammopathy. When IgM paraprotein is produced, this disease can be termed Waldenström’s Macroglobulinemia (WM) [1]. They are indolent but incurable diseases. The incidence of LPL is reported to be 0.27 and WM 0.36 per 100,000 people in the USA, based on cancer registry data [4]. WM has a median age of onset of 65-70 years [5] and a median survival of 5.3 years for those [6]. More than 95% of WM demonstrate an L265P mutation in the adaptor protein MYD88 (Myeloid Differentiation Primary Response 88) involved in IRAK1 and NF-κB signalling, promoting cell survival. [7] This mutation leads to the constitutive homodimerisation of MYD88 and subsequent recruitment and activation of several intracellular molecules, including Bruton Tyrosine Kinase, as well as PI3K/AKT and MAPK/ERK1/2. [8]The symptoms of WM are largely due to bone marrow infiltration and associated cytopaenias, but initial presentation commonly includes constitutional symptoms such as weight loss and fatigue [1]. Further common presentations of WM include moderate hepatosplenomegaly and lymphadenopathy as well as anaemia due to increased plasma volume. Occasionally, platelet dysfunction or coagulopathy may be observed due to paraproteinaemia [1]. Another specific complication of the IgM paraprotein is blood hyperviscosity. Aside from increasing the risk of headaches and strokes [9], some of the most frequent vessels affected are those of the retina. Thus, a common consequence of hyperviscosity is visual changes due to retinal haemorrhages and engorged veins [1]. Furthermore, the paraprotein may induce an inflammatory response, and cause neuropathies [9].Management of symptomatic patients with WM generally includes Rituximab as monotherapy, or in combination with chemotherapy (e.g. bendamustine, cyclophosphamide and dexamethasone, chlorambucil, or fludarabine) [3]. These therapies confer good 2-year progression-free survival (PFS) of 89% with Rituximab and Bendamustine and 81% with Bortezomib, Dexamethasone, Rituximab and Cyclophosphamide in a recent meta-analysis [10]; but chemotherapy is associated with side effects including gastrointestinal symptoms, cytopenias, risk of infections and neutropenic sepsis, and the longer-term risk of secondary cancers [11]. Also there is a limited number of lines of chemotherapy that can be used due to cumulative toxicity.More recently, BTK inhibitors (Ibrutinib, Zanubrutinib) have been licensed for WM and Zanubrutinib has been approved by NICE for treatment of patients with relapsed WM [2]. BTK inhibitors reduce the pro-survival downstream signalling from dysregulated MYD88 (L265P) homodimers [7] These targeted therapies have revolutionised WM treatment, with a high response rate and favourable safety profile [12].Here we present three patients with rare extranodal manifestations of WM, each with the MYD88 L265P mutation, and assess their response to the BTK inhibitor Zanubrutinib. The first of these three patients, Patient A, had a cutaneous relapse of WM. Cutaneous WM encompasses IgM bullous disease, IgM-storage papules, and neoplastic cell infiltrates [13]. There is limited literature about the use of Zanubrutinib to treat cutaneous presentations of WM.Patient B had orbital infiltration of WM, leading to periorbital swelling and diplopia. There are very few reports of this presentation in the literature; those reported are usually bilateral. Treatment for orbital infiltration is poorly defined, but has previously included solely chemotherapy, or a chemoradiotherapy combination [14].Patient C presented with a decline in mobility and cognition and was found to have nodular leptomeningeal infiltration. Bone marrow biopsy confirmed MYD88 L265P mutation and histology consistent with LPL. Patient C’s condition was deemed highly likely to be Bing Neel syndrome (BNS), a rare presentation, caused by central nervous system (CNS) involvement by LPL [15]. BNS is usually diagnosed by LPL findings on biopsy of cerebrum or meninges, which Patient C declined, or LPL cells in cerebrospinal fluid (CSF) [15].3 Case History and examination3.1 Patient APatient A was first diagnosed with WM in 2011 at the age of 76 years, having presented with night sweats, weight loss, generalised debility, lymphadenopathy and bone marrow failure. He had an IgM paraprotein of 17g/L and bone marrow trephine biopsy revealed a lymphoplasmacytoid infiltrate of >50%. He underwent four cycles of fludarabine-cyclophosphamide combination chemotherapy which he completed in January 2012. He subsequently relapsed and completed four cycles of Rituximab-Bendamustine chemotherapy in September 2014. Treatment was stopped at this point due to pancytopenia and he subsequently suffered with recurrent infections. He was commenced on immunoglobulin replacement therapy for panhypogammaglobulinaemia. He remained in remission from lymphoma until 2022, when he had an atypical, rare relapse.3.2 Patient B Patient B was diagnosed with LPL in December 2021, at the age of 69 years. She presented with exertional breathlessness and pancytopenia. She initially required blood transfusion, and bone marrow trephine biopsy demonstrated 60% infiltration with LPL. MYD88 L265P mutation was detected by PCR. She had a low-level IgM paraprotein of 11g/L. A staging CT scan revealed no lymphadenopathy or splenomegaly. Treatment with Rituximab monotherapy was commenced, and she completed four cycles. She had an excellent response to treatment with normalisation of the haemoglobin, a fall in the paraprotein to <2g/L, and she was able to resume her previous activities, including cycling. However, in November 2022, the LPL began to relapse with pancytopenia and a rise in the IgM paraprotein to 7g/L. A restaging CT scan revealed multiple enlarged abdominal and left pelvic lymph nodes. She was treated again with four cycles of Rituximab monotherapy and prednisolone, and once again responded well to treatment, until 2023 when, like patient A, she presented with a rare, but distinct relapse.3.3 Patient CPatient C, unlike patients A and B, had a rare, atypical presentation of LPL as his first presentation, rather than as a relapse. He was diagnosed with LPL in May 2023 at the age of 70 years, having presented with a gradual decline in mobility and cognition over 12-18 months.Investigations and treatment4.1 Patient AIn 2022, patient A developed an ulcer on his left ankle with associated cellulitis, which, when biopsied was in keeping with a low-grade lymphoma. On analysis, it was confirmed MYD88 L265P mutation was present, as with his original lymphoma, however there was no detectable paraprotein in his blood. He underwent a CT scan, which revealed multiple cutaneous and subcutaneous lesions on both sides of the diaphragm. Given widespread disease, radiotherapy was not a treatment option. As Ibrutinib had stopped being funded on the NHS for LPL, the decision was made to wait for Zanubrutinib to become available. Throughout the year he developed further skin lesions (Figure 1) that came and went, predominantly on his lower legs, and small, palpable groin nodes, though his blood counts remained stable, still with no detectable paraprotein. When reviewed again in August of 2023, the clinical picture was the same, with no palpable lymphadenopathy or hepatosplenomegaly. His blood counts were stable, but he still had firm nodular lesions, and the non-tender, indurated erythematous purple plaques that they would leave behind. These plaques were now also noted on his abdomen, left chest and left upper arm. Biopsy of these plaques confirmed that they were, as suspected, the LPL.When reviewed in clinic in January 2024, it was evident that the nodules on his lower legs were interfering with his daily activities. In particular, a recent lesion on his left medial ankle was open and weeping, having rubbed on footwear. He also exhibited an itchy rash on his chest, with pink macules of approximately 1cm. The decision was made to start treatment with Zanubrutinib, 320mg daily, along with an antihistamine.4.2 Patient BIn October 2023, patient B presented with bilateral proptosis (Figure 2) and binocular vertical diplopia. Examination in the ophthalmology clinic revealed right superior oblique weakness with secondary left inferior rectus under action. There was also bilateral restriction of abduction and elevation with a restriction of right adduction. An urgent MRI of the brain and orbits demonstrated soft tissue infiltration bilaterally in the superior intra-orbital regions with no evidence of brain involvement. Right orbital biopsy was performed and confirmed recurrent LPL. At this time her haemoglobin was normal and <2g/L IgM paraprotein was detectable. A restaging CT scan showed small volume enlarged lymph nodes in the right lower cervical and axillary regions and a mesenteric mass which had reduced in size compared with her previous imaging and measured 45 x 17mm. Zanubrutinib was commenced in December 2023, at a dose of 320mg daily.4.3 Patient CMRI head revealed unusual nodular leptomeningeal infiltration and an extra-parenchymal paranasal ethmoid mass. The diagnosis of LPL was confirmed on bone marrow examination and on biopsy of the ethmoid mass, with presence of MYD88 L265P mutation. He had a low-level IgM paraprotein of 4g/L. Although Patient C did not undergo a brain biopsy and no lymphoma cells were found in the CSF, it was felt highly likely that he had BNS, with leptomeningeal involvement with LPL. A baseline PET-CT scan identified scattered metabolically active lesions within the axial skeleton, but no lymphadenopathy or hepatosplenomegaly.Treatment options were discussed including high-dose methotrexate and intrathecal methotrexate versus Zanubrutinib, which can be accessed in specific circumstances for the first-line setting for LPL using private healthcare insurance. There have been reports of successful treatment of BNS using Zanubrutinib [16]. He chose to start treatment with Zanubrutinib.Outcome and follow-up5.1 Patient APatient A observed a reduction in the size of the cutaneous lesions after day 4 of Zanubrutinib, and the ulcerating lesion on his ankle had begun to heal. By day 12, when reviewed in clinic, the patient estimated that the skin lesions had halved in size and reported no side effects. When reviewed again 5 days later however, he reported marked fatigue, sleepiness, and anorexia, so was advised to halve the dose of Zanubrutinib to 160mg daily. His pruritis resolved, and on day 26 of treatment when reviewed again in clinic, he continued to exhibit a profound reduction in size of the lesions.After 8 weeks of treatment the cutaneous lesions had continued to regress, leaving behind only skin discoloration. The patient continued to experience fatigue as a side effect, having increased his dose to 160mg BD. He was therefore again prescribed half the dose for the next month. He continued taking Zanubrutinib, and after 7 months of treatment he continues on standard dose therapy, the skin lesions remain flat, his blood counts are stable and there is no detectable paraprotein.5.2 Patient BWhen seen for a 2-week follow-up, patient B’s eyes were less erythematous and swollen, but the diplopia remained. She had experienced no side effects of Zanubrutinib and was feeling well. At 4 weeks the diplopia was improved, and she was prescribed a further two cycles of Zanubrutinib 320mg once daily. At 96 days, the proptosis was improved but not completely resolved; Carmellose eye drops were used for symptom relief. At 3 months after starting Zanubrutinib, the diplopia had resolved, and her vision was 6/6 in both eyes.5.3 Patient CWithin the first month, Patient C experienced an improvement in his memory and in his mobility and balance. After 3 months of Zanubrutinib 320mg daily, he had an MRI head which showed that both the leptomeningeal disease and ethmoid mass were responding (Figure 3). The interim PET-CT scan showed reduction in fluorodeoxyglucose uptake at all skeletal sites in keeping with a complete metabolic remission. He continues treatment with Zanubrutinib and has an ongoing excellent response 16 months after starting Zanubrutinib. He has tolerated the treatment well and has a very mild sensory neuropathy affecting his feet, but reports no other side effects.DiscussionLymphoplasmacytic lymphoma is a rare haematological malignancy involving post-germinal centre B-cell lymphoproliferation. It typically presents with constitutional features, as well as cytopaenias due to bone marrow infiltration [1]. There has been good evidence for Zanubrutinib, a selective BTK inhibitor, in the treatment of LPL [17]. While there are documented cases of extranodal manifestations of the disease leading to tissue-specific symptoms, there is minimal reported evidence of the response of these cases to Zanubrutinib.There are few reported cases of cutaneous presentations of LPL. In 2020, a retrospective study [18] characterised the disease in nineteen patients with WM with cutaneous manifestations. Seven of these patients had cutaneous involvement associated with histological transformation to large B-cell lymphoma, but twelve of these patients had non-transformed WM. Amongst those without transformation, skin lesions preceded diagnosis in two cases, in four cases the lesions were concomitant with diagnosis, and six cases with WM preceded occurrence with median delay of 3.5 years. Non-transformed WM patients developed plaques (83%), nodules or tumours (42%) or papules (25%). A systematic review has been published looking at primary macroglobulinaemia-induced immunobullous dermatosis [19], however this article also included ‘IgM monoclonal gammopathy of undetermined significance’ as well as WM patients.Cutaneous presentations of WM may be treated with BTK inhibitors, but again the literature on this is limited. Ibrutinib is a first class BTK inhibitor, efficacious in treating WM. One case report demonstrated a good response, sustained at 18 months [20], but with severe toxicities that led to the choice of the more selective, next generation Zanubrutinib in its place [17]. In a two-person case series of the use of Zanubrutinib for cutaneous LPL, one patient experienced near complete remission, while the other relapsed and sadly died, and as such, the authors hypothesised that the cutaneous lesions progress with the development of the underlying disease regardless of treatment [13]. We present Patient A as a case of cutaneous LPL trialled on Zanubrutinib, showing excellent response, exhibiting evidence for the use of Zanubrutinib in similar future cases. This patient observed rapid reduction in tumour size within from the first few days of treatment. Patient A reported fatigue, a well-documented side effect of Zanubrutinib [21] which was managed successfully with dose reduction.Orbital involvement with low-grade non-Hodgkin lymphoma is very commonly due to marginal zone lymphoma (MZL) [22]. There are a limited number of published cases detailing orbital involvement of LPL or WM. A systematic review [14] detailed 18 cases including their own, dating back to 1967. They explored different ocular manifestations, including unilateral and bilateral orbital masses, infiltration of rectus muscle and lacrimal gland involvement. Another case [23] details a patient with orbital mass and extra-ocular muscle involvement, who went on to be treated with ibrutinib monotherapy, followed by rituximab, bortezomib (a proteasome inhibitor) and dexamethasone following disease relapse. This patient remained stable for over 3 years before orbital swelling recurred. Patient B presented with a history of WM, diplopia and proptosis. MRI revealed intraorbital soft tissue infiltration with effect on extra-orbital muscle action, and she was trialled on Zanubrutinib. She showed marked improvement within the first month, and at 3 months her diplopia had resolved.Orbital involvement in WM has also been demonstrated in patients with BNS, [24,25] a rare manifestation of WM involving infiltration of LPL of the CNS causing neurological deficits [15]. One case report described treatment with Ibrutinib leading to resolution of bilateral optic nerve swelling. Other cases of orbital involvement of WM in association with BNS , differed in their treatment regimens (without the use of zanubrutinib), with some success [24, 25, 26]. This contrasts with other cases in which despite aggressive chemotherapeutic treatment, patients had only partial resolution or suffered severe vision loss or total blindness. [27, 28]While patient B did not display evidence of having BNS, Patient C did have a clinical picture and investigations consistent with BNS. The marked improvement in neurological and MRI signs following Zanubrutinib in this patient provides further evidence for this treatment for BNS. Elsewhere in the literature, in a case series of 44 WM patients, BNS developed at a median time of 4 years from diagnosis, although in 36% of these patients BNS was the first manifestation [29] of WM. Ibrutinib has been shown in a cohort study of 28 patients to lead to an 85% improvement or resolution of BNS symptoms and 47% clearance of disease from CSF [30]. There has also been a report of Zanubrutinib as a monotherapy [16] following unsuccessful treatment of WM in a 75-year-old female with rituximab, cyclophosphamide, vincristine and prednisolone. She re-presented with difficulty walking, and subsequent investigation revealed contrast enhancing lesions on MRI and CSF showing an increased total protein and lambda light chain restricted monoclonal B cells. She was diagnosed with BNS and received 12 cycles of high dose intravenous methotrexate. Unfortunately, the neurological dysfunction worsened, and she was trialled on 160mg BD Zanubrutinib which led to marked neurological improvement and maintained IgM paraprotein below 2g/L at 15 months.In conclusion, we present here three cases of a rare malignancy, lymphoplasmacytic lymphoma, with extranodal manifestations that are rarer still, namely: cutaneous, optic and leptomeningeal. Not only do we provide case studies of reference for these unusual presentations, but also provide insight into the ability of the next-generation BTK inhibitor, Zanubrutinib, to rapidly and successfully treat them. Two of these patients were treated in relapse, one as first line, but all exhibited rapid and complete improvement (though will continue to be monitored long-term). Moreover, in contrast to chemotherapy, side effects were minimal if any, including fatigue and mild peripheral neuropathy. These results are encouraging, and we recommend that further studies with larger patient cohorts should be conducted on the therapeutic benefit of Zanubrutinib, particularly in relapsed, atypical cases of LPL.References[1] A.V. Hoff brand, P.A.H. Moss. Essential Haematology – 6th ed. ISBN 978-1-4051-9890-5[2] Final scope for the appraisal of zanubrutinib for treating Waldenström’s macroglobulinaemia Issue Date: October 2020. National Institute for Health and Care Excellence 2020.[3] Pratt, G. et al (2022) Diagnosis and management of Waldenström macroglobulinaemia-A British Society for Haematology guideline. British Journal of Haematology. DOI: 10.1111/bjh.18036[4] McMaster, M. (2023) The epidemiology of Waldenström macroglobulinemia. Seminars in Hematology. 10.1053/j.seminhematol.2023.03.008[5] Varettoni, M. et al. (2019) Waldenström Macroglobulinemia in Young Patients Treated in the Modern Era: A Multi-Institutional Italian Study. Blood. DOI: 10.1002/ajh.25961.[6] Kastritis E. et al. (2015) Competing risk survival analysis in patients with symptomatic Waldenström macroglobulinemia: the impact of disease unrelated mortality and of rituximab-based primary therapy. Haematologica. DOI: 10.3324/haematol.2015.124149[7] Varettoni, M. et al. (2013) Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenström’s macroglobulinemia and related lymphoid neoplasms. Blood. DOI: 10.1182/blood-2012-09-457101[8] Treon, S. et al. (2020) Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies. Journal of Clinical Oncology. DOI: 10.1200/JCO.19.02314[9] Owen, R. et al. (2014) Guidelines on the diagnosis and management of Waldenström macroglobulinaemia. British Journal of Haematology. DOI: 10.1200/JCO.19.02314[10] Chane, W. et al (2023) Efficacy and safety of front-line treatment regimens for Waldenstrom macroglobulinaemia: a systematic review and meta-analysis. Blood Cancer Journal. DOI: 10.1038/s41408-023-00916-5[11] Paludo, J. et al (2018) Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia. Annals of Hematology. DOI: 10.1007/s00277-018-3311-z[12] Sarosiek, S. et al. (2024) Waldenström Macroglobulinemia: Targeted Agents Taking Center Stage. Drugs. DOI: 10.1007/s40265-023-01974-6[13] Appenzeller, P. et al. (1999) Cutaneous Waldenstrom macroglobulinemia in transformation. American Journal of Dermatopathology. DOI: 10.1097/00000372-199904000-00007[14] Paggi, R. et al. (2023) Orbital Infiltration in a Patient with Waldenström Macroglobulinemia: Need for Multidisciplinary Approach and Comparison with the Literature. Mediterranean Journal of Hematology and Infectious Diseases. DOI: 10.4084/MJHID.2023.028[15] Castillo JJ. et al. (2019) How we manage Bing-Neel syndrome. British Journal of Haematology. DOI: 10.1111/bjh.16167[16] Wong, J. et al. (2018) Efficacy of Zanubrutinib in the Treatment of Bing-Neel Syndrome. Hemasphere. DOI: 10.1097/HS9.0000000000000155[17] Deshpande, A. et al. (2022) Zanubrutinib in Treating Waldenström Macroglobulinemia, the Last Shall Be the First. Therapeutics and Clinical Risk Management. DOI: 10.2147/TCRM.S338655[18] Stien, S. et al. (2020) Cutaneous Involvement in Waldenström’s Macroglobulinaemia. Acta Derma Venereologica. DOI: 10.2340/00015555-3535[19] Armolo IF. Et al. (2023) Primary macroglobulinemia-induced immunobullous dermatosis: A systematic review. International Journal of Dermatology. DOI: 10.1111/ijd.16546[20] Lindhold, KE. (2021) Ibrutinib response in cutaneous transformed lymphoplasmacytic lymphoma. EJHaem. DOI: 10.1002/jha2.253[21] Zanubrutinib (Brukinsa): CADTH Reimbursement Review: Therapeutic area: Waldenström macroglobulinemia (2022) Canadian Agency for Drugs and Technologies in Health.[22] Olsen, TG. Et al. (2019) Orbital lymphoma. Survey of Ophthalmology. DOI: 10.1016/j.survophthal.2018.08.002[23] Guerin, C. et al. (2022) Orbital involvement in Waldenstrom macroglobulinaemia: a multidisciplinary approach. Irish Journal of Medical Science. DOI: 10.1007/s11845-021-02846-2[24] Gavriatopoulou, M. et al. (2019) Treatment of Bing–Neel syndrome with first line sequential chemoimmunotherapy. Medicine. DOI: 10.1097/MD.0000000000017794[25] Stacy, RC. Et al. Orbital Involvement in Bing-Neel Syndrome. Journal of Neuro-Ophthalmology. DOI: 10.1097/WNO.0b013e3181dee96c[26] Hughes, MS. Et al. (2014) Isolated Optic Nerve, Chiasm, and Tract Involvement in Bing–Neel Syndrome. Journal of Neuro-Ophthalmology. 10.1097/WNO.0000000000000138[27] Doshi, RR. Et al. (2011) Orbital involvement in Bing-Neel syndrome. Journal of Nueo-Ophthalmology. DOI: 10.1097/WNO.0b013e31820ecbc1[28] Cuenca Hernandez, R. et al. (2015) Bing-Neel syndrome as an initial sign of Waldenström macroglobulinaemia associated with orbital infiltration. DOI: 10.1016/j.nrleng.2013.04.007[29] Simon, L. et al (2015) Bing-Neel syndrome, a rare complication of Waldenström macroglobulinemia: analysis of 44 cases and review of the literature. Haematologica. DOI: 10.3324/haematol.2015.13374[30] Castillo, JJ. et al. (2019) Ibrutinib for the treatment of Bing-Neel syndrome: a multicenter study. Blood. DOI: 10.1182/blood-2018-10-879593FiguresFigure 1

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Avian tracking studies have proliferated due to the miniaturization of tags and the opportunities for massive data collection facilitated by an extensive satellite and cellular infrastructure. However, assessments of the effects of tags on the behaviour and survival of birds are rarely conducted and disseminated – raising animal welfare concerns, risking project failure, and hindering the optimization of tagging methods within the ornithological community. Here we quantified the effects of tags on banded dotterels (Anarhynchus bicinctus) – a threatened small-bodied (median 59 g) partially migratory shorebird native to New Zealand and a priority species for conservation planning on Austral flyways. We deployed ten 1.2 g archival GPS tags and ten 1.8–2 g Argos satellite tags on breeding dotterels in Kaikōura, New Zealand. Including leg bands and silicone-tubing leg-loop harness, tag deployments constituted 2.7–4.3% of an average individual’s mass (or 1.9–3.4% based on the tag alone). Both tag types documented the curiously mixed winter strategies characteristic of banded dotterels: migrants flew north to the upper North Island or south to inland Canterbury, while other individuals stayed resident in Kaikōura. Compared to a control group of 74 untagged dotterels, neither tag technology had adverse effects on subsequent breeding outcomes, annual apparent survival, behaviour, or body condition, but Argos satellite tags provided data over a longer period than archival GPS tags. One possible reason for the absence of adverse effects could be that banded dotterels (and other Charadriinae species) primarily rely on ground-based locomotion, characterized mainly by walking and running – movements that are less hindered by the added mass of auxiliary attachments. Our findings support the ‘3% rule’ (i.e., using tag weight alone as a guideline), but we suggest that tag deployment limits could be refined by considering both the species’ ability to carry additional weight and its primary mode of locomotion.

Climate change is a major driver of biodiversity loss, particularly for ectothermic species such as reptiles and amphibians (hereafter herpetofauna), which are highly sensitive to environmental changes. While extensive research has evaluated the effectiveness of protected areas (PAs) in conserving biodiversity under climate change in developed and rapidly developing countries, similar studies in Africa remain scarce despite the continent’s exceptional biodiversity. This study focuses on Kenya, home to over 110 amphibians and 290 reptile species, as a model to address this conservation gap in the face of climate change. We used species distribution models (SDMs) to predict herpetofauna distributions for 2050 under three climate scenarios: SSP1-2.6, SSP2-4.5, and SSP5-8.5. Our results indicate that 20 herpetofauna species (5 amphibians and 15 reptiles) are at risk of local extinction. Furthermore, over 80% of species in both groups currently have less than 30% of their range protected within existing PAs, a trend that persists under future scenarios. We applied a systematic conservation planning approach to address this shortfall to identify priority areas for future conservation efforts. Our findings suggest that Kenya’s PA network would need to expand by approximately 16–19% of the total land area to safeguard herpetofauna both now and in the future effectively. This study underscores the urgent need to optimize Kenya’s PA network to mitigate the effects of climate change on herpetofauna. A proactive approach to conservation planning is essential to enhance species resilience and ensure their long-term survival in a rapidly changing climate.

Pranab Dev Sharma1*, Abdullah Al Noman21Biotechnology program, Department of Mathematics and Natural Science, BRAC University, Dhaka, Bangladesh.2School of Pharmacy, BRAC University, Dhaka, Bangladesh.Dear Editor,The increase of norovirus outbreaks all over the world at the present time is an alert for healthcare professionals, policymakers, and the general population. It is a very infectious virus that causes major digestive issues, which are sometimes ignored by taking them as normal health issues. However, the effects of this virus on public health, economies, and healthcare systems are much more serious than people think.Every year, more than 685 million individuals get infected globally by the norovirus, which causes around 200,000 deaths [1]. The groups of people, including children, older people, and people with weakened immune systems, are at high risk. Norovirus has the capacity to spread by various pathways, such as contaminated food and drink, direct contact, and even small airborne particles from vomit, which makes it particularly concerning. Moreover, it is not easy to manage the virus in busy environments like schools, care residences, markets, and hospitals.Recent outbreaks have made it clear how tricky this virus is to control. Hospitals have had to close wards in the UK because of a rising number of cases—putting huge amounts of pressure on resources [2]. In the US, the cruise ships have reported extensive infections, hurting travel and tourism. For example, in Japan, dozens of children at a childcare facility came down with the virus: an indication of the danger this virus presents for vulnerable groups. This is part of a troubling global pattern, not isolated incidents.Norovirus has an astounding economic cost. In the U.S. alone, related illnesses run up costs of over $10 billion a year, spanning health care, lost productivity, and the sanitation effort [3]. Outbreaks in the food industry can result in product recalls, lawsuits, and damage to a company’s reputation. In developing countries, where medical systems are even more fragile, the strain is even more acute, resulting in longer outbreaks and higher death rates.While common, prevention strategies lag behind. Antibiotics do not work against norovirus, and there is no approved vaccine at this point [4]. The virus is hardy, surviving on surfaces for extended periods and resisting many common disinfectants. Public awareness is low; many people mistakenly attribute norovirus symptoms to food poisoning or other illnesses, hampering containment efforts. And the absence of effective diagnostics adds to the difficulty of the response.To address the problem, we need a concerted effort in many areas. Governments have to spend money on vaccine research—after all, already we have some interesting proposals in the development stage [5]. Healthcare facilities must also carry out enhanced infection control measures, such as compulsory handwashing campaigns and stricter sanitation procedures in high-risk areas. The food industry should instill a culture of safety to minimize opportunities for contamination. Public health agencies need to mobilize education campaigns too so that people recognize symptoms in the early stages and practice good hygiene. Enabling people to obtain the most rigorous diagnostic tools is crucial for early discovery and containment.Norovirus outbreaks are not just a seasonal problem. This is a global health issue that needs urgent and continuous attention. Without strategic intervention, we risk putting healthcare systems under additional strain, massive economic losses, and millions of lives at risk. It is time to take action.Sincerely,Pranab Dev Sharma, Abdullah Al NomanReference[1] Carlson KB, Dilley A, O’Grady T, Johnson JA, Lopman B, Viscidi E. A narrative review of norovirus epidemiology, biology, and challenges to vaccine development. Npj Vaccines 2024 9:1 2024;9:1–9. https://doi.org/10.1038/s41541-024-00884-2.[2] National norovirus and rotavirus report, week 10 report: data to week 8 (data up to 23 February 2025) - GOV.UK n.d. https://www.gov.uk/government/statistics/national-norovirus-and-rotavirus-surveillance-reports-2024-to-2025-season/national-norovirus-and-rotavirus-report-week-10-report-data-to-week-8-data-up-to-23-february-2025?form=MG0AV3 (accessed March 21, 2025).[3] How to prevent (and recover from) norovirus, the stomach bug that’s surging - UChicago Medicine n.d. https://www.uchicagomedicine.org/forefront/health-and-wellness-articles/norovirus?form=MG0AV3 (accessed March 21, 2025).[4] A Norovirus Vaccine Is in the Works | TIME n.d. https://time.com/7205731/norovirus-vaccine-mrna-moderna/?form=MG0AV3 (accessed March 21, 2025).[5] Research identifies key antibodies for development of broadly protective norovirus vaccine | ScienceDaily n.d. https://www.sciencedaily.com/releases/2025/03/250305164340.htm?form=MG0AV3 (accessed March 21, 2025).

A document by Shaktiyavesh Nandan Pratap Singh. Click on the document to view its contents.

Aim: Efforts to mitigate underreporting have focused on the ability of different methods, independent of spontaneous reporting, to identify ADRs. However, there is limited data on the effectiveness of these methods in detecting ADRs of interest. In this study, we collected data on this issue using the ICD-10 codes we routinely employ to detect unreported ADRs. Methods: We defined ADRs of interest as those that were severe, involved biological agents or drugs under additional monitoring, affected a child, and were previously unknown, while providing sufficient data on both the reaction and the drug. We generated a list of all patients whose discharge reports included any of the selected codes. The medical records of these patients were manually reviewed to verify the presence of an ADR and determine whether it met the criteria for being of interest. Results: We observed a significant difference between a code’s ability to detect ADRs and its effectiveness in identifying ADRs of interest. Of the 50 codes analysed, 17 were useful in identifying ADRs of interest. Conclusions: There isn‘t a small set of codes that allow to identify interesting ADRs nor any ADR related code identifies an interesting ADR every time it appears. Every unit going to use this method to identify ADRs should previously explore the utility of each code, although the codes proposed by us seems to be a good starting point.

Bottom-up proteomics relies on efficient and repeatable sample preparation for accurate protein identification and precise quantification. This study evaluates the performance of adapted SPEED (Sample Preparation by Easy Extraction and Digestion) protocols, a simplified, detergent-free approach tailored for various biological matrices, including lysis-resistant samples. Protein extraction and denaturation steps were refined for 12 biological matrices enabling standardized, high-throughput, and scalable proteomics analysis on 96-well plates. For tissue samples requiring downstream applications like Western blotting, we used a low-detergent RIPA buffer, ensuring robust protein extraction and epitope integrity. Notably, the protocols demonstrate remarkable down-scalability, enabling robust proteomics measurements from as few as 3,000 cells per sample and even down to 300 cells per injection. Key advancements include a 30-minute nLC-MS/MS run, significantly enhancing throughput, and leveraging the power of DIA-PASEF using thoroughly optimized DIA-windows to enhance proteome coverage. These adaptations streamline workflows, enabling proteomics analyses in matrices with challenging physical and biochemical properties. This study underscores the importance of early-stage optimization and feasibility testing in proteomics pipelines to inform study design and sample selection. By showcasing robust, scalable adaptations of the SPEED protocol, we provide a foundation for reproducible, high-throughput proteomic studies across diverse biological contexts.

Head and neck squamous cell carcinoma (HNSCC) is a major clinical challenge due to its aggressive nature and poor prognosis in advanced stages. Late detection, often due to delayed diagnosis, limits treatment success. This study investigates non-invasive diagnostic methods to identify early-stage molecular biomarkers using a proteogenomic approach. We analyzed urine samples from 19 male HNSCC patients and identified 1427 proteins by mass spectrometry. Of these, 730 overlapped with healthy controls, highlighting prognostic markers such as RNASE1, LRG1 and CD44. Machine learning techniques, including principal component analysis and partial least squares discriminant analysis, distinguished HNSCC patients from controls and revealed unique proteomic signatures. Pathogenic variants such as GAA p.(Trp746Cys) and SIAE p.(Pro210Leu) were found to be potential indicators of advanced disease. Functional analyzes linked the identified proteins to important tumor-related processes, including epithelial-mesenchymal transition and neutrophil degranulation. These results support urinary proteomics as a promising non-invasive diagnostic tool for early detection of HNSCC and disease monitoring. Future research should validate these biomarkers in larger, more diverse cohorts to improve clinical applicability.

Research on deception focused on the neurophysiological assessment of the deceiver, showing activation of specific brain areas and increased autonomic activity. However, deception is an interpersonal process where both the deceiver and the deceived interact in a constant process of evaluation that requires demanding cognitive resources. The present study aimed to investigate inter-brain synchronization (IBS) and heartbeats synchrony between an interviewer intent on detecting deception and an interviewee during a deception (Deception Group; “DG”) or truth-telling (Non-Deception Group; “NDG”) task using an ecological mock crime experiment. The results showed that DG exhibited higher IBS before the interview in the theta band and during the interview in the alpha band while displaying decreased heartbeats synchrony across all experimental phases compared to NDG. The greater IBS in DG involved particularly the left temporal area of the interviewee. These findings highlight the relevance of studying deception according to a two-person neuroscience perspective, suggesting that while neural processes are synchronized before and during a deceptive interaction, autonomic processes follow different activation patterns. Integrating the hyperscanning techniques with existing lie-detection methods could enhance the identification of neurophysiological markers of deception.

Clouds play a critical role in the evolution and change of climate. However, their interaction with turbulent atmosphere is still a source of uncertainty. Direct numerical simulation (DNS) has become an indispensable tool to investigate the dynamics of atmospheric clouds. In this paper, a DNS model is presented that solves the governing equations for the flow of air, temperature, and water vapor mixing ratio in Eulerian fashion, assuming homogeneous and isotropic turbulence. Aerosol particles and cloud droplets are tracked using Lagrangian particle tracking method. Curvature and solute effects are included in our model, and the initial dry aerosol size distribution is assumed to be lognormal. By varying the intensity of flow turbulence, the mutual conversion of aerosol particles and cloud droplets is examined. The results indicate that a higher level of turbulence promotes the deactivation of cloud droplets into aerosol particles.

We investigated the cerebrovascular and executive function responses to increased inspiratory muscle work. Seven healthy men (33 ± 6 years) performed two separate 10 min bouts of inspiratory pressure threshold loading (ITL) targeting 70% of maximal inspiratory mouth pressure (P Imax) (ITL-Load) and two separate 10 min bouts of ITL targeting 2% of P Imax (ITL-Control). The order in which each participant undertook ITL-Load and ITL-Control conditions was randomized. Transcranial Doppler ultrasonography was used to measure middle cerebral artery blood velocity (MCA V) and executive function was measured using the trail making task (TMT) Parts A and B during the 4-6th min of ITL-Load and ITL-Control. The cerebrovascular conductance index (CVCi) and cerebrovascular resistance index (CVRi) were calculated. There were time x condition interactions ( P <0.01) for MCA V, CVCi and CVRi. This demonstrated during ITL-Load a time-dependent modest increase in MCA V and CVCi, and a time-dependent modest decrease in CVRi. Part A ( P = 0.007) and Part B ( P = 0.013) times for the TMT were slower for ITL-Load compared to ITL-Control. There were no significant correlations between the change in MCA V from rest to the end of ITL and TMT times and errors for Part A ( r = 0.522, P = 0.156) or Part B ( r = 0.370, P = 0.193). This is the first study to demonstrate that ITL results in an increase in MCA V, and a decreased executive function measured by the TMT, but these two measures were not related.

RNA-seq data provide valuable insights into both host transcriptomes and microbial transcripts from active microbiota within host tissues. The presence of microbial transcripts within specific tissues indicates the replication and transcriptional activity of microorganisms. Integrative analyses of the host transcriptome and the meta-transcriptome allow for the characterization of microbial gene expression and the interactive response of the host to the microbiome in each sample. In this study, we employed metatranscriptomics to explore microbial communities in the telencephalon and liver of Carollia perspicillata. By combining host and microbial RNA-seq data, we identified 287 microbial species in the liver and 283 in the telencephalon, revealing tissue-specific microbial diversity. Bacteria were the most abundant taxa in both tissues, followed by notable eukaryotic, archaeal, and viral populations. Using the Metatranscriptome Detector pipeline and NCBI databases, we identified species of potential epidemiological relevance and characterized the host's transcriptional response to the microbiome. Functional analyses indicated differential expression of microbial and host genes across tissues, with enriched metabolic pathways and Gene Ontology terms aligning with hepatic and neural functions. This research underscores the tissue-specific adaptation of the microbiome to host physiology, offering new insights into host-microbiome dynamics in the telencephalon and liver of this frugivorous bat.

Context: Cookies have transitioned from simple data fragments to essential components in digital interactions, playing a significant role in shaping user experiences and privacy. Regulatory frameworks like GDPR and CCPA have emphasized the importance of explicit user consent for cookie settings, making privacy decisions an integral part of the online experience. Objectives: The study aims to investigate the impact of user privacy-related decisions on cookie consent configurations, particularly how different settings affect system resource usage and user experience. The research seeks to provide insights into the behavior of cookies under varying consent scenarios to benefit developers and users alike. Methods: We developed cookie preference configuration sets representing distinct user privacy profiles as identified in literature. An experiment was designed to collect reliable data on the impact of these configurations on system resources. Our methodology involved 1,500 measurements, analyzing 15 websites utilizing the five most common Consent Management Platforms (CMP) for cookie functionalities. Data collection focused on CPU and RAM usage, mass storage drive content, loaded cookies, and JavaScript scripts. Results: The findings revealed notable differences in system resource consumption across various cookie consent configurations. These variations highlighted how consent settings influence the behavior of cookies and the associated impact on CPU, RAM, and storage usage. Conclusion: This study underscores the significant effects of cookie consent settings on system resource utilization. By understanding these impacts, developers can optimize CMP implementations, and users can make informed privacy decisions. These insights contribute to enhancing user experience and fostering a better understanding of cookies’ role in digital interactions.

：Parkinson’s disease (PD) is a relatively common neurodegenerative disorder of the nervous system, mainly characterized by motor disorders and non-motor symptoms. Although the specific causes of this disease have not been fully clarified yet, significant progress has been made in the research on its pathological mechanism. Currently, while there is no cure, drug development has made notable advancements in symptom relief and short-term improvement. In recent years, immunotherapy has shown great potential in PD treatment, with vaccines and monoclonal antibodies targeting α-synuclein（a-syn） being actively developed. Early identification of non-motor symptoms in PD is crucial for timely intervention and disease management. Research indicates that immune system abnormalities, including autoimmunity and activation of both central and peripheral immune systems, play a significant role in the development of PD. Currently, various immunotherapy strategies are in clinical trials, such as active and passive immunotherapies, aiming to clear or prevent the aggregation of harmful proteins and thereby slow disease progression. This article reviews the progress of immunotherapy in PD patients, explores the impact of non-motor symptoms and treatment strategies, and summarizes the development of new drugs in clinical trials. By reviewing existing literature, this article aims to provide new ideas and methods for the future drug treatment of PD.

IntroductionFactor V (FV) deficiency, inherited or acquired, is a rare bleeding disease with an estimated prevalence of 1 per 1 million live births [1-2]. Patients with FⅤ deficiency may be bleeding by external or internal, from mild mucosal bleeding to severe, life-threatening hemorrhage. Patients with FⅤ deficiency usually need to improve their FⅤ levels to more than 25% to 30% by infusion of fresh frozen plasma (FFP) or cryoprecipitate (cryo) to ensure hemostasis and surgical safety during bleeding episodes or operative procedures. Platelets can be transfused when patients with FV deficiency have severe bleeding and do not respond well to conventional treatment [2]. The coagulation profile and factor assays are usually used to assess the coagulation status. Thromboelastogram (TEG) can provide information about the coagulation and fibrinolysis phases of the coagulation process, which includes the interactions of various blood components (platelets, plasma, and leukocytes) to guide transfusion therapy during surgeries [3]. In this report, we describe a patient with FV deficiency who underwent a surgical procedure. We used the above mentioned methods to assess and manage blood transfusion strategies.

Psychological resilience serves as a protective factor against depression, yet the associated white matter microstructural features remain unclear. This study investigated white matter differences in 56 depression patients stratified by resilience levels (low, medium, high) using diffusion spectrum imaging (DSI) and neurite orientation dispersion and density imaging (NODDI). Metrics including generalized fractional anisotropy (gFA), isotropic volume fraction (FISO), intracellular volume fraction (FICVF), and orientation dispersion index (ODI) were analyzed. Results showed that the low-resilience group exhibited significantly reduced gFA in the right anterior corona radiata (R-ACR) and genu of the corpus callosum (GCC) compared to the high-resilience group. Additionally, ODI in the R-ACR was lower in the low-resilience group, while ODI in the left anterior corona radiata (L-ACR) and right posterior corona radiata (R-PCR) was elevated. Correlation analyses revealed positive associations between resilience scores and both gFA and ODI in the R-ACR, whereas ODI in the R-PCR correlated negatively with resilience. Mediation analysis indicated that ODI in the R-ACR partially mediated the relationship between resilience and depression severity. These findings suggest that variations in psychological resilience among depression patients are closely linked to microstructural integrity alterations in the R-ACR and GCC. The study provides novel insights into the neuroanatomical underpinnings of resilience, highlighting potential biomarkers for early clinical diagnosis and therapeutic strategies targeting resilience-related neural pathways.

GD2-CAR T Cell Therapy for H3K27M+ Diffuse Intrinsic Pontine Glioma: A Phase I Clinical Trial and Mechanistic InsightsCongfa Jiang1,2,*,#, Hening Xu3,#, Jianqiao Shentu3, Shiwei Duan3,*Department of Hematology, Ningbo Fourth Hospital, Ningbo 315700, Zhejiang, ChinaXiangshan First People’s Hospital Medical and Health Group, Ningbo 315700, Zhejiang, ChinaDepartment of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou 310015, Zhejiang, China.#: These authors contributed equally to this work.*: Correspondence should be addressed to Drs. Congfa Jiang (jiangcongfa01@163.com) and Shiwei Duan (duansw@hzcu.edu.cn).Keywords: GD2-CAR T cell therapy, H3K27M mutation, diffuse intrinsic pontine glioma, solid tumors, cytokine release syndrom

Title PagePrimary Diffuse Large B-Cell Lymphoma of the Seminal Vesicles: A Rare Case with Diagnostic and Therapeutic ImplicationsMohammad Soleimani, Mostafa Farajpour, Behrang KazeminejadKeywords: DLBCL, Seminal Vesicle, Lymphoma, R-CHOP, Pelvic Mass, HydroureteronephrosisKey Clinical MessagePrimary diffuse large B-cell lymphoma of the seminal vesicles is rare but treatable. Multimodal imaging and biopsy confirmed the diagnosis in a 68-year-old male. Eight cycles of R-CHOP chemotherapy achieved a favorable outcome, emphasizing early intervention in atypical pelvic masses.IntroductionPrimary tumors of the seminal vesicles are uncommon, with most cases representing secondary involvement from adjacent organs (e.g., prostate, bladder) or distant metastases. Primary seminal vesicle lymphomas, particularly diffuse large B-cell lymphoma (DLBCL)—the most common subtype of non-Hodgkin lymphoma—are exceptionally rare and poorly documented. Unlike typical extranodal lymphoma sites (e.g., gastrointestinal tract, skin), the seminal vesicles present unique diagnostic difficulties due to their rarity and nonspecific symptoms, often mimicking urological conditions. This report describes a rare case of primary DLBCL of the seminal vesicles, aiming to enhance clinician awareness, outline diagnostic challenges, and discuss therapeutic strategies based on a 68-year-old male patient’s presentation and management.Case History/ExaminationA 68-year-old male presented with a 4-week history of intermittent, dull flank pain that progressively worsened. He had no prior hematuria, renal, or prostate issues; last year’s abdominopelvic sonography was normal. Physical examination revealed flank discomfort on palpation. Digital rectal examination (DRE) identified a palpable mass in the right seminal vesicle, raising suspicion of an abscess or malignancy. Laboratory results showed elevated creatinine at 2.5 mg/dL, suggesting renal impairment possibly due to ureteral obstruction. Imaging studies included:- Abdominopelvic Sonography: Right hydroureteronephrosis.- CT Scan (non-contrast): A 44 x 35 mm soft-tissue mass in the right seminal vesicle, compressing the ureter, with no calcification (Figure 1).- Bi-parametric MRI: A hyperintense T2-weighted, hypointense T1-weighted mass in the right seminal vesicle, consistent with malignancy (Figure 2).- PET-CT: Hypermetabolic mass involving the seminal vesicle, prostate, and bladder wall; hypermetabolic lymph nodes in bilateral iliac, para-aortic, and mediastinal regions; and two foci in the gastric body.- Chest CT: No evidence of metastasis.Histopathology and immunohistochemistry (IHC) from a biopsy revealed large, atypical tumor cells with vesicular nuclei and prominent nucleoli. IHC showed: CD20+ (diffuse), CD79a+, BCL2+ (80%), BCL6+ (40%), CD10-, MUM1+ (80%), and Ki67 ~70%, confirming DLBCL (Figures 3, 4). The patient underwent eight cycles of R-CHOP (Rituximab 375 mg/m², Cyclophosphamide 750 mg/m², Doxorubicin 50 mg/m², Vincristine 1.4 mg/m², Prednisone 100 mg/day for 5 days) over five months. Filgrastim was used to manage neutropenia. No significant dose adjustments were required. Written informed consent was obtained from the patient for publication of this case report.Differential DiagnosisInitial considerations included urinary tract malignancy, benign prostatic hyperplasia, secondary seminal vesicle tumors, or abscess, prompted by hydroureteronephrosis and DRE findings. DLBCL was confirmed post-biopsy, ruling out alternatives like sarcoma or benign vesicular tumors due to IHC and imaging characteristics.Conclusion and Results (Outcome and Follow-up)Follow-up PET-CT at 3 and 6 months showed a marked response: the pelvic mass reduced in size and metabolic activity, and hypermetabolic lymph nodes resolved. A persistent hypermetabolic focus in the right prostate lobe prompted a TRUS-guided biopsy, which was negative for malignancy. The gastric foci were not pursued further due to clinical improvement and lack of symptoms. This case highlights primary DLBCL of the seminal vesicles as a rare but critical differential in pelvic masses. Multimodal diagnostics and early R-CHOP initiation were pivotal to achieving a favorable outcome. Clinicians should remain vigilant for lymphoma in atypical urological presentations, supported by integrated imaging and histopathology.DiscussionPrimary DLBCL of the seminal vesicles is a diagnostic rarity, often mistaken for common urological conditions like abscesses or prostatic hyperplasia due to its nonspecific presentation (e.g., flank pain, pelvic mass). This case exemplifies the challenge, as initial findings suggested a urinary tract issue, yet comprehensive evaluation—DRE, sonography, CT, MRI, and histopathology—revealed DLBCL. Compared to prior reports [1-3], our case is notable for extensive lymphatic involvement and gastric foci, though their relevance remains unclear without further investigation. The diagnostic process underscores the value of multimodal imaging and IHC, with CD20 positivity and high Ki67 index confirming the aggressive B-cell lineage. Unlike Zhu et al. [2], who reported renal failure, our patient’s creatinine elevation was reversible with treatment, suggesting obstruction rather than parenchymal damage. Therapeutically, R-CHOP yielded a robust response, aligning with outcomes in seminal vesicle DLBCL cases [5, 6], though the persistent prostatic lesion highlights the need for vigilant follow-up. Limitations include the short follow-up period and lack of genetic subtyping (e.g., germinal center vs. activated B-cell DLBCL), which could refine prognosis. A multidisciplinary approach involving urology, oncology, and pathology was critical to success, emphasizing its necessity in rare extranodal lymphomas.Conflict of InterestThe authors declare no conflict of interest.Author ContributionsMohammad Soleimani contributed to the conceptualization and methodology of the study. Mostafa Farajpour was responsible for conceptualization, data curation, investigation, and writing the original draft. Behrang Kazeminejad contributed to data curation, investigation, and writing, reviewing, and editing the manuscript.ConsentWritten informed consent was obtained from the patient for the publication of this case report and any accompanying images.References1. Kwag KS, et al. Primary diffuse large B-cell lymphoma of the seminal vesicle: A case report. Investigative Magnetic Resonance Imaging. 2016;20(4):259-63.2. Zhu J, et al. Primary diffuse large B-cell lymphoma of the seminal vesicles: Ultrasonography and computed tomography findings. Urology. 2011;78(5):1073-4.3. Zhu B, et al. Primary lymphoma of the seminal vesicles presented with acute renal failure: PET-CT findings. Open J Urol. 2012;2:137.4. Handa N, et al. Seminal vesicle involvement: A rare extranodal manifestation of non-Hodgkin’s lymphoma. BMJ Case Rep. 2016;2016:bcr2016217045.5. Garcia Fernandez A, et al. Seminal vesicles tumor: Rare localization of lymphoma. Urol Case Rep. 2021;36:101560.6. Harley F, et al. Primary non-metastatic extra-nodal diffuse large B-cell lymphoma of the prostate and seminal vesicle. Urol Case Rep. 2022;40:101945.Figure LegendsFigure 1: Axial CT scan showing a 44 x 35 mm mass in the right seminal vesicle causing ureteral compression.Figure 2: Bi-parametric MRI of the right seminal vesicle mass. (A) Axial T1-weighted image showing a hyperintense mass with adjacent compression. (B) Coronal T2-weighted image demonstrating the mass with ureteral compression effects. (C) Sagittal T2-weighted image highlighting the extent of the mass and its impact on surrounding structures.Figure 3: Immunohistochemical staining for CD20 (x400) showing diffuse membranous positivity in tumor cells.Figure 4: Immunohistochemical staining for Ki67 (x400) indicating high proliferative activity (~70%).

INTRODUCTIONInvasive plants vary in their physiological and ecological traits (Van Kleunen et al., 2010) and may respond differently to management efforts (Ramula et al., 2008). Therefore, effectively managing an invasive plant requires knowledge of its biology, e.g. its habitat requirements (Jiménez-Valverde et al., 2011). Because the habitat requirements, or niche, of a species will be reflected in where it does or does not occur, the former can to some extent be inferred from the latter. This is the idea behind habitat suitability modeling (Elith & Leathwick, 2009). Such models can thus guide management by, for example, identifying potentially suitable but hitherto uncolonized areas (Elith et al., 2010; Formoso-Freire et al., 2023; Roura-Pascual et al., 2011).However, the distribution of a species does not only reflect environmental variation; rather, it results from the interplay between the abiotic and biotic environment, the species’ niche, and the dispersal rate (Pulliam, 2000; Soberón, 2007). In the case of an exotic species in a novel geographic region, the current distribution will additionally depend on the location(s) of the initial introduction, and the amount of time elapsed since then (Jiménez-Valverde et al., 2011). Gauging the amount of dispersal limitation is important for predicting the future course of an invasion, because if suitable but as-yet uncolonized environments are naively treated as unsuitable, projections in time and space become unreliable (Hattab et al., 2017; Jiménez-Valverde et al., 2011). Environmental data from the native range, where the species can be assumed to have dispersed to most suitable areas, can be used to improve niche estimates and predict performance in the invasive range (Formoso-Freire et al., 2023; Hui, 2023). However, the native range is likely to be constrained by biotic interactions (e.g. predation) that may not exist in the invaded region, which may also bias estimates of the potential invasive distribution (Early & Sax, 2014). Ideally, then, information from both the native and invasive ranges should be combined to get a more complete picture of an invasive species’ requirements and tolerances (Early & Sax, 2014; Guisan et al., 2014).A long-standing question in ecology is how and to what extent the effects of environmental variation on species’ distributions depend on spatial scale — from a species occurring or not occurring within a given region, to the number of populations in each region, to the density of individual populations (Crisfield et al., 2024; McGill, 2010; VanDerWal et al., 2009). The spatial scale of an analysis can drastically change variable effects in distribution models (Kotowska et al., 2022; Mod et al., 2020; Nyström Sandman et al., 2013), and models built to predict species presence/absence at larger scales transfer poorly to predicting local abundance (Lee-Yaw et al., 2022). Therefore, to get a fuller understanding of the factors that drive ongoing biological invasions, there is a need for investigations that model distributions at multiple spatial scales, and complement presence-absence data with more direct measurements of abundance.Here we address these issues with an extensive survey of the large-leaved lupine, Lupinus polyphyllus , in Sweden. Originally native to the Pacific coast of North America, L. polyphyllus has established populations on nearly all continents (Hejda, 2013; Meier et al., 2013; reviewed by Eckstein et al., 2023), and has been ranked among the twenty highest-impact invasive plants in Europe (Rumlerová et al., 2016). In its introduced range, it tends to outcompete native plants, especially smaller species (Thiele et al., 2010; Valtonen et al., 2006). As a result, plant communities heavily invaded by lupines tend to drop in diversity (Prass et al., 2022; Ramula & Pihlaja, 2012; Valtonen et al., 2006), and may become homogenized across habitat types (Hansen et al., 2021). Arthropod abundance has also been shown to be lower in lupine-invaded plots (Ramula & Sorvari, 2017; Valtonen et al., 2006).L. polyphyllus can inhabit a broad range of habitat types, and appears to have wide physiological tolerances (Eckstein et al., 2023; Vetter et al., 2019). However, its niche characteristics have yet to be evaluated quantitatively using high-resolution spatial data, and analyses linking its expansion to environmental variation are still lacking, especially in the context of ongoing climate change (Eckstein et al., 2023). Furthermore, to better understand the current distribution and potential for further spread, it is important to consider dispersal limitation in such analyses.We set out to investigate two central questions:What environmental factors best define the niche of L. polyphyllus and shape its distribution, and does the relative importance of these factor differ across spatial scales?To what extent is the species’ current invasive distribution constrained by patterns of dispersal?To answer these questions, we produced two parallel datasets of invasiveL. polyphyllus across Sweden (Fig. 1): i) a high-resolution presence/absence dataset based on a survey of 73 roadside transects (2100 km in total), and ii) in-depth habitat and population characteristics for 152 point-sampled lupine populations. We also complemented these two datasets with citizen-science observations of the species from both its native and global invasive ranges.We addressed Q1 by analyzing the effects of climate, soil, and other environmental predictors on lupine occurrence at four spatial scales: occupancy across transects, occupancy within transects, and patch filling within transects (using the survey data), and ground cover (using the point-sampled data). Furthermore, we tested for differences in environmental responses between road types (highways versus minor roads), and for effects of the environment on lupine size.We addressed Q2 in three ways: i) by measuring the association of lupine occurrence with human activity, ii) by modeling habitat suitability with putatively dispersal-limited absences removed from the input data, and iii) by using global citizen-science data on lupine occurrence to compare the positions in climate space of Swedish populations and other parts of the species’ range.

Background: The HIT-network was established in 2000 to create a population-based structure aiming to improve survival rates and reduce late effects for children with central nervous system (CNS) tumors by conducting comprehensive clinical trials. Methods: The HIT-network currently consists of 10 coordinating trial centers mandated by the German Society for Pediatric Oncology and Hematology (GPOH) to conduct clinical trials and research projects, and to provide counselling to local centers for individual patients. The network is complemented by 11 reference centers (neuropathology, tumor biology, neuroradiology, pediatric neurosurgery, cerebrospinal fluid (CSF), assessments, radiotherapy, biology), biostatistical support, and currently 72 local treatment sites. Results: Numbers of children and adolescents with newly diagnosed CNS tumors registered to trials and registries increased from approximately 500 to more than 600 per year, corresponding to >95% of affected HIT-eligible children and adolescents in Germany. Clinical counselling and upfront reference assessments ensure homogeneous clinical standards and avoid inadequate treatment of individual patients. Since 2007, the established reference services have been partially re-funded by German health insurances. Discussion: The HIT-network provides a unique structure for population-based state-of-the-art diagnostic assessments, treatment recommendations and counselling. It increases the ‘a priori’ accuracy of stratification parameters, and the timely inclusion into clinical trials and tumor-specific registries. Favorable outcomes are achieved within the trials and registry landscape e.g. through consistent reference assessments, reducing the gap to real world data. Resulting data facilitate representative, unbiased high-quality research projects across all CNS tumor entities. Interdisciplinary cooperation and competitive scientific output are enhanced.