Artículos de revistas: "Leptomeningeal Stem Cell"

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Jiang, Wulin, Alain Valdivia, Alison Mercer-Smith, Carey Anders y Shawn Hingtgen. "56. TUMOR-HOMING STEM CELL THERAPY INHIBITS THE PROGRESSION OF BREAST CANCER LEPTOMENINGEAL CARCINOMATOSIS". Neuro-Oncology Advances 2, Supplement_2 (agosto de 2020): ii11—ii12. http://dx.doi.org/10.1093/noajnl/vdaa073.044.

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Abstract INTRODUCTION Leptomeningeal carcinomatosis remains one of the most lethal forms of central nervous system metastasis, with a median survival of only 4 months. Effective new therapies are urgently needed to treat this highly aggressive cancer. In this study, we used models of both prophylactic and established leptomeningeal disease to investigate the efficacy of engineered tumor-homing neural stem cells (NSCs) therapy for breast cancer leptomeningeal carcinomatosis. METHODS Personalized NSC carriers were created using Sox2 overexpression to transdifferentiate human fibroblasts into induced NSCs (iNSCs) that home to cancer cells and carry therapeutic agents to induce tumor kill. Leptomeningeal models were created by engineering MDA-MB231-Br human breast cancer cells with fluorescent and bioluminescent reporters, then using intracisternal injection to inoculate Nude mice with the tumor cells. iNSC therapy was evaluated by infusing iNSCs releasing the pro-apoptotic agent TRAIL into the lateral ventricle of mice either 1 week prior to or 3 days after tumor inoculation for prophylactic or established tumor treatment respectively. Tumor progression in the brain and spinal cord was monitored by serial bioluminescence imaging (BLI). RESULTS Serial BLI showed that intracerebroventricular (ICV) iNSC-TRAIL therapy reduced the volume of metastatic tumor burden 99.49% in the brain and 99.80% in the spine within 2 weeks post-infusion and extended survival from 24 to 42 days. Additionally, prophylactic iNSC-TRAIL therapy delivered ICV markedly delayed tumor development, with tumors in the brain remaining >1000-fold smaller than control through 1-month post-treatment, below the limit of detection in the spinal cord through 1 month, and eliminating mortality through 50 days post-therapy. CONCLUSION These data suggest that iNSC therapy could be a promising treatment option for breast cancer patients with leptomeningeal carcinomatosis.

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Mercer-Smith, Alison, Wulin Jiang, Alain Valdivia, Noah Bell, Alex Woodell, Scott Floyd y Shawn Hingtgen. "MMAP-04 CYTOTOXIC, TUMOR-HOMING INDUCED NEURAL STEM CELLS AS AN ADJUVANT TO RADIATION IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER LEPTOMENINGEAL METASTASES". Neuro-Oncology Advances 4, Supplement_1 (1 de agosto de 2022): i15. http://dx.doi.org/10.1093/noajnl/vdac078.060.

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Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) is the most common cancer to spread to the brain, and spread to the leptomeninges is particularly devastating, with a median survival of only months. While radiation may offer symptomatic relief, new adjuvant therapies are needed for more durable tumor kill. Spheroidal, human induced neural stem cells (hiNeuroS) transdifferentiated from fibroblasts are inherently tumoritropic. When engineered to secrete the cytotoxic protein TRAIL, they provide the potential for a personalized, targeted approach to NSCLC leptomeningeal metastases. METHODS hiNeuroS-TRAIL in vivo efficacy was determined by tracking the progression and survival of mice with NSCLC leptomeningeal tumors treated with intracerebroventricular hiNeuroS, radiation, or both. To determine the impact of radiation on the tumor tropism of hiNeuroS, we performed 2-dimensional motion assays on hiNeuroS with and without the presence of NSCLC pre- and post-radiation. Migrational capacity in vivo was determined by infusing hiNeuroS into the lateral ventricles of mice with established NSCLC tumors and monitoring hiNeuroS accumulation using post-mortem fluorescent analysis. RESULTS/CONCLUSION Mice treated with the combination of hiNeuroS-TRAIL and 2 Gy showed a significantly reduced mean tumor signal (2.7%) compared to controls (100%) or 2 Gy-only (54.9%). Mice treated with 2 Gy alone showed no significant survival difference compared to controls. Both combination and hiNeuroS-TRAIL-only-treated mice showed a significant improvement in median survival compared to controls (36.6% and 46.3% improvement, respectively). hiNeuroS showed enhanced directionality and displacement in the presence of NSCLC in 2-dimensional motion assays, indicating directional migration, and they maintained this ability following exposure to radiation. Co-localization of hiNeuroS with NSCLC was also observed in vivo. These results suggest the potential of hiNeuroS-TRAIL as a powerful adjuvant to radiation in the treatment of leptomeningeal NSCLC.

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Savage, David G., J. Gregory Mears, Casilda Balmaceda, John Rescigno, Igor Shendrik, Mahesh Mansukhani y Attilio Orazi. "Leptomeningeal relapse of multiple myeloma following allogeneic stem cell transplantation". Leukemia Research 26, n.º 7 (julio de 2002): 689–92. http://dx.doi.org/10.1016/s0145-2126(01)00190-4.

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Fults, Daniel W., Michael D. Taylor y Livia Garzia. "Leptomeningeal dissemination: a sinister pattern of medulloblastoma growth". Journal of Neurosurgery: Pediatrics 23, n.º 5 (mayo de 2019): 613–21. http://dx.doi.org/10.3171/2018.11.peds18506.

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Leptomeningeal dissemination (LMD) is the defining pattern of metastasis for medulloblastoma. Although LMD is responsible for virtually 100% of medulloblastoma deaths, it remains the least well-understood part of medulloblastoma pathogenesis. The fact that medulloblastomas rarely metastasize outside the CNS but rather spread almost exclusively to the spinal and intracranial leptomeninges has fostered the long-held belief that medulloblastoma cells spread directly through the CSF, not the bloodstream. In this paper the authors discuss selected molecules for which experimental evidence explains how the effects of each molecule on cell physiology contribute mechanistically to LMD. A model of medulloblastoma LMD is described, analogous to the invasion–metastasis cascade of hematogenous metastasis of carcinomas. The LMD cascade is based on the molecular themes that 1) transcription factors launch cell programs that mediate cell motility and invasiveness and maintain tumor cells in a stem-like state; 2) disseminating medulloblastoma cells escape multiple death threats by subverting apoptosis; and 3) inflammatory chemokine signaling promotes LMD by creating an oncogenic microenvironment. The authors also review recent experimental evidence that challenges the belief that CSF spread is the sole mechanism of LMD and reveal an alternative scheme in which medulloblastoma cells can enter the bloodstream and subsequently home to the leptomeninges.

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Bifari, Francesco, Ilaria Decimo, Christian Chiamulera, Emanuela Bersan, Giorgio Malpeli, Jan Johansson, Veronica Lisi et al. "Novel stem/progenitor cells with neuronal differentiation potential reside in the leptomeningeal niche". Journal of Cellular and Molecular Medicine 13, n.º 9b (18 de febrero de 2009): 3195–208. http://dx.doi.org/10.1111/j.1582-4934.2009.00706.x.

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Di Trapani, Mariano, Giulio Bassi, Mario Ricciardi, Emanuela Fontana, Francesco Bifari, Luciano Pacelli, Luca Giacomello et al. "Immune Regulatory Properties Are a Common Feature Of Stem Cells". Blood 122, n.º 21 (15 de noviembre de 2013): 5419. http://dx.doi.org/10.1182/blood.v122.21.5419.5419.

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Abstract Allogeneic stem cell-based therapy is a promising tool for the treatment of a range of human degenerative and inflammatory diseases. Many reports highlighted the immune modulatory properties of some stem cell (SC) types, such as mesenchymal stromal cells (MSCs), but a comparative study with SCs of different origin, to assess whether immune regulation is a general SC property, is still lacking. To this aim, we applied highly standardized methods employed for MSC characterization to compare the immunological properties of bone marrow-MSCs, olfactory ecto-mesenchymal stem cells, leptomeningeal stem cells, and three different c-Kit-positive SC types, i.e. amniotic fluid SCs, cardiac SCs, and lung SCs. We found that all the analyzed human SCs share a common pattern of immunological features, in terms of expression of activation markers, modulatory activity towards immune effector cells, immunogenicity and molecular inhibitory pathways, with some SC type-related peculiarities. In addition, we found that the inhibitory behaviour is not a constitutive property of SCs, but is acquired as a consequence of immune effector cell activation, as previously described for MSCs. Thus, immune regulation is a general property of stem cells and the characterization of this phenomenon may be useful for a proper therapeutical use of SCs. Disclosures: No relevant conflicts of interest to declare.

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Mercer-Smith, Alison, Morrent Thang, Andrew Buckley, Alain Valdivia, Wulin Jiang, Noah Bell, Rashmi Kumar et al. "EXTH-01. SECOND GENERATION OF INDUCED NEURAL STEM CELLS TO MIGRATE AND KILL AS AN ADJUVANT TO RADIOTHERAPY IN NON-SMALL CELL LUNG CANCER METASTASIS". Neuro-Oncology 23, Supplement_6 (2 de noviembre de 2021): vi163. http://dx.doi.org/10.1093/neuonc/noab196.640.

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Abstract Non-small cell lung cancer (NSCLC) spread to the leptomeninges is devastating with a median survival of only a few months. Radiation is frequently offered for symptomatic relief but alone does not eliminate leptomeningeal metastases (LMM). With no standard-of-care for patients with LMM, new adjuvant therapies are desperately needed in order to combat this disease. Neural stem cells (NSCs) have shown remarkable promise as drug delivery vehicles in the treatment of brain tumors due to their inherent tumoritropic properties. Using a cell sphere culture-based system, we have transdifferentiated fibroblasts into a second-generation induced neural stem cell (hiNeuroS) secreting the cytotoxic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to allow for the possibility of readily available, autologous cell carriers. Herein, we provide evidence that hiNeuroS-TRAIL cells can migrate to and suppress growth of NSCLC metastases in combination with radiation. In vitro time-lapse motional analysis and in vivo post-mortem tissue analysis showed that hiNeuroS-TRAIL cells migrate to NSCLC tumors. In vitro co-cultures with isobologram analysis suggests that TRAIL and radiation together have a synergistic cytotoxic effect on NSCLC tumors. In an intratumoral injection model of hiNeuroS-TRAIL, mice treated with the combination therapy of hiNeuroS-TRAIL and 2 Gy together had a small fraction of the mean tumor volume (6.4%) of controls (100%) compared to monotherapies (107.3% radiation-only, 46.6% hiNeuroS-TRAIL only). Only combination-treated mice demonstrated a significant extension in survival, which amounted to a 42% extension compared to controls. In the LMM model with ICV-infused therapy, the combination-treated mice showed significantly smaller tumor volumes (2.0%) compared to control (100%) or 2 Gy (54.9%) treated mice. Mice treated with hiNeuroS-TRAIL-only also showed only 4.6% of the tumor volume of control mice. Combination-treated mice and hiNeuroS-TRAIL-treated mice both showed significant improvements in survival (36.6% and 46.3% median extension in survival, respectively compared to controls).

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Reynoso, Eduardo E. y Carlos Quintero. "How to Treat Isolated Leptomeningeal Relapse of Multiple Myeloma 11 Years after Autologous Stem Cell Transplantation (ASCT)". Blood 140, Supplement 1 (15 de noviembre de 2022): 12503. http://dx.doi.org/10.1182/blood-2022-163447.

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Jiang, Wulin, Alain Valdivia, Alison Mercer-Smith, Carey Anders y Shawn Hingtgen. "EXTH-02. TUMOR-HOMING INDUCED NEURAL STEM CELL THERAPY INHIBITS THE PROGRESSION OF BREAST CANCER BRAIN METASTASIS AND LEPTOMENINGEAL CARCINOMATOSIS". Neuro-Oncology 22, Supplement_2 (noviembre de 2020): ii86—ii87. http://dx.doi.org/10.1093/neuonc/noaa215.356.

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Abstract INTRODUCTION Breast cancer brain metastasis, including leptomeningeal carcinomatosis (LC), remains one of the most lethal CNS diseases. New therapies are urgently needed to treat this highly aggressive disease. Here we used models of both breast cancer brain parenchymal metastasis and leptomeningeal metastasis to investigate the efficacy of engineered tumor-homing neural stem cells (NSCs) therapy. METHODS Personalized NSCs were created using Sox2 overexpression to transdifferentiate human fibroblasts into induced NSCs (iNSCs), followed by genetic engineering to enable iNSCs to secrete cytotoxic TRAIL (iNSC-TRAIL). For the parenchymal metastasis study, iNSC-TRAIL therapy was infused intracerebroventricularly (ICV) into Nude mice bearing established intracranial MDA-MB-231-Br human breast cancer cells expressing fluorescent and bioluminescent reporters. For LC studies, we established the disease model by inoculating Nude mice with MDA-MB-231-Br tumor cells via intracisternal infusion. iNSC-TRAIL therapy was evaluated by infusing therapy ICV either 1 week prior to or 3 days after tumor inoculation to mirror prophylactic or established tumor treatment, respectively. Tumor progression in the brain and spine was monitored by serial bioluminescence imaging (BLI), and survival was analyzed. RESULTS Serial BLI showed ICV-infused iNSC-TRAIL reduced parenchymal tumor volumes by 72% 3 weeks post-ICV infusion, and extended median survival from 37 to 52 days. Testing iNSC-TRAIL therapy against established LC tumors, serial BLI showed ICV iNSC-TRAIL therapy reduced established tumors 196-fold in the brain and 500-fold in the spine within 2 weeks post-infusion, while extending median survival from 25 to 47 days. In the prophylactic LC model, iNSC-TRAIL therapy markedly delayed tumor development with tumors in the brain remaining > 1000-fold smaller than control, and tumors in the spine below the limit of detection through 1 month post-treatment. The therapy also eliminated mortality through 50 days post-therapy. CONCLUSION These data suggest iNSC therapy could be a promising treatment option for breast cancer brain metastasis patients.

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Quach, H., G. Ryan, V. Ganju y H. M. Prince. "Effective treatment of leptomeningeal multiple myeloma with total craniospinal irradiation supported by second allogeneic donor stem cell infusion". Bone Marrow Transplantation 35, n.º 4 (20 de diciembre de 2004): 423–24. http://dx.doi.org/10.1038/sj.bmt.1704777.

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Saeed, Zabila. "Extramedullary Acute Myeloid Leukemia: Testicular Myeloid Leukemia, Leukemia Cutis with Leptomeningeal Involvement". Blood 138, Supplement 1 (5 de noviembre de 2021): 4376. http://dx.doi.org/10.1182/blood-2021-146659.

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Abstract Extramedullary Acute Myeloid Leukemia: Testicular myeloid leukemia, leukemia cutis with leptomeningeal involvement Z Saeed, H Aslam, A Weil, M Muzaffar Myeloid sarcoma also called granulocytic sarcoma, myeloblastoma, or chloroma is an extramedullary tumor of immature granulocytic cells. Extramedullary soft tissue manifestations are relatively rare in hematological malignancies. One of the rarest manifestations is myeloid sarcoma (MS). MS develops as part of acute myeloid leukemia, myeloproliferative neoplasm, or myelodysplastic syndrome or at relapse, especially following allogeneic hematopoietic stem cell transplant. Demographically, it has a slight male predominance with a male to female ratio of 1.2: 1. It may occur at any age and any site in the body leading to varied clinical presentations. The most reported sites are lymph nodes, skin and soft tissues, bone, testes, gastrointestinal tract, and peritoneum. 44 year old male with past medical history of diabetes mellitus type 2 and morbid obesity presented with right testicular pain and swelling and underwent radical orchiectomy. Pathology reported seminoma and received adjuvant Carboplatin for pT3 disease. He developed left testicular pain and swelling 2 months later and underwent left radical orchiectomy. Pathology reported CD4+, CD56+ high grade hematopoietic neoplasm. It was sent for second opinion to NIH and was consistent with myeloid sarcoma with monoblastic features. Repeat evaluation of right testicular specimen was CD45+. Bone marrow biopsy showed normocellular marrow with multilineage hematopoiesis. PET scan showed hyper metabolic activity in the right hemi scrotum, widespread osseous areas of increased uptake and 3 soft tissue nodules within the subcutaneous tissues of the left abdominal wall. FNA of the subcutaneous nodule showed CD56 positive monocytoid cells. Induction chemotherapy with 7+3 (cytarabine 200 mg/m2, daunorubicin 60mg/m2) with gemtuzumab 3mg/m2 on day 1, 4, 7 was completed. Cerebrospinal fluid studies (CSF) showed monoblastic/monocytic proliferation and received intrathecal (IT) chemotherapy alternating between methotrexate and cytarabine every week. CSF studies were cleared after 2 IT chemotherapy. Patient remained in the hospital for 87 days due to poor count recovery and development of pulmonary embolism. Myeloid mutation screening identified a mutation in NRASG13D. Repeat PET scan showed 7 areas of hypermetabolic foci involving nodular densities of bilateral lower anterior abdominal wall. One of the lesion was biopsied that was negative. He completed 2 cycles of high dose cytarabine for consolidation but had repeated hospital admissions and therapy was switched to azacytidine and venetoclax. Patient was evaluated by bone marrow transplant team. He had disease progression at tenth month when he presented with severe back pain and lower extremity weakness. MRI brain and spine showed new patchy T2 hyperintense signal in the right frontal white matter, increased number and size of marrow replacing lesions throughout the visualized skeleton. Patient underwent bone biopsy that showed >90% marrow involvement (sheets of infiltrative cells with identical phenotype. Positive for CD56 (>90% of marrow cellularity), CD4 and lysozyme. Hospital course was complicated with renal failure, electrolytes imbalance and hemodynamically instability requiring vasopressor support. Discussions were held for re-induction with CLAG (cladribine 5mg/m2, and cytarabine 2gm/m2) vs best supportive care. Patient decided to pursue comfort care and passed away peacefully. The uniqueness of this case is the myeloid sarcoma of testes as initial presentation with normal bone marrow. Misdiagnosis is not uncommon and can delay the appropriate treatment. Extra medullary involvement from leukemia is very aggressive and needs high suspicious and prompt treatment. Systemic chemotherapy using AML-like regimens should be commenced early, even in non leukemic disease. Allogeneic hematopoietic stem cell transplantation has demonstrated promising results, particularly in patients who achieved complete remission with AML-induction protocols, and recent advances in genetic profiling may enable the development of novel targeted therapies. Prospective multicenter controlled trials are required to further refine management decisions and investigate the role of novel targeted therapies. Disclosures No relevant conflicts of interest to declare.

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Torbidoni, Ana V., Claudia Sampor, Viviana E. Laurent, Rosario Aschero, Saipriya Iyer, Jorge Rossi, Daniel Alderete, Daniel F. Alonso, Irene Szijan y Guillermo L. Chantada. "Minimal disseminated disease evaluation and outcome in trilateral retinoblastoma". British Journal of Ophthalmology 102, n.º 11 (27 de agosto de 2018): 1597–601. http://dx.doi.org/10.1136/bjophthalmol-2018-312263.

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Trilateral retinoblastoma (TRb) presents a management challenge, since intracranial tumours are seldom times resectable and quickly disseminate. However, there are no risk factors to predict the final outcome in each patient.ObjectiveTo evaluate minimal disseminated disease (MDD) in the bone marrow (BM) and the cerebrospinal fluid (CSF) at diagnosis and during follow-up and reviewing its potential impact in the outcome of patients with TRb.Methods and analysisWe evaluated MDD in five patients with TRb, detecting the mRNA of CRX and/or GD2, in samples from BM and CSF, obtained at diagnosis, follow-up and relapse.ResultsTreatment involved intensive systemic chemotherapy in four patients, one did not receive this treatment and died of progression of the disease. Two patients underwent stem cell rescue. Three patients had leptomeningeal relapse and died. One patient remains disease-free for 84 months. RB1 mutations were identified in the five patients, all of them were null mutations. At diagnosis, one patient had tumour cells in the CSF, and none had the BM involved. Only one case of four presented MDD during follow-up in the CSF, without concomitant detection in the BM. On leptomeningeal relapse, no case had MDD in the BM. In all these cases, cells in the CSF were positive for GD2 and/or CRX.ConclusionCSF dissemination always concluded in the death of the patient, without concomitant systemic dissemination denoting the importance of increasing treatment directed to the CSF compartment. The MDD presence could indicate a forthcoming relapse.

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Abdallah, Al-Ola, Shebli Atrash, Jameel Muzaffar, Nisar Ahmad, Sajjad Haider, Monica Grazziutti, Senu Apewokin et al. "Patterns of CNS Involvement in Relapsed and/or Refractory Multiple Myeloma." Blood 120, n.º 21 (16 de noviembre de 2012): 2925. http://dx.doi.org/10.1182/blood.v120.21.2925.2925.

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Abstract Abstract 2925 Background: Multiple myeloma (MM) patients can present with neurologic manifestation either as part of the disease process or as a therapeutic complication, such as due to metabolic disorders such as hypercalcemia, uremia and hyperviscosity; due to peripheral neuropathy, spinal cord compression and cranial nerve infiltration. Invasion of the central nervous system (CNS) in MM disease is an extremely rare occurrence and is associated with advanced disease with poor prognosis. Herein, we are presenting the UARK experience of CNS involvement in MM. Patients and Methods: The UARK MM database was used to conduct a retrospective analysis identifying CNS MM cases presenting between January 1996 and March 2012. Cases were identified from a review of the cytology laboratory archive material; data were also retrieved from the cytogenetic laboratory database, and magnetic resonance imaging (MRI). Descriptive analyses were performed on available data on patient characteristics, disease course and outcomes. Results: 35 patients were identified with mean age at diagnosis being 55.4 years (range: 32–80 years) presenting with neurologic symptoms enlisted in Table 1. All patients had received prior systemic chemotherapy (SC) alone (n=11), or combination of SC and autologous stem cell transplant (ASCT, n=21), or combination of ASCT and allogeneic stem cell transplant (n=3). Eight (23.5%) patients had elevated B2M >5.5 mg/L, twenty four (71%) patients had elevated LDH (> 2 times upper limit of normal) and 5 (14%) had secondary plasma cell leukemia. The mean interval from diagnosis of MM to diagnosis of CNS MM was 23.5 months (range: 3–121 months). At the time of diagnosis of CNS MM, 3 (8.6%) patients were in complete remission (CR) by standard criteria and 15 (42.9%) patients were in progressive disease (PD). Magnetic resonance imaging (MRI) was performed in 34 patients, showing diffuse or localized leptomeningeal disease in 20 (58.8%) patients, 3 (8.8%) patients had a combination of both leptomeningeal disease with adjacent breakout MM focal lesion, and 2 (6%) patients had MM focal lesions adjacent to the meninges and sinuses without leptomeningeal disease. All 35 patients had malignant plasma cells in CSF analysis. 31 patients received chemotherapy to include intrathecal chemotherapy (IT) as a part of their treatment. IT consisted of cytarabine, methotrexate and hydrocortisone +/− thiotepa. 28 patients were treated with both IT and SC together: alone (n=8), or in combination of ASCT (n=13), or combination of ASCT and cranial irradiation (CI) (n=4), or combination with CI (n=1), or combination with both CI and Allogeneic SCT (n=1), or with Allogeneic SCT (n=1). Conclusion: In our experience, CNS MM is an aggressive terminal disease feature associated with other poor prognostic disease features such as high B2M, LDH and secondary plasma cell leukemia. The present review suggests that the patterns for CNS involvement are variable, such as hematogenous spread of plasma cells seen in PCL, or direct continuous spread from the eroded lytic lesions of the skull. The available novel agents do not provide therapeutic concentrations of drug in the CSF as they do not cross the blood-brain barrier. The study highlights an unmet need in this subset of high risk, relapsed/refractory MM patients. Adequate CNS penetration needs to be considered in MM novel drug development. Disclosures: No relevant conflicts of interest to declare.

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Berthier, Sylvie, Louis Larrouquère, Pierre Champelovier, Edwige Col, Christine Lefebvre, Cécile Cottet-Rouselle, Josiane Arnaud et al. "A New Patient-Derived Metastatic Glioblastoma Cell Line: Characterisation and Response to Sodium Selenite Anticancer Agent". Cancers 11, n.º 1 (21 de diciembre de 2018): 12. http://dx.doi.org/10.3390/cancers11010012.

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Glioblastoma multiform (GBM) tumors are very heterogeneous, organized in a hierarchical pattern, including cancer stem cells (CSC), and are responsible for development, maintenance, and cancer relapse. Therefore, it is relevant to establish new GBM cell lines with CSC characteristics to develop new treatments. A new human GBM cell line, named R2J, was established from the cerebro-spinal fluid (CSF) of a patient affected by GBM with leptomeningeal metastasis. R2J cells exhibits an abnormal karyotype and form self-renewable spheres in a serum-free medium. Original tumor, R2J, cultured in monolayer (2D) and in spheres showed a persistence expression of CD44, CD56 (except in monolayer), EGFR, Ki67, Nestin, and vimentin. The R2J cell line is tumorigenic and possesses CSC properties. We tested in vitro the anticancer effects of sodium selenite (SS) compared to temozolomide TMZ. SS was absorbed by R2J cells, was cytotoxic, induced an oxidative stress, and arrested cell growth in G2M before inducing both necrosis and apoptosis via caspase-3. SS also modified dimethyl-histone-3-lysine-9 (H3K9m2) levels and decreased histone deacetylase (HDAC) activity, suggesting anti-invasiveness potential. This study highlights the value of this new GBM cell line for preclinical modeling of clinically relevant, patient specific GBM and opens a therapeutic window to test SS to target resistant and recurrent GBM.

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Solomon, Isaac H., Hojun Li, Leslie A. Benson, Lauren A. Henderson, Barbara A. Degar, Mark P. Gorman, Christine N. Duncan, Hart G. Lidov y Sanda Alexandrescu. "Histopathologic Correlates of Familial Hemophagocytic Lymphohistiocytosis Isolated to the Central Nervous System". Journal of Neuropathology & Experimental Neurology 77, n.º 12 (22 de septiembre de 2018): 1079–84. http://dx.doi.org/10.1093/jnen/nly094.

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AbstractFamilial hemophagocytic lymphohistiocytosis (HLH) is an immune hyperactivation syndrome caused by mutations in genes associated with cytotoxic T-cell and NK-cell function. While neurological manifestations frequently accompany systemic inflammation at initial presentation, isolated central nervous system (CNS) involvement is rare, and the histological correlates are not well described. We present 3 patients (ages 5, 6, and 7 years) with CNS-isolated familial HLH, who presented with a variety of neurological symptoms and underwent brain biopsies for multifocal enhancing supratentorial and infratentorial lesions. Biopsy slides from all 3 patients revealed similar findings: perivascular lymphocytes, predominantly CD3+ T-cells (CD4>CD8) with occasional intramural infiltration of small vessels; scattered histiocytes without hemophagocytosis; parenchymal and leptomeningeal inflammation varying from mild and focal to severe and sheet-like with associated destructive lesions. There was no evidence of demyelination, neoplasia, or infection. Genetic testing identified compound heterozygous mutations in PRF1 (Patients 1 and 2) and UNC13D (Patient 3), with no evidence of systemic disease except decreased NK-cell function. All 3 patients were treated with hematopoietic stem cell transplantation with marked improvement of symptoms. These findings combined with the poor outcomes associated with delayed diagnosis and lack of aggressive treatment highlight the need to consider HLH in the differential diagnosis of inflammatory brain lesions.

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Alegre, Adrian, Beatriz Aguado, Miriam González-Pardo, Evelyn Acuña, Álvaro Arriero, Maria Aragonés, Lourdes Del Campo, S. Llorente, Elena Ocón y Nieves Gómez León. "Comparison of Assesment of Imaging Response with Magnetic Resonance (MR) and 18fdg-PET/TC in Multiple Myeloma (MM). Single Centre Experience". Blood 124, n.º 21 (6 de diciembre de 2014): 5707. http://dx.doi.org/10.1182/blood.v124.21.5707.5707.

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Abstract Introduction: Conventional radiography remains the “gold standard” technique for bone involvement assessment in patients with multiple myeloma (MM). Newer imaging modalities such as whole-body Magnetic Resonance (MR) and 18FDG-PET/CT have emerged as more sensitive techniques than routine skeletal survey in the detection of bone involvement in the diagnostic and follow up of patients with MM. The advantages and disadvantages of MR and 18FDG-PET/CT are discussed. Patients and methods: We have retrospectively analyzed 12 patients since 2012 to 2014 with multiple myeloma in our institution whose bone involvement was evaluated with MR and 18FDG-PET/CT. Age range: 36-70. Seven patients were female and five were male. Eight cases were treated with an induction regimen containing bortezomib, three cases with chemotherapy with alternating VBCMP/VBAD and one of them with VAD. After induction, ten of them received autologous stem cell transplantation (ASCT), one patient allogeneic stem cell transplantation and one patient no transplantation. Results: All patients presented bone lesions on MR and all of them were also positive at PET/CT. One showed leptomeningeal involvement on RM and PET. Regarding extramedullar disease two patients presented soft tissue masses and in other two cases there was ganglionar involvement, all of them positives by both techniques. Of nine evaluable patients after complete treatment, six of them have a negative PET and three have a low positive SUV value, however eight of them still had persistent residual lesions on MR, what could indicate not stringent complete response. The patient with leptomeningeal involvement had both MR and PET negative result after treatment. Comments and conclusions: Our data suggest that whole-body MR and 18FDG-PET/CT provide valuable complementary information, MR could be superior to assess extent of lesions and PET to monitor disease activity and to detect asymptomatic relapse. The optimal imaging technique for the management of patients with MM is not well defined and our proposal is a multimodality imaging approach according to individualized criteria. References: Caers J et al. The role of positron emission tomography-computed and magnetic resonance imaging in diagnosis and follow-up of multiple myeloma. Haematologica 2014;99(4):629-637. doi:10.3324/haematol.2013.091918. Agarwal A et al. Evolving Role of FDG PET/CT in Multiple Myeloma Imaging and Management. AJR 2013;200:884-890. Dimopoulos D et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma. Leukemia 2009, 1–12. doi:10.1038/leu.2009.89 Disclosures Alegre: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Rubenstein, James L., Lingjing Chen, Ranjana Advani, Jan Drappatz, Elizabeth Gerstner, Tracy Batchelor, Hendrikus Krouwer et al. "Multicenter Phase I Trial of Intraventricular Immuno-Chemotherapy in Recurrent CNS Lymphoma". Blood 118, n.º 21 (18 de noviembre de 2011): 959. http://dx.doi.org/10.1182/blood.v118.21.959.959.

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Abstract Abstract 959 Background: We recently studied the safety and activity of intraventricular rituximab monotherapy in the treatment of recurrent intraocular and CNS non-Hodgkin lymphoma (NHL) (JCO 2007 25: 1350–1356). Rapid dissemination throughout the craniospinal axis was demonstrated and cytologic responses were detected in six out of ten patients. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. The major goals of this current trial are to perform the first study of intraventricular immuno-chemotherapy in humans and to evaluate the safety of two dose levels of intraventricular rituximab as well as its pharmacokinetics in combination with intraventricular methotrexate (MTX). Secondary goals are to obtain information regarding the efficacy of this approach in the treatment of patients with recurrent CNS lymphoma, (brain parenchyma, intraocular or the leptomeningeal compartment). Methods: Thirteen patients with recurrent/refractory CD20+ CNS NHL were treated at UCSF, Dana Farber Cancer Institute and Massachusetts General Hospital on a phase I clinical trial involving twice weekly intraventricular rituximab at 10 mg and 25 mg dose levels, administered over a planned four week schedule. Rituximab is combined with MTX (12 mg) during the second intraventricular injection each week. Patients achieving partial response or better were eligible for a second month of combination intraventricular rituximab plus MTX. Results: No serious treatment-related toxicity has been detected with intraventricular rituximab/MTX at the 10 mg and 25 mg dose levels. The most common treatment-related toxicity was paresthesias (grade 1). One patient exhibited NHL progression outside of the CNS at three weeks and thus was not evaluable for CNS response, and one patient exhibited stable disease. Complete cytologic responses were detected in ten out of thirteen patients at the one-month restaging. Parenchymal responses were detected in three out of six subjects with one partial response within the corpus callosum, and two complete regressions of lesions within temporal lobe and cerebral cortex. One patient with leptomeningeal lymphoma non-responsive to intravenous rituximab and refractory to high-dose intravenous and intrathecal methotrexate, oral temozolomide and intrathecal liposomal cytarabine, obtained a sustained complete response with the intraventricular rituximab/MTX protocol and subsequently was approved for consolidative autologous stem cell transplant. Two patients have participated in extended dosing on protocol without progression for five and eight months respectively. Thus far, there is no evidence for a relationship between FcGR3A polymorphism and therapeutic resistance in a preliminary analysis (n=8 patients). The maximum tolerated dose of intraventricular rituximab with this combination was established as 25 mg. The mean maximum intraventricular rituximab concentration after intraventricular injection of rituximab was 285 microgram/ml at the 10 mg dose level (N=3) and 882 microgram/ml at the 25 mg dose level (N=10); (p<0.038). The rate of Rituximab clearance from the intraventricular compartment at two hours post injection was 30% slower when administered in combination with methotrexate compared to intraventricular rituximab monotherapy (p <0.02). Conclusions: Intraventricular rituximab/MTX appears to be safe in recurrent CNS NHL. Twelve of thirteen patients completed at least one month of therapy, without any treatment-associated serious adverse events at any of the institutions. Intraventricular administration of methotrexate may significantly attenuate rituximab clearance from the leptomeningeal compartment. There is encouraging evidence for significant activity of intraventricular immuno-chemotherapy in the treatment of drug-resistant CNS NHL, refractory or non-responsive to intravenous rituximab. These results provide strong support for further investigation of this novel therapeutic approach. NCT00221325. Supported by Leukemia and Lymphoma Society and NIH Grant CA13908301. Disclosures: Off Label Use: We will discuss the off-label use of rituximab within the leptomeningeal compartment to treat recurrent/refractory CNS lymphomas. Advani:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Chung, Seok Jong, Tae Yong Lee, Yang Hyun Lee, KyoungWon Baik, Jin Ho Jung, Han Soo Yoo, Chang Jae Shim et al. "Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy". Stem Cells International 2021 (19 de octubre de 2021): 1–10. http://dx.doi.org/10.1155/2021/9886877.

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Background. This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). Methods. This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 10 5 cells/kg; medium-dose, 6.0 × 10 5 cells/kg; high-dose, 9.0 × 10 5 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. Results. One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. Conclusion. The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

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McLaughlin, Nicole, Yucai Wang, David James Inwards, Jose Caetano Villasboas, Ivana N. M. Micallef, Thomas Matthew Habermann, Grzegorz S. Nowakowski et al. "Outcomes in mantle cell lymphoma with central nervous system involvement." Journal of Clinical Oncology 39, n.º 15_suppl (20 de mayo de 2021): e19527-e19527. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e19527.

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e19527 Background: While extra nodal involvement by MCL is relatively common, involvement of the central nervous system (CNS) is a rare ( < 5% of cases) complication with limited treatment options. We report the outcomes of a large cohort of patients (pts) with CNS MCL. Methods: MCL pts with CNS involvement seen at Mayo Clinic between 1/1/1995-9/16/2020 were identified. CNS involvement was defined by histologically confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS lymphoma. Medical records were reviewed for baseline characteristics, treatment, and outcome. Kaplan-Meier method was used for time to event analysis. Results: Out of 1,753 pts with MCL, 36 (2%) had CNS involvement by MCL. Median age at MCL diagnosis was 64 years (range 36-83) and 26 were male (72%). At MCL diagnosis, non-CNS extranodal involvement was seen in 30 pts, 24 with 1 site and 6 with ≥ 2 sites; 24 had bone marrow involvement. 11 (31%) pts had blastoid variant. Median Ki-67 was 40% (range 15-100%). MIPI score was available in 17 pts [low risk (n = 5, 29%), intermediate risk (n = 9, 53%), high risk (n = 3, 18%)]. The most common frontline regimen for MCL was R-CHOP and 14 (39%) pts underwent autologous stem cell transplant in CR1. The incidence of CNS involvement was overall similar over the study period. Median time from MCL diagnosis to CNS involvement was 25 months (m) (range 0-167). 4 (11%) pts presented with CNS involvement at initial diagnosis and 32 presented at relapse (12 isolated CNS relapse and 20 concurrent CNS and systemic relapse. Abnormal CSF was noted in 27 (87%) pts [consistent with MCL diagnosis (n = 26), atypical lymphocytes (n = 1)]. Abnormal CNS imaging was reported in 27 (75%) pts [leptomeningeal (n = 18), leptomeningeal and parenchymal (n = 5), parenchymal (n = 2), ocular (n = 2)]. First line CNS-directed therapy data was available in 33 (92%) pts. 12 (34%) received intrathecal (IT) therapy alone, 19 (54%) received systemic +/- IT therapy, 2 (6%) received radiation alone, and 2 (6%) pts received no treatment (hospice). The overall CNS response to therapy was CR in 13 (42%) pts, PR in 3 (10%), SD in 8 (26%), and PD in 7 (22%) pts. Three pts received BTK inhibitors [ibrutinib (n = 2) or acalabrutinib (n = 1)] as the first CNS-directed therapy. One patient achieved a CR with a response lasting 4 m, another patient achieved a PR with response lasting 10 m. CNS response data was not available in the remaining pts. Median follow up from CNS involvement was 72 m (95% CI: 41-NR). Median EFS for the 1st CNS-directed therapy was 3.7 m (95% CI: 1.6-6.1). At last follow up, 30 pts were deceased. The cause of death was CNS lymphoma in 10 (33%) pts and systemic lymphoma in 9 (30%) pts. Median OS from CNS involvement was 4.7 m (95% CI: 2.3-6.7). Conclusions: CNS involvement by MCL has dismal outcomes as evident by a median OS of approximately 5 m. BTK inhibitors may have a role in treatment of this rare complication, but further prospective investigation is needed.

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Green, Richard, Colleen Thornton y Ruben Guzman. "CTNI-59. MATRIX REGIMEN FOR NEWLY DIAGNOSED PRIMARY CNS DIFFUSE B-CELL LYMPHOMA". Neuro-Oncology 24, Supplement_7 (1 de noviembre de 2022): vii86. http://dx.doi.org/10.1093/neuonc/noac209.324.

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Abstract We report our experience treating 22 patients with newly diagnosed primary CNS diffuse B-cell lymphoma with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 64 y (range 45-85); 10 patients were men and 12 were women. Twenty had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 16 patients completed initial chemotherapy. Fourteen of these 16 went on to transplantation; one patient had had early disease progression, and in one no stem cells could be collected. Five patients (median 73 y; range 64-85 y) died early after 1-2 cycles. The causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One patient who completed the entire regimen including transplantation died of fungal pneumonia and the other 13 experienced no serious acute toxicity. One patient had late disease progression and one developed symptomatic leukoencephalopathy. Fourteen of the 22 patients remain alive. Median OS for the cohort is 663 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 65 y suggests that the regimen may be too toxic for older individuals.

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Xu, Zhenhua, Najiba Murad, Samuel Rivero-Hinojosa, Ulrich Schüller, Peng Zhang, Xiao Liu, Brian Rood, Roger Packer y Yanxin Pei. "EMBR-02. OLIG2 REPRESENTS A PROGNOSTIC MARKER AND THERAPEUTIC TARGET IN MYC-AMPLIFIED MEDULLOBLASTOMA RELAPSE AND METASTASIS". Neuro-Oncology 23, Supplement_1 (1 de junio de 2021): i5—i6. http://dx.doi.org/10.1093/neuonc/noab090.020.

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Abstract Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Among the multiple MB subtypes, MB with MYC amplification confers an extremely poor prognosis with an overall survival rate of less than 30%. Relapse is often mediated by a small population of therapy-resistant tumor cells which expand and ultimately progress to lethal tumors. Moreover, MYC-amplified MB exhibits a high incidence of leptomeningeal metastases. Approximately one-third of patients with MYC-amplified MB present with metastases and nearly all have this complication at relapse. Metastatic MYC-amplified MB is highly fatal. As such, our ability to effectively treat MYC-amplified MB is largely dependent on our capacity to eradicate the therapy resistant tumor cells, particularly the metastatic tumor cells. The development of clinically effective therapies for this disease will be facilitated by the identification of therapy-resistant tumor cell populations and their molecular signatures involved in tumor metastasis and relapse. Using patient-derived xenograft (PDX) mouse models, we recently discovered that a subset of MYC-amplified MB tumors with strong OLIG2 expression (OLIG2-high) is resistant to radiation and prone to metastasize, whereas MYC-amplified MB tumors without OLIG2 expression (OLIG2-low) are sensitive to radiation without dissemination. Irradiation of OLIG2-high tumors led to either a small number of quiescent OLIG2- cancer stem-like cells (CSLCs) remaining in the cerebellar bed or to the dissemination of highly proliferative OLIG2+ tumor cells along the leptomeninges. All mice harboring these radioresistant CSLCs succumbed to relapse. Further studies demonstrated that the quiescent OLIG2- CSLCs did not contribute to tumor recurrence directly, while elimination of OLIG2+ radioresistant CSLCs with a small molecule OLIG2 antagonist significantly prevented metastatic recurrence, delayed tumor growth and prolonged animal survival. Thus, our studies provide new insights into the role of OLIG2 in radiotherapy resistance and metastasis in MYC-amplified MB and propose a novel therapeutic approach to treating metastatic MYC-amplified MB.

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Ramaglia, Antonia, Elena Arkhangelskaya, Angela Rita Sementa, Giovanni Morana, Andrea Rossi, Maura Faraci, Gianluca Piccolo et al. "IMG-12. Transient atypical brain and spine MRI features after high-dose chemotherapy may represent clumps of CD34+ hematopoietic stem cells". Neuro-Oncology 24, Supplement_1 (1 de junio de 2022): i79. http://dx.doi.org/10.1093/neuonc/noac079.288.

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Abstract High-dose chemotherapy is a therapeutic option in selected cases of pediatric high-grade brain tumor (pHGBT). Following high-dose chemotherapy, bone marrow is reconstituted by means of CD34+ peripheral blood stem cell (PBSC) infusion. Intravenously injected PBSCs have been reported to migrate to the Central Nervous System (CNS) and to persist for weeks. We report two cases of pHGBT in which, following PBSC infusion, we observed peculiar brain MRI signal alterations suggestive of clumps of CD34+ cells. A 15-month-old female underwent surgery and chemotherapy for an infratentorial, non-disseminated, Atypical Teratoid Rhabdoid Tumor. Following the second course of high-dose chemotherapy, MRI excluded residual disease, but revealed two contrast-enhancing nodules in the supratentorial ventricular system, with no evidence of diffusion restriction, unlike the primary tumor. Cerebrospinal fluid was collected by means of lumbar puncture and centrifuged: no neoplastic cells were found, while a few cells were positive when immunostained with anti-CD34 antibody. As no disease progression was documented, the patient completed her treatment with focal radiotherapy. Three months after the end of therapy, MRI showed new enhancing nodules with restricted diffusion, in keeping with leptomeningeal spread of disease; these progressively increased in size, despite subsequent lines of treatment, while the above-mentioned ventricular nodules shrank. Similar transient alterations were detected in a 4-year-old boy who had received treatment for high-risk Medulloblastoma, including high-dose chemotherapy. CONCLUSIONS: In the setting of new enhancing brain and spine findings with atypical MRI features, after high-dose chemotherapy to treat pHGBT, the hypothesis of CNS homing of CD34+ hematopoietic stem cells should be considered in the differential diagnosis.

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Lee, Daniel W., Maryalice Stetler-Stevenson, Constance M. Yuan, Nirali N. Shah, Cindy Delbrook, Bonnie Yates, Hua Zhang et al. "Long-Term Outcomes Following CD19 CAR T Cell Therapy for B-ALL Are Superior in Patients Receiving a Fludarabine/Cyclophosphamide Preparative Regimen and Post-CAR Hematopoietic Stem Cell Transplantation". Blood 128, n.º 22 (2 de diciembre de 2016): 218. http://dx.doi.org/10.1182/blood.v128.22.218.218.

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Abstract Relapsed pre-B acute lymphoblastic leukemia (ALL) portends a poor prognosis even with hematopoietic stem cell transplantation (HSCT). CD19 chimeric antigen receptor (CAR) T cells have shown promise in early studies although morbidity related tohigh gradecytokine release syndrome (CRS) and/or neurotoxicity could limit its wide applicability in patients with high disease burden. The lympho depleting chemotherapy regimen may affect both toxicity and response and has not been well studied. Relapse rates among complete responders to CD19 CAR therapy occur in nearly half of patients in the first year. We report outcomes from our completed clinical trial of 53 children and young adults with relapsed/refractory ALL (n=51) or lymphoma (n=2) with a median follow up (mF/U) of 18.7 months. The first 21 patients received a low dose fludarabine (25 mg/m2/day Days -4 to -2) and cyclophosphamide (900 mg/m2 Day -2) preparative regimen (LDflu/cy) and results are reported in Lancet 385:517-28. The regimen for the subsequent 32 patients, who all received 1x106 CAR+ T cells/kg, was stratified based on disease burden. Subjects with low burden ALL (lowALL; <25% marrow blasts) received LDflu/cy while those with high burden disease (highALL; >25% marrow blasts or lymphomatous disease) received an alternative regimen [FLAG (n=6), ifosfamide/etoposide per AALL0031 (n=2) or fludarabine (30mg/m2/day Days -6 to -3) and cyclophosphamide (1200 mg/m2/day Days -4 and -3) (HDflu/cy; n=8)] in an attempt to mitigate severe CRS risk and improve response. Four highALL subjects received LDflu/cy due to comorbidities including Trisomy 21. CRS was graded and anti-cytokine therapy was instituted as per Blood 124:188-95. Date for data cutoff was July 31, 2016. Of the 53 subjects 11 had primary refractory ALL, 5Ph+, 3 with Trisomy 21, 4 with CNS2 and 2 with CNS3 ALL including one with extensive leptomeningeal and parenchymal involvement. Cells were manufactured in 7-11 days and none underwent a test expansion. One patient was not infused due to rapidly progressive fungal pneumonia but was accounted for in all analyses. Of 51 ALL patients, 31 (60.8%) achieved a complete response (CR) with 28/31 (90%) of responders negative for minimal residual disease (MRD-). All 6 subjects with CNS ALL were rendered into CNS1 status with resolution of leptomeningeal enhancement, where appropriate, and CAR cells in CSF. The median leukemia free survival (mLFS) of MRD- CR responders is 18 months with a 49.5% probability of LFS beginning at 18 months (mF/U 22.6 months). Grade 3 (n=5) and 4 (n=2) CRS combined for a severe CRS incidence of 13.5%. Three grade 3 neurotoxicities(1 each: dysphasia, delirium, headache) and 2 seizures (one grade 1, one grade 2) occurred. There were no grade 4 neurotoxicities, even in the subject with extensive CNS disease. Subjects with low ALL had a significantly higher CR rate (18/21; 85.7%) than those with high ALL (13/32; 40.6%) (p=0.0011) and use of a flu/cy regimen correlated with higher response (29/44; 65.9% vs 2/8; 25%; p=0.0301). Overall survival in all subjects receiving a flu/cy regimen was 13.3 months with a 34.7% probability of survival beginning at 38 months (mF/U 18.7 months), which is significantly longer than those who did not receive a flu/cy regimen (5.5 months, no survivors beyond 11 months). The hazard ratio (HR) of not receiving a flu/cy regimen was 6.35 (1.906-21.14; p=0.0026). mLFS of subjects with MRD- CR who received a flu/cy regimen was not reached with a 53.3% probability of LFS beginning at 18 months (mF/U 22.6 months). Of the 28 subjects achieving MRD- CR, 21 had a subsequent HSCT with a median time to HSCT of 54 days from CAR infusion. 8/28 (28.6%) relapsed with CD19+ (n=2), CD19-/dim (n=5), CD19 unknown (n=1) blasts. Relapse was significantly more common in subjects who did not have a HSCT after CAR therapy (6/7; 85.7%) compared to those who did (2/21; 9.5%) (p=0.0001). Even accounting for transplant related mortality, them LFS in the HSCT group was not reached with a 62% probability of LFS beginning at 18 months. This is significantly longer than them LFS of 4.9 months in MRD- CR subjects who did not proceed to HSCT (p=0.0006) with a HR of 16.9 (3.37-85.1) of not having a subsequent HSCT. In all, CD19 CAR T cell therapy was effective and safe with a low incidence of severe CRS and neurotoxicity. In this nonrandomized series, the rate of durable remission was higher when a flu/cy preparative regimen was used and consolidation HSCT was employed. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Lee: Juno: Honoraria. Kochenderfer:bluebird bio: Patents & Royalties, Research Funding; Kite Pharma: Patents & Royalties, Research Funding. Rosenberg:Kite pharma: Research Funding. Mackall:NCI: Patents & Royalties: B7H3 CAR.

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Gaut, Daria, Caspian Oliai y Monica Mead. "Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Secondary Central Nervous System Lymphoma". Blood 138, Supplement 1 (5 de noviembre de 2021): 4911. http://dx.doi.org/10.1182/blood-2021-145358.

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Abstract Introduction: Aggressive non-Hodgkin's lymphoma (aNHL) with secondary central nervous system (sCNS) involvement has a poor prognosis. Studies have reported a response to induction treatment as low as 35%, leaving less than half of patients eligible for autologous stem cell transplant (ASCT). Outcomes of patients in these clinical scenarios are dismal and treatment is ill-defined. Small case series suggest chimeric antigen receptor (CAR)-T cell therapy may play a role in the management of relapsed/refractory (R/R) B-cell lymphoma (BCL) with sCNS involvement, but follow-up is limited and response duration is uncertain. Allogeneic hematopoietic stem cell transplant (alloHCT) offers a durable remission for a subset of patients with R/R systemic aNHL primarily mediated through a graft versus lymphoma (GVL) effect, but it is unclear if GVL properties include the immune-privileged CNS. The present study aims to describe outcomes of a cohort of patients with R/R aggressive B- and T-cell NHL with sCNS involvement who underwent alloHCT at a single academic institution. Methods: This is a retrospective analysis that includes all patients with R/R aNHL with sCNS involvement who underwent alloHCT at the University of California, Los Angeles from 2005-2020. The UCLA Institutional Board Review approved this study. Relevant clinical data was extracted from medical records. Hematopoietic cell transplantation comorbidity index (HCT-CI) and time to neutrophil and platelet engraftment were measured according to Center for International Blood and Marrow Transplant Research criteria. Results: Ten patients were included (3 females, 7 males). Histologic subtypes included anaplastic BCL (1), mantle cell lymphoma (1), blastic natural killer-cell lymphoma (1), peripheral T-cell lymphoma, not otherwise specified (1), primary mediastinal BCL (1), and diffuse large B-cell lymphoma (DLBCL) (non-germinal center=3, germinal center-like=2). Two DLBCL patients had histologic transformed lymphoma (follicular lymphoma =1, chronic lymphocytic lymphoma = 1). Four patients had sCNS involvement at the time of initial diagnosis or during frontline treatment; the remaining 6 patients developed sCNS lymphoma at relapse. sCNS lymphoma was identified in the parenchymal (n=4), leptomeningeal (n=3), or both (n=3) compartments. The median age at the time of alloHCT was 49.5 (range 28-68), and 1 patient was ˃ 60. At the time of alloHCT, 1 patient had residual disease in the CNS and the remaining 9 patients were in a complete remission. Eight patients received ˃ 3 prior lines of therapy, and 3 patients failed prior ASCT. HCT-CI scores were 0 (n=1), 1 (n=2), 2 (n=3), 3 (n=1), and unknown (n = 3). Donor types included 10/10 matched related (3), 10/10 matched unrelated (4), 9/10 mismatched related (1), and double umbilical cord blood (2). Graft source was peripheral blood in 8 patients and cord blood in 2 patients. Conditioning regimens included myeloablative, reduced intensity and non-myeloablative in 6, 3 and 1 patient(s), respectively. Six patients received total body irradiation-containing conditioning. The average time to neutrophil engraftment was 18 days (range 11-29), and the average time to platelet engraftment was 26.5 days (range 18-59). One patient had primary graft failure. Of the 6 patients with day 100 disease reassessment (CR at time of alloHCT=5, PR in CNS at time of alloHCT=1), all were in CR. With a median follow-up of 341 days, 2 patients relapsed (CNS=1 and systemic = 1), and 6 patients died. Cause of death included infection (n=3), lymphoma (n=1), primary graft failure (n=1), and organizing pneumonia (n=1). Six patients developed acute graft versus host disease (GVHD) (grade 1-2, n=1; grade 3, n=5), and 4 patients developed chronic GVHD (score 1-2, n= 2; score 3, n=2). The median overall and progression-free survival for the entire cohort was 341 days (range 23-4825) and 268.5 days (range 23-4825), respectively. Conclusions: AlloHCT in patients with R/R aNHL with sCNS involvement is feasible and may provide a durable response in a subset of patients. Four patients remained alive and free of disease one year post-alloHCT and one patient converted from a PR to a CR in the CNS 100 days post-alloHCT, suggesting effective donor immune surveillance within the CNS. Transplant-related morbidity and mortality limits the widespread application of this therapeutic modality and less toxic approaches are urgently needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Green, Richard, Ruben Guzman-Marin, Keng Lam y Colleen Thornton. "CTNI-57. MATRix REGIMEN FOR NEWLY DIAGNOSED PRIMARY DIFFUSE B-CELL LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM". Neuro-Oncology 23, Supplement_6 (2 de noviembre de 2021): vi73. http://dx.doi.org/10.1093/neuonc/noab196.282.

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Abstract We report our experience treating 20 patients with newly diagnosed primary diffuse B-cell lymphoma of the central nervous system with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 65 y; 8 patients were men and 12 were women. Eighteen had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 14 patients completed initial chemotherapy. Twelve of these 14 went on to transplantation; one patient had early disease progression, and in one no stem cells could be collected. All 4 patients over 70 y died early after 1-2 cycles; the median age of these was 80 y, and the causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One patient who completed the entire regimen including transplantation died of fungal pneumonia; the other 13 experienced no serious acute toxicity. One patient had late disease progression; one developed symptomatic leukoencephalopathy. Thirteen of the 20 patients remain alive. Median OS for the cohort is 698 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 70 y suggests that the regimen may be too toxic for elderly individuals.

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Kata, Dariusz, Jerzy Holowiecki, Jerzy Wojnar, Malgorzata Krawczyk-Kulis, Beata Stella-Holowiecka, Slawomira Krzemien, Maria Sadus-Wojciechowska y Grzegorz Helbig. "Isolated Extramedullary Relapses after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukaemia: Single-Center Experience with 220 Patients." Blood 106, n.º 11 (16 de noviembre de 2005): 5394. http://dx.doi.org/10.1182/blood.v106.11.5394.5394.

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Abstract Extramedullary (EM) relapses of acute leukaemia (AL) without concomitant bone marrow (BM) involvement are rare after allogeneic hematopoietic stem cell transplantation (alloHSCT) and little is known about their incidence in larger series of patients (pts) and long-term outcome. We retrospectively analysed this mode of leukemia recurrence in a cohort of 220 consecutive pts with AL (88 with ALL, 132 with AML) who underwent alloHSCT in our institution between June 1993 and May 2005. 5 out of 48 pts who relapsed (4 B-line ALL, 1 45 X, -Y, t,(8;21) AML, F/M 4/1, median age 29 years, range 28–38 years) developed isolated EM infiltrates after a median time of 13 months (range, 8–23 months) post alloHSCT. There was no evidence of leukaemic BM involvement at relapse in 5/5 pts. We revealed complete donor chimerism in 4/4 studied pts. The leukaemic origin of pathologic massess was confirmed in each case by immunohistochemical methods or flow cytometry with the use of appropriate combination of the following markers: CD10, CD19, CD20, CD45, CD79a, CD34, TdT, MPO. Our data indicate that isolated EM disease following alloBMT affects predominantly high-risk ALL pts. Sites of EM relapses varies widely among the pts, however, in most of them are localised outside the well-defined sanctuaries (i.e. CNS or testis). Local radiation therapy seems to be the most effective treatment option, however, the long-term ouctomes of the pts with EM tumors remain poor. According to our experience in selected pts individualized menagement, such as intraarterially administered anthracyclines or “total skin irradiation” may be of value. Characteristics and clinical course of pts with isolated EM relapse post alloHSCT are summarized in the table below. The extramedullar relapses after AlloHSCT Patient no Age/sex Disease/subtype, cytogenetics Sites of relapse (post-allHSCT months) Treatment after relapse Survival post relapse (months) Outcome ND = not done, CNS = central nervous system, DLI = donor lymphocyte infusion 1 30/F ALL/CD10+; t(9;22) skin of the head (13) imatinib, chemotherapy 18 Progressive disease with systemic relapse; hypoplastic death following induction 2 29/F ALL/pre-pre B, ND Left distal tibia with soft tissue (23), then soft tissues of the left hand, right forearm, skin at various sites, cervical and axillary lymph nodes (30-52) Radiotherapy (including “total skin irradiation”), IFN-alpha, DLI, daunorubicine injections to the left femoral artery, chemotherapy 30 Systemic relapse; hypoplastic death following palliative chemotherapy 3 28/F ALL/pre-preB; t(4;11) Subcutaneous tissue of the left arm (17) Radiotherapy, oral cytostatics (mercaptopurine, methotrexate), IFN-alpha 17 Systemic relapse, death during induction treatment due to pneumonia 4 28/F ALL/CD10+;t(9;22) CNS, leptomeningeal (8) Chemotherapy (high-dose cytarabine), methotrexate +steroids intrathecally, imatinib 10 Death due to fulminant gastrointestinal infection 5 38/M AML/M2, 45, X,-Y, t(8;21) Small intestine and the root of mesentery (8) Surgery 1 Immediate systemic relapse; death due to infectious complications

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Vukovic, Vojin, Darko Antic, Vladimir Otasevic, Nikica Sabljic, Sofija Sarac y Biljana Mihaljevic. "Primary central nervous system lymphoma - an overview". Medical review 75, Suppl. 1 (2022): 73–81. http://dx.doi.org/10.2298/mpns22s1073v.

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Introduction. Primary central nervous system lymphoma is a rare entity mostly presenting with non-GCB diffuse large B-cell lymphoma, being confined to the brain, spinal cord, meninges, and eyes. Diagnosis. The diagnosis is frequently established by stereotactic or open the brain biopsy, but in some cases with isolated leptomeningeal involvement, the only way is to identify atypical/monoclonal lymphocytes in cerebrospinal fluid. By workup, we aim to define the extent of disease in the central nervous system and to exclude systemic involvement. Treatment. Treatment is tailored according to the patient?s age, fitness, vital organ function, comorbidities, and available therapy. The backbone of induction treatment is high-dose methotrexate, usually within polychemotherapy. Consolidation phase is a matter of debate between two approaches: 1. high dose chemotherapy with autologous stem cell transplantation, which appears to be the preferable option for young fit patients, and 2. whole brain radiotherapy, preserved for transplant-ineligible ones. Whole brain radiotherapy has been raising concerns because of frequent cognitive impairment, which has been significantly diminished by reducing the irradiation dose. Despite a comprehensive treatment approach, many patients relapse, and since the prognosis of relapsed/refractory disease is devastating, there is a sense of urgency for novel treatment strategies. Several targeted agents and immunomodulatory drugs have been investigated in the settings of both relapsed/refractory and initial therapy, but with limited success. Ibrutinib monotherapy can induce durable remissions in the first line, but in relapse/refractory settings, the results are controversial. Conclusion. Adequate patient selection and new prospective trials should improve survival and preserve the patient?s neurological status.

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Almansour, Mubarak A., Saif Saif, Ziyad Alhrbi, Abdulrhamn Alhwaity, Ahmed Almasrahi, Waleed Alnejadi, Mohammed anwar Khan, Sarah surur Hussain y Ahmad Absi. "The Outcome of Diffuse Large B-Cell Lymphoma with CNS Involvement at Diagnosis, Single-Center Experience". Blood 136, Supplement 1 (5 de noviembre de 2020): 29. http://dx.doi.org/10.1182/blood-2020-140344.

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Introduction Central nervous system involvement is uncommon in diffuse large B cell lymphoma but always associated with a poor prognosis. We reviewed the risk of CNS involvement at diagnosis, clinical features, and survival outcome of patients with diffuse large B cell lymphoma with CNS involvement. Patients and Methods All patients with diffuse large B cell lymphoma from January 2005 to December 2019 at Princess Noorah Oncology Center were retrospectively reviewed. We included patients 15 years old or over, with biopsy-proven diffuse large B cell lymphoma. Patients with HIV disease, double or triple hit lymphomas, or Burkitt's like lymphomas were excluded. CNS involvement was confirmed by clinical, brain imaging, cerebrospinal fluid flow cytometry or biopsy Results A total of 406 patients with DLBCL were identified. The median age was 58 years. The majority of patients had stage III and IV disease (68%) and had more than one site of extranodal involvement (66%). The majority of the patients had intermediate to high IPI (66%) and elevated LDH (67%). A large proportion of patients had high CNS IPI (36%), and a minority of patients received either intravenous prophylaxis high dose methotrexate (11%) or Intrathecal methotrexate (3%). The majority of patients were treated with R-CHOP chemotherapy (92%). In total, 17 (4%) patients had CNS involvement: 9 patients (2.2 %) at diagnosis and 8 (2%) at relapse. All the nine patients who had CNS involvement at diagnosis had advanced-stage disease except one patient. Six patients had another extranodal involvement. Four out of nine patients had a non-germinal center phenotype, and all four patients had parenchymal rather than leptomeningeal involvement. All the patients received R-CHOP chemotherapy alternating with high dose methotrexate except one patient who received palliative treatment. Five out of nine patients achieved CR and survived. For those patients who had CNS relapse, the median time to relapse was 11.8 months (range 6 to 19 months), and most of the patients experienced a relapse in the first 6-13 months. All patients had an advanced stage, extranodal involvement, intermediate to high CNS-IPI, and only two of them received high dose methotrexate, and one patient received radiotherapy. Only two patients are alive: one patient received high dose methotrexate and high dose Ara C followed by high dose chemotherapy and autologous stem cell transplant. Another patient received salvage R-ESHAP for systemic relapse alternating with intrathecal MTX and waiting for stem cell transplant. The 5-year overall and progression-free survival rates for the entire DLBCL group were 84% and 73 %, respectively. Conclusion CNS involvement in diffuse large B cell lymphoma carries a poor prognosis. Aggressive CNS-directed therapy should be considered, especially in young fit patients. Disclosures No relevant conflicts of interest to declare.

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Kipar, A., W. Baumgärtner, C. Vogl, K. Gaedke y M. Wellman. "Immunohistochemical Characterization of Inflammatory Cells in Brains of Dogs with Granulomatous Meningoencephalitis". Veterinary Pathology 35, n.º 1 (enero de 1998): 43–52. http://dx.doi.org/10.1177/030098589803500104.

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The inflammatory cells of eleven dogs with canine granulomatous meningoencephalitis were characterized immunohistochemically. Macrophages were identified by antibodies directed against lysozyme and the DH82 antigen (expressed by cells of a malignant histiocytosis). T cells were demonstrated by CD3, CD43, and CD45R antigen, and B cells by immunoglobulin G and immunoglobulin M expression. Furthermore, staining for the major histocompatibility complex (MHC) class II antigen was evaluated. Diseased animals ranged from 1 to 9 years of age. Small and medium-sized breeds were affected predominantly. Lesions were widespread and localized mainly in the brain stem, less frequently in the cerebrum or cerebellum. Alterations were represented by perivascular cuffs, parenchymal granulomas, and leptomeningeal infiltrates. Lymphocytes and macrophages comprised the dominant cell populations; their percentage varied substantially between different animals and between sections from the same individual. Immunohistochemically, the bulk of lymphocytes were CD3 antigen-positive T cells, while only a few cells were CD43 and CD45R antigen-positive or were classified as B cells. The majority of macrophages expressed both lysozyme and DH82 antigen; however, some were positive for only one antigen. MHC class II antigen-expression, observed only within and in close proximity to the lesions, was found on all inflammatory cells, pericytes/endothelial cells, and microglia. Results were negative for canine distemper virus antigen and nucleoprotein mRNA, rabies virus antigen, fungi, bacteria, and protozoal agents. This immunomorphologic study reveals that inflammatory lesions in canine granulomatous meningoencephalitis consist of a heterogeneous population of MHC class II antigen-positive macrophages and predominantly CD3 antigen-positive lymphocytes. The data suggest a T cell-mediated delayed-type hypersensitivity of an organ-specific autoimmune disease as a possible pathogenic mechanism for this unique canine brain lesion.

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Vojnic, Morana, Igor Odintsov, Michael D. Offin, Allan J. W. Lui, Inna Khodos, Qing Chang, Marissa S. Mattar, Elisa De Stanchina, Marc Ladanyi y Romel Somwar. "MODL-01. TRACTABLE PATIENT-DERIVED MODELS FOR PRECLINICAL THERAPEUTIC STUDIES OF CNS METASTASES". Neuro-Oncology 24, Supplement_7 (1 de noviembre de 2022): vii290—vii291. http://dx.doi.org/10.1093/neuonc/noac209.1129.

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Abstract INTRODUCTION Brain metastases are the most common brain tumors and occur in 10-30% of cancer patients, whereas leptomeningeal disease (LMD) occurs in approximately 5% of adults with systemic malignancies. Tractable preclinical disease models that faithfully represent metastasis to the brain and recapitulate LMD are needed to improve our understanding of the biological basis of CNS disease as well developing effective therapeutic strategies. Our goal in this study was to generate representative preclinical disease models using two methods. METHODS We isolated tumor cells from CSF of 16 patients with cytologically proven LMD (9 NSCLC, 1 melanoma, 1 ovarian cancer, 1 endometrial cancer, and 4 breast cancer) and implanted the cells subcutaneously into the flank of immunocompromised mice. Cell lines were also generated from PDX tissues. Models were characterized by next-generation sequencing (NGS). We also generated a model of CNS metastasis of kinase-driven sarcoma by intracardiac (IC) injection of human mesenchymal stem cells (HMSC) expressing a SPECC1L::RET fusion (CRISPR-Cas9 gene editing). The cells (HMSC-RET) were also labeled with a luciferase construct to allow non-invasive bioluminescence imaging. RESULTS We established three PDX models (2 lung, 1 ovarian) from CSF (19% success rate compared to approximately 33% for solid tumors) and matched cell lines from the resulting PDX tissues. Intracardiac injection of HMSC-RET cells resulted in tumors establishing in several peripheral organs and the brain. SUMMARY AND CONCLUSIONS We have established disease models of CNS metastasis and LMD. Translational studies where patients with clinical suspicion of LMD undergo CSF sampling, NGS/ctDNA analysis, and PDX modeling are crucial in improving our understanding of this metastatic compartment and investigating novel treatment paradigms. Future studies will be focused on examining the biochemical and genetic nature of these tumors as well as developing effective therapeutic strategies.

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Garg, N., D. Bakhshinyan, B. Manoranjan, C. Venugopal, R. Hallett, S. Mahendram, T. Vijayakumar et al. "PS1 - 170 Bmi1 is a Therapeutic Target in Recurrent Childhood Medulloblastoma". Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 43, S4 (octubre de 2016): S10. http://dx.doi.org/10.1017/cjn.2016.358.

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Medulloblastoma (MB) is the most common malignant pediatric brain tumour, and is categorized into four molecular subgroups, with Group 3 MB having the worst prognosis due to the highest rate of metastatic dissemination and relapse. In this work, we describe the epigenetic regulator Bmi1 as a novel therapeutic target for treatment of recurrent Group 3 MB. Through comparative profiling of primary and recurrent MB, we show that Bmi1 defines a treatment-refractory cell population that is uniquely targetable by a novel class of small molecule inhibitors. We have optimized an in vivo mouse-adapted therapy model that has the advantage of generating recurrent, human, treatment-refractory MBs. Our preliminary studies showed that although chemoradiotherapy administered to mice engrafted with human MB showed reduction in tumour size, Bmi1 expression was enriched in the post-treatment residual tumour. Furthermore, we found that knockdown of Bmi1 in human recurrent MB cells decreases proliferation and self-renewing capacities of MB cells in vitro as well as both tumour size and extent of spinal leptomeningeal metastases in vivo. Oral administration of a potent Bmi1 inhibitor, PTC 028, resulted in a marked reduction in tumour burden and an increased survival in treatment cohort. Bmi1 inhibitors showed high specificity for MB cells and spared normal human neural stem cells, when treated with doses relevant for MB cells. As Group 3 medulloblastoma is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious agent such as Bmi1 inhibitor could be rapidly transitioned to clinical trials.

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Yeh, Wei Z., Subramanian Muthusamy, Penny McKelvie, Steven Collins, Ann French, Robin Filshie y Katrina Reardon. "081 Lymphoma: a great imitator in neurology and its many faces". Journal of Neurology, Neurosurgery & Psychiatry 90, e7 (julio de 2019): A26.1—A26. http://dx.doi.org/10.1136/jnnp-2019-anzan.69.

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IntroductionThe label ‘great imitator’ refers to conditions which can cause varied manifestations and mimic diseases. Lymphoma is worthy of this title. We present three cases.Cases1: 66-year-old-man with progressive vertical diplopia and unsteady gait over four weeks. MRI brain and spine demonstrated a supratentorial para-falcine soft tissue lesion, mid-thoracic cord enhancement and right axillary mass. Serum ACE was elevated. Serum HIV serology was positive. Right axillary mass core biopsy diagnosed Burkitt lymphoma.2: 50-year-old man with a 4-week history of constitutional symptoms on a background of ITP and splenomegaly. During admission he developed urinary retention, bilateral lower limb weakness and numbness and confusion. Infectious and vasculitic screens were unremarkable. CT chest, abdomen and pelvis demonstrated splenomegaly. CSF and bone marrow analyses were non-diagnostic. A random skin biopsy diagnosed intravascular lymphoma.3: 65-year-old man with two weeks of headache and diplopia on a background of previously treated Burkitt lymphoma. CSF analysis showed 45×106/L white cells and glucose < 0.6 mmol/L. Cytologic analysis was negative for malignancy. Bacterial culture and Cryptococcal antigen were negative. FDG-PET dramatically showed disseminated spinal and cranial leptomeningeal disease. MRI brain showed thin dural thickening correlating to area of increased uptake on PET. He was diagnosed with Burkitt lymphoma relapse and treated with chemotherapy and autologous stem cell transplant.ConclusionThe varied manifestations in our cases demonstrate the ability for lymphoma to mimic infective, inflammatory, granulomatous (including sarcoidosis) and neoplastic aetiologies. When the diagnosis is uncertain, the possibility of this great imitator should be considered.

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Shah, Khalid, Yohei Kitamura, Wanlu Du y Nobu Kanaya. "OTHR-02. Engineered “of the shelf” allogeneic cellular therapies for metastatic brain tumors". Neuro-Oncology Advances 3, Supplement_3 (1 de agosto de 2021): iii14. http://dx.doi.org/10.1093/noajnl/vdab071.057.

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Abstract Brain metastatic patients have multiple metastatic lesions or diagnostically challenging asymptomatic lesions, making surgery an inadequate therapeutic option. Given the challenges related to systemic delivery of a majority of therapeutic agents across the BBB, engineered cell based therapies offer an excellent platform to target metastatic tumors in the brain. We have established the use tumor cell surface receptor targeted allogeneic “off the shelf” gene engineered cellular therapies and developed two different approaches to treat brain metastases. In one approach, we have armed allogenic stem cells (SC) with oncolytic herpes virus (oHSV) variants and tested them in different mouse models of brain metastatic (BM) tumor derived from brain seeking metastatic melanoma tumor cells from patients. We show that intracarotid artery administration of SC-oHSV effectively tracks metastatic tumor lesions and significantly prolongs the survival of brain tumor bearing mice. We also show that a combination of SC-oHSV and PD-L1 blockade increases IFNγ-producing CD8+ tumor-infiltrating T lymphocytes and results in a profound extension of the median survival in syngeneic brain metastatic melanoma mouse models. In another approach, we have explored the versatility of cell mediated bi-functional EGFR and DR4/5-targeted treatment in basal like breast cancer (BLBC) mouse models featuring different patterns of brain metastasis. Most BLBC lines demonstrated a high sensitivity to EGFR and DR4/5 bi-targeting therapeutic protein, EVDRL [anti-EGFR VHH (EV) fused to DR ligand (DRL)]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the EV domain facilitated in augmenting DR4/5-DRL binding and enhancing DRL-induced apoptosis. EVDRL releasing allogeneic SCs alleviated tumor-burden and significantly increased survival in mouse models of residual-tumor after macrometastasis resection, perivascular niche micrometastasis, and leptomeningeal metastasis. These findings provide a clinically applicable therapeutic platform to target disseminated metastatic lesions in the brain and define a new paradigm for treatment of brain metastases.

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Bociek, R. Gregory, Peerapon Wong, Fausto R. Loberiza, Philip Bierman, Julie M. Vose, Nicole Shonka y James O. Armitage. "High-Dose Therapy (HDT) with Hematopoietic Stem Cell Transplantation (HSCT) Is Effective Therapy for Patients with Non-Hodgkin Lymphoma (NHL) and Central Nervous System (CNS) Involvement". Blood 116, n.º 21 (19 de noviembre de 2010): 1358. http://dx.doi.org/10.1182/blood.v116.21.1358.1358.

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Abstract Abstract 1358 Patients with NHL and CNS involvement have a poor prognosis when treated with conventional therapy. We performed a retrospective review of the Nebraska Lymphoma Study Group database to identify patients with NHL and CNS involvement who underwent HSCT. CNS involvement was defined as the presence of lymphomatous cells in cerebrospinal fluid, clear evidence of leptomeningeal disease by imaging studies, or biopsy proven parenchymal disease. Between January 1991 and December 2006, 24 such patients underwent HDT/HSCT. The median age at transplantation was 43 years (range 20–61). Fifty four percent of patients had diffuse large B-cell lymphoma. Sixty three percent of patients had parenchymal CNS involvement. CNS directed therapy as part of salvage prior to transplantation included intrathecal chemotherapy in 19 patients, high-dose methotrexate in 15 patients, and cranial irradiation in 10 patients. All but one patient achieved CNS remission prior to transplant. Twenty patients underwent autologous HSCT and four underwent allogeneic HSCT. The majority of patients were conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM). At a median follow-up of 67 months for surviving patients (range 35–224 mo) the 1-year progression-free survival (PFS) is 50% (95% confidence interval [CI] 30–67) and the 5-year PFS is 38% (95% CI 20–56). The 1-year overall survival (OS) is 65% (95% CI 44–80) and the 5-year overall survival is 52% (95% CI 31–70). Eleven patients have relapsed and all relapses occurred within 13 months of HSCT. Thirteen patients remain alive and in remission. There have been 9 deaths due to disease recurrence and one death with no evidence of relapse. Among 15 patients who received high-dose methotrexate as part of CNS directed therapy the 5-year probability of PFS was 47% (95% CI 23–68) compared with 22% (95% CI, 3–51) in 9 patients not receiving high-dose methotrexate (p = 0.24). For patients transplanted as consolidation of initial therapy (n = 9) the 3-year probability of PFS was 63% (95% CI 29–96) compared with 36% (95% CI 0–71) for 12 patients transplanted in sensitive relapse (p = 0.36). Those same 9 patients had an 88% probability of survival at three years post transplant (95% CI 65%-100%) compared with 33% (95% CI 0–68) for the 12 patients with sensitive relapse (p = 0.046). In conclusion patients with NHL and CNS involvement who undergo HDT/HSCT appear to have similar outcomes to patients transplanted without CNS involvement. Patients destined to relapse appear to do so relatively soon after transplantation. Patients who received high-dose methotrexate as CNS directed therapy prior to transplant had a trend toward superior PFS compared with those receiving only intrathecal methotrexate, CNS irradiation, or both. Disclosures: No relevant conflicts of interest to declare.

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Kata, Dariusz, Jerzy Holowiecki, Jerzy Wojnar, Beata Stella-Holowiecka, Slawomira Krzemien, Krzysztof Wozniczka y Grzegorz Helbig. "Occurrence and Treatment of Isolated Extramedullary Relapses after Allogeneic Hematopoietic Stem Cell Transplantation for Leukaemias: A Single Institute Experience with 442 Patients." Blood 108, n.º 11 (16 de noviembre de 2006): 5337. http://dx.doi.org/10.1182/blood.v108.11.5337.5337.

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Abstract Isolated extramedullary (EM) relapses of leukaemias are rare after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the data regarding their incidence in larger series of patients (pts) and long-term outcome are scarce. We retrospectively analysed this pattern of leukaemia recurrence in a cohort of 442 consecutive pts with leukaemias (103 with ALL, 155 with AML, 184 with CML) who underwent allo-HSCT in our center between June 1993 and December 2005. 7 out of 68 pts who relapsed (4 B-line ALL, 2 AML, 1 CML, F/M 4/3, median age 28 years, range 28–38 years) developed isolated EM infiltrates after a median time of 15 months (range, 8 – 33 months) post allo-HSCT. There was no evidence of leukaemic bone marrow involvement at relapse in 7/7 pts. We revealed complete donor chimerism in 5/7 studied pts. The leukaemic origin of pathologic masses was confirmed in each case by immunohistochemical methods or flow cytometry. Our data indicate that isolated EM disease following allo-HSCT occurs predominantly in high-risk ALL pts, being rarely observed in pts with CML. Sites of relapses varies widely among the pts, however, in most of them EM infiltrates are localized outside the well-defined sanctuaries (CNS or testis), predominantly within the skin and/or subcutaneous tissue. Local radiation therapy seems to be effective treatment option, but it does not prevent from dissemination and should be followed by other therapeutic modalities. In selected pts individualized management, such as intraarterially administered anthracyclines or “total skin irradiation” may be of value. Tyrosine kinase inhibitors such as imatinib or dasatinib should also be considered in cases of Ph+ ALL or c-kit positive AML. Occurrence of EM relapse offers only a narrow window for quick intervention, however, optimal treatment remains a challenge. Characteristics and clinical course of pts with isolated EM relapse post allo-HSCT Case no. Age/Sex Disease/subtype, cytogenetics Sites of relapse (post-allo-HSCT months) Treatment after relapse Survival post relapse (months) Outcome ND = not done, CNS = central nervous system, DLI = donor lymphocyte infusion, BP = blastic phase 1 30/F ALL/CD10+, t(9;22) Skin (13) Imatinib, chemotherapy 18 Systemic relapse;death following induction 2 29/F ALL/pre-preB, ND Tibia with soft tissue (23), then soft tissues and skin at various sites, lymph nodes (30–52) Radiotherapy (including “total skin irradiation”), IFN-alpha, DLI, daunorubicine intraarterially, chemotherapy 30 Systemic relapse; death following palliative chemotherapy 3 28/F ALL/pre-preB, t(4;11) Subcutaneous tissue (17) Radiotherapy, oral cytostatics (mercaptopurine, methotrexate), IFN-alpha 17 Systemic relapse, death during induction treatment due to pneumonia 4 28/F ALL/CD10+, t(9;22) CNS, leptomeningeal (8) High-dose cytarabine, methotrexate + steroids intrathecally, imatinib 10 Death due to fulminant gastrointestinal infection 5 38/M AML/M2, 45, X,-Y, t(8;21) Small intestine and the root of mesentery (8) Surgery 1 Immediate systemic relapse; death due to infectious complications 6 28/M AML/M4 (CD117+), 46, XY, t(19;11), del 13 Skin (33) Imatinib, dasatinib 6+ Alive with systemic relapse, treated with dasatinib 7 28/M CML/BP, Ph+, t(3;21)(q34;q11) Testicle, paraspinal (15) Surgery, local radiotherapy 3 Death due to cytomegalovirus pneumonia

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Koeniger, Tobias, Luisa Bell, Anika Mifka, Michael Enders, Valentin Hautmann, Subba Rao Mekala, Philipp Kirchner et al. "Bone marrow-derived myeloid progenitors in the leptomeninges of adult mice". Stem Cells 39, n.º 2 (11 de diciembre de 2020): 227–39. http://dx.doi.org/10.1002/stem.3311.

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Abstract Although the bone marrow contains most hematopoietic activity during adulthood, hematopoietic stem and progenitor cells can be recovered from various extramedullary sites. Cells with hematopoietic progenitor properties have even been reported in the adult brain under steady-state conditions, but their nature and localization remain insufficiently defined. Here, we describe a heterogeneous population of myeloid progenitors in the leptomeninges of adult C57BL/6 mice. This cell pool included common myeloid, granulocyte/macrophage, and megakaryocyte/erythrocyte progenitors. Accordingly, it gave rise to all major myelo-erythroid lineages in clonogenic culture assays. Brain-associated progenitors persisted after tissue perfusion and were partially inaccessible to intravenous antibodies, suggesting their localization behind continuous blood vessel endothelium such as the blood-arachnoid barrier. Flt3Cre lineage tracing and bone marrow transplantation showed that the precursors were derived from adult hematopoietic stem cells and were most likely continuously replaced via cell trafficking. Importantly, their occurrence was tied to the immunologic state of the central nervous system (CNS) and was diminished in the context of neuroinflammation and ischemic stroke. Our findings confirm the presence of myeloid progenitors at the meningeal border of the brain and lay the foundation to unravel their possible functions in CNS surveillance and local immune cell production.

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Doolittle, Nancy D., Lauren Abrey, Tamara Shenkier, Tali Siegal, Jacoline Bromberg, Edward Neuwelt, Carole Soussain et al. "Isolated Brain Parenchyma Relapse of Non-Hodgkin’s Lymphoma (NHL): A Descriptive Analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG)." Blood 108, n.º 11 (1 de noviembre de 2006): 2026. http://dx.doi.org/10.1182/blood.v108.11.2026.2026.

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Abstract Background: Isolated brain parenchyma relapse as initial site of relapse is a rare complication of NHL and carries a poor prognosis. Few large series focus on treatment characteristics and outcomes of isolated brain parenchyma relapse of NHL. Methods: The IPCG conducted a retrospective review of patient and treatment characteristics and outcomes of this complication. Following initial diagnosis and treatment of NHL (1980–2004), cases with brain parenchyma relapse as initial relapse site, with no evidence of lymphoma elsewhere in the body at the time of brain relapse, were eligible. Cases with brain, spine or leptomeningeal involvement at NHL diagnosis were not eligible. Results: 113 cases were assembled from 13 investigators in 8 countries. Preliminary data summaries are: 94 (83%) cases had diffuse large B-cell NHL, 5 (4%) follicular lymphoma, 3 (3%) Burkitt’s lymphoma, other NHL subtypes (11) . Median age at NHL diagnosis was 61yrs (16–85 yrs). 55% were male. Median ECOG at NHL diagnosis was 1. Median time from NHL diagnosis to isolated brain relapse was 1.8 yrs (3 months–15.9 yrs). 76 (67%) relapsed in brain less than 3 yrs after NHL diagnosis. Symptoms at brain relapse included mental status changes in 37%, gait/balance disturbance (27%), motor/sensory symptoms (23%). Median ECOG at brain relapse was 2. Parenchyma relapse was documented by brain imaging plus biopsy in 54 (48%), or imaging without biopsy in 58 (52%); not reported (1). 53 (48%) cases had one brain lesion; 56 (50%) had two or more lesions; not reported (4). Site of relapse was cerebral hemispheres in 53 (48%) cases, deep brain structures (brain stem/cerebellum) in 30 (27%), cerebral hemispheres and deep brain structures in 23 (21%); not reported (7). At brain relapse, CSF was positive in 11 (10%) cases, negative in 56 (50%); not reported (46[40%]). Treatment for brain relapse was chemotherapy alone in 52 (46%) cases, WBRT alone in 34 (30%), chemotherapy followed by RT in 26 (23%), and brain surgery alone (1). 78 (69%) cases are deceased. Median survival from brain parenchyma relapse to death was 1.6 yrs (95% CI: 11 months–2.6 yrs). Effect of treatment type at brain relapse on survival, will be reported. Brain lymphoma was the cause of death in 49 (63%) cases; CNS toxicity was the cause in 6 (8%) cases. Conclusion: Though a rare relapse site, prospective studies are needed to improve understanding and outcomes of isolated brain parenchyma relapse of NHL.

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Sahebi, Firoozeh, Amrita Krishnan, George Somlo, Leslie Popplewell, P. Parker, Ji-Lian Cai, Len Farol et al. "A Phase II Study of Sequential Velcade/Thalidomide/ Dexamethasone (VTD) as Maintenance Therapy Post Single Autologous Peripheral Stem Cell (PSCT) in Patients with Multiple Myeloma." Blood 114, n.º 22 (20 de noviembre de 2009): 3403. http://dx.doi.org/10.1182/blood.v114.22.3403.3403.

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Abstract Abstract 3403 Poster Board III-291 Autologous PSCT remains standard treatment in younger patients (pts) with multiple myeloma. However, relapse is the major cause of treatment failure. Several studies have reported improved progression-free survival (PFS) and possibly overall survival with thalidomide alone or in combination with steroid and chemotherapy as maintenance/consolidation therapy post autologous PSCT. We performed a phase II study investigating the role of sequential velcade/thalidomide/dexamethasone (VTD) as maintenance therapy post single PSCT. The objectives were to examine the toxicities of prolonged course of sequential VTD, CR rate, PFS and overall survival following single autologous PSCT. Within 4-8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly velcade (vel) at 1.3mg/m2 /wk x 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d x 4 d for 6 months, followed by thalidomide (thal) at 50 -200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Twenty-eight pts have been enrolled. Median age is 54 years (29-66). Median time from diagnosis is 7.9 mo. (4.2 – 145). Disease stage at diagnosis; by Salmon-Durie (II/III 6/22) and by ISS (I/II/III 11/9/7/missing data in 1 pt). Pts received induction treatment with thal/dex (14), velcade based (15) and revlimid based regimens (7). Median B2M at enrollment is 1.75 mg/L (1.14 -5.3). Disease status at enrollment; CR (7) VGPR (9), PR (11), SD (1). Three pts have chromosome 13 abnormalities (1 pt by karyotype and 2 pts by FISH). Results: All pts have undergone transplant. Four pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (3), and persistent thrombocytopenia (1) after PSCT. Twenty-four pts started maintenance vel/dex within 4-8 weeks of PSCT. Nine pts have completed 6 months of vel/dex. Two pts stopped vel/dex because of low WBC (1) or PN (1). With a median F/U of 5.2 mo. (1.2 -17.3) nine of 28 pts (33%) have achieved CR post PSCT and six out of 11 evaluable pts (55%) have achieved CR after vel/dex. Six out of 9 pts (66%) who have completed 6 mo. of vel/dex achieved CR. Two out of 9 pts (22%) have upgraded their response with vel/dex. Four pts have completed 6 month of thal/dex and are beyond 1 year post PSCT. Two out of 4 pts remain in CR at one year post PSCT. One pt is in PR and 1 pt has progressed. Two pts could not complete thal/dex phase of therapy because of relapse (1) and grade III GI toxicity (1). Three pts have relapsed of whom 1 pt died of relapsed myeloma (leptomeningeal disease). No grade IV toxicity has been noted. Grade III toxicities have occurred in 4 pts; low platelet (1), fatigue (1), mood alteration (1), GI (severe constipation) (1). Thirteen pts have peripheral neuropathy (PN). Ten pts had PN grade I at enrollment. Only 3 pts have developed PN on the study and all are grade I - II. Median velcade dose is 1.3 mg /m2/wk and thalidomide dose is 100mg /d. Conclusion: Prolonged sequential velcade/thalidomide/dexamethasone maintenance therapy post single autologous PSCT is well tolerated with no severe peripheral neuropathy. Fifty-five percent of pts have achieved CR and 22% have upgraded their response after six months of velcade/dexamethasone therapy suggesting this is an active and well tolerated maintenance strategy post PSCT. Disclosures: Sahebi: Celgene: Honoraria; Millennium Pharmaceutical: Research Funding. Off Label Use: The use of bortezomib(Velcade)in combination with thalidomide and dexamethasone is investigated as maintenance therapy post autologuous stem cell transplant in patients with multiple myeloma.

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Fleming, Megan, Ying Huang, Emily Dotson, David A. Bond, John C. Reneau, Narendranath Epperla, Jonathan E. Brammer et al. "Outcomes of Patients with Diffuse Large B Cell and High-Grade B Cell Lymphomas with Synchronous CNS and Systemic Involvement at Diagnosis Treated with High-Dose Methotrexate and R-CHOP: A Single-Center Retrospective Study". Blood 138, Supplement 1 (5 de noviembre de 2021): 1425. http://dx.doi.org/10.1182/blood-2021-148662.

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Abstract Introduction. The optimal treatment of patients with diffuse large B cell (DLBCL) and high-grade B cell (HGBCL) lymphomas with synchronous central nervous system (CNS) and systemic involvement at diagnosis is not well defined. High-dose methotrexate (MTX) administered concurrently with R-CHOP (RM-CHOP) is a commonly used regimen, but data on outcomes achieved with this regimen are limited. Methods. We included consecutive patients with DLBCL and HGBCL with synchronous CNS and systemic involvement at diagnosis treated with RM-CHOP from 1/2012 - 1/2021. Progression-free survival (PFS) was calculated from the time of diagnosis to either progression or death, and overall survival (OS) from the time of diagnosis to death due to all causes; patients without events were censored at the time of the last follow-up. PFS and OS were estimated through the Kaplan-Meier method. Results. Fifty patients were included. Median age was 62 years (range, 19 - 80), 58% were male, 82% had DLBCL (n=41) and 18% had HGBCL (n=9). Six patients (14%) had MYC with BCL2 and/or BCL6 rearrangements by fluorescence in situ hybridization (available for n=43), and 11 patients (55%) had MYC and BCL2 double-expression by immunohistochemistry (available for n=20). ECOG performance status was ≥2 in 16 patients (36%). LDH was elevated in 41 patients (87%).The IPI score classified 40% and 56% of patients as having intermediate- or high-risk disease, respectively. The median number of extranodal sites was 2 (range, 1-7) with 48% having ≥3 extranodal sites. CNS involvement was parenchymal in 14 patients (28%), leptomeningeal in 28 (56%), or both in 8 (16%). The most common extranodal sites outside the CNS were renal/adrenal (n=6, 12%), paraspinal (n=5, 10%), and testicular (n=4, 8%). The majority of R-CHOP cycles (89%, n=222) included MTX with a median number of MTX-containing R-CHOP cycles administered per patient of 5 (range, 1-6). MTX starting dose was 3.5 g/m 2 in all but 3 patients (range, 1.5 - 2 g/m 2). Intrathecal MTX was administered in 21 patients (42%). Treatment with RM-CHOP was followed by consolidative stem cell transplantation in 15 patients (30%) including 14 autologous (28%) and 1 (2%) allogeneic. The objective response rate following RM-CHOP was 66% including complete response in 60%. With a median follow-up of 31 months (range, 4 - 100), the median PFS and OS were 17.7 months (95% confidence interval (CI), 6.9 - not reached [NR]) and NR (95% CI, 12.5 - NR), respectively, with 1-year PFS and OS of 57% (95% CI, 42-69%) and 68% (95% CI, 52-79%), respectively (Figure A). Twelve patients had CNS relapse/progression with a 1-year cumulative incidence of CNS progression/relapse of 21% (95% CI, 10-33%) (Figure B). Outcomes were particularly poor in patients with HGBCL, with median PFS and OS of 6.3 (95%CI, 1.2 - 9.8) months and 7.3 (95%CI, 1.2 - 21.2) months, and 1-year PFS and OS of 13% (95%CI, 1-44%) and 38% (95% CI, 9-68%), respectively (Figures C and D). Of the 7 patients with HGBCL who relapsed/progressed, 3 had CNS involvement only (1 parenchymal, 2 leptomeningeal), 3 had systemic involvement only, and 1 had both (parenchymal). Three patients received subsequent systemic treatment and only 1 responded (partial response). In patients with DLBCL, with a median follow-up of 33.5 months (range, 4 - 100), the median PFS and OS were both NR (95%CI, 9.5 months - NR and 21 months - NR, respectively) and the 1-year PFS and OS were 65% (95% CI, 49-78%) and 74% (95%CI, 57-85%), respectively. Of the 14 patients with DLBCL who relapsed/progressed, 8 had CNS involvement only (4 parenchymal, 2 leptomeningeal, 2 both) and 6 had systemic involvement only. Nine patients received subsequent systemic treatment of whom 5 patients responded (3 complete and 2 partial responses) Conclusions. To our knowledge, this is one of the largest studies of patients with DLBCL and HGBCL with synchronous CNS and systemic involvement at diagnosis treated with RM-CHOP. Patients with HGBCL had poor outcomes with median PFS and OS of 6 and 7 months, respectively. Patients with DLBCL had more favorable outcomes with median PFS and OS not reached after a median follow-up of 33.5 months. CNS involvement was more common than isolated systemic involvement at relapse/progression. CNS involvement in aggressive B-cell non-Hodgkin lymphoma at diagnosis remains a major therapeutic challenge, dictates clinical outcomes, and requires more effective treatment options. Figure 1 Figure 1. Disclosures Dotson: AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Bond: Kite/Gilead: Honoraria. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Christian: Millenium: Other: Institution: Research Grant/Funding; Triphase: Other: Institution: Research Grant/Funding; Celgene/BMS: Other: Institution: Research Grant/Funding; Acerta: Other: Institution: Research Grant/Funding; Seattle Genetics: Consultancy, Other: Institution: Research Grant/Funding; Genentech: Consultancy, Other: Institution: Research Grant/Funding; AstraZeneca: Consultancy; VeraStem: Consultancy; Morphosys: Consultancy, Other: Institution: Research Grant/Funding; Immunomedics: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding. Baiocchi: Prelude Therapeutics: Consultancy; Atara Biotherapeutics: Consultancy; Codiak Biosciences: Research Funding; viracta: Consultancy, Current holder of stock options in a privately-held company. Maddocks: Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months; Morphosys: Divested equity in a private or publicly-traded company in the past 24 months; ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Beigene: Divested equity in a private or publicly-traded company in the past 24 months; KITE: Divested equity in a private or publicly-traded company in the past 24 months; Celgene: Divested equity in a private or publicly-traded company in the past 24 months; Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months; BMS: Divested equity in a private or publicly-traded company in the past 24 months; Merck: Divested equity in a private or publicly-traded company in the past 24 months; Novatis: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Divested equity in a private or publicly-traded company in the past 24 months; Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months. Sawalha: Epizyme: Consultancy; BeiGene: Research Funding; Celgene/BMS: Research Funding; TG Therapeutics: Consultancy, Research Funding.

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Chi, S., S. Gardner, L. Y. Ji, R. Sposto, G. Dhall y J. Finlay. "Newly diagnosed high-risk malignant brain tumors with leptomeningeal dissemination in young children: A final update on Head Start II Regimen A2 intensified with high-dose methotrexate". Journal of Clinical Oncology 25, n.º 18_suppl (20 de junio de 2007): 9552. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.9552.

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9552 Background: The prognosis for young children with newly diagnosed malignant brain tumors with leptomeningeal dissemination remains poor. From Jan 1997 to Mar 2003, “Head Start II” Regimen A2, intensified with high-dose methotrexate, was offered to this high-risk population. Methods: Eligibility: patients < 10 yrs of age; confirmed diagnosis of medulloblastoma (MB), primitive neuroectodermal tumor (PNET), ependymoma and choroid plexus carcinoma (CPC); and high-risk status as determined by neuroaxis dissemination. Patients with atypical teratoid/rhabdoid tumor (ATRT), regardless of stage, were also eligible. Treatment: 5 cycles of vincristine (0.05 mg/kg/week × 3 doses), cisplatin (3.5 mg/kg), etoposide (4 mg/kg/day × 2 days), cyclophosphamide (65 mg/kg/day × 2 days), and methotrexate (400 mg/kg) with leucovorin. Children without progressive disease (PD) by the end of induction underwent a single consolidation cycle (carboplatin, etoposide, thiotepa) with autologous stem cell rescue. Reduced dose RT (2340cGy CSI and focal boost) was reserved for any with residual disease at the end of induction or for the older patient (>6 yrs of age). Results: 40 patients were enrolled (MB, 22; PNET, 6; ependymoma, 5; AT/RT, 6; CPC, 1), med age at diagnosis 38 mos (range 5 to 119 mos). Significant toxicities of this intensified regimen included GI toxicities and infections. Among the entire cohort, there were 26 CR, 6 PR, 2 with stable disease and 4 with PD (and 2 toxic deaths), for a CR +PR response rate of 82%. For disseminated MB (4 M1; 2 M2; 16 M3), the CR rate alone is 77% (17/22). The 5-year EFS and OS for disseminated MB are 45% (95% CI, 24 % to 64%) and 54% (95% CI, 31% to 72%), respectively. Of note, 6/12 MB survivors (all M3) did not receive RT and all are NED >5 years from diagnosis. In addition, there are 3 AT/RT survivors, 12, 54 and 66 mos post-diagnosis who did not receive RT. Conclusions: This intensified regimen is feasible and tolerable. For patients with disseminated MB, the majority of whom had M3 disease at diagnosis, the impressive response rate and outcomes suggest that the addition of methotrexate is justified for future studies. Long- term neuropsychological outcomes are being studied at this time. No significant financial relationships to disclose.

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Zamarin, Dmitriy, Manisha Bhutani, Danielle Chimento, Sergio Giralt, Nikoletta Lendvai, Heather Landau, Alex Lesokhin, David Chung, Dilip Babu y Hani Hassoun. "Patterns of Disease Relapse and Progression in Patients with Multiple Myeloma After First Line Therapy with Autologous Stem Cell Transplantation: Implications for Patient Monitoring After Transplantation". Blood 118, n.º 21 (18 de noviembre de 2011): 825. http://dx.doi.org/10.1182/blood.v118.21.825.825.

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Abstract Abstract 825 BACKGROUND: Autologous stem cell transplantation (ASCT) is a widely used therapeutic option in first line treatment of multiple myeloma (MM). However, many patients eventually relapse. While precise knowledge of relapse and progression (R/PD) patterns would be important to generate evidence based surveillance recommendations after ASCT, such data is limited in the literature, especially in the era following the introduction of the free light chain assay. The purpose of this study is to examine the patterns of post-ASCT relapse and to derive evidence based recommendations for optimal surveillance of patients. METHODS: We performed a retrospective analysis on 258 patients with MM who underwent ASCT within one year of diagnosis at MSKCC between 2000 and 2010, as part of first line therapy. We used the IMWG standard criteria for serologic and clinical R/PD. We first determined for all patients the date of serologic R/PD. Patients identified as having serologic R/PD were further examined to determine whether clinical (anemia, renal failure, hypercalcemia, development of soft tissue lesions), radiologic (skeletal survey) or urinary R/PD had anteceded serologic R/PD. Several groups of patients were derived and further analyzed in terms of relapse patterns and adequacy of follow up. RESULTS: Among 258 patients, 173 were determined to have serologic R/PD at a median of 19.2 months post-transplant. Among these patients, on the dates of their serologic R/PD, 17 (9.8%) had concurrent overt symptomatic evidence of clinical/radiologic R/PD (Group A symptomatic R/PD), while 156 (90.2%) were found to have isolated asymptomatic serologic R/PD without apparent evidence of concomitant clinical/radiologic R/PD (Group B asymptomatic R/PD). Group A included patients with distinct and sometimes coinciding clinical characteristics (poor risk cytogenetics with aggressive disease (n=3), leptomeningeal relapse (n=1), soft tissue relapse (n=4) and acute severe anemia at relapse (n=3)); patients with IgA gammopathy (n=5); and patients considered to have inadequate serologic follow up intervals (range of follow up interval between date of serologic R/PD and prior serologic testing 149 to 245 days) (n=6). Upon further examination of group B, 44 patients had radiologic imaging at the time of serologic R/PD (within 4 weeks following the date of serologic R/PD). Fourteen among them (32%) had evidence of new bone lesions. Among all 173 patients with serologic R/PD, 83 patients had a skeletal survey within one year prior to the date of serologic R/PD. Only 3 (3.6%) had evidence of radiologic R/PD anteceding serologic R/PD. All 3 patients were considered to have had inadequate serologic follow up interval (Range 208 to 252 days). Abnormal urine immunofixation (UIF) anteceded serologic R/PD in 5 out of 41 (12%) patients tested who had achieved CR post transplant. In these patients the abnormal UIF anteceded the serologic R/PD by a mean of 2.4 months. Abnormal UPEP anteceded serologic R/PD by 1.9 months in only 1 out of 40 (2.5%) patients tested who had achieved less than CR post transplant. CONCLUSIONS: Based on the results of this analysis, several conclusions can be drawn: 1) The vast majority of R/PD in patients with MM are asymptomatic R/PD detected first by serologic studies. A small percentage of patients (those with aggressive cytogenetics, specific relapse types including soft tissue, severe cytopenia, and IgA gammopathy) will have symptomatic R/PD with overt concomitant evidence of clinical and/or radiologic R/PD at the time of serologic R/PD; 2) Among patients who have apparent asymptomatic R/PD, a significant percentage will have evidence of skeletal lesions and therefore imaging should be recommended in these patients; 3) In the absence of serological R/PD, routine surveillance screening with yearly skeletal surveys cannot be recommended based on this analysis since this test was not useful in any of the analyzable patients in whom it was obtained; 4) Aside from few patients in CR whose relapse may be detected earlier by UIF (with probably no clinical benefit), all patients with multiple myeloma whose disease progresses will have serologic R/PD at the time of progression and follow up limited to serologic testing may well be sufficient for monitoring patients with MM post transplant. Disclosures: No relevant conflicts of interest to declare.

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Sanghrajka, Reeti, I.-li Tan, Alexandre Wojcinski, Harikrishna Rallapalli, Daniel Turnbull, Kai Ge y Alexandra Joyner. "TMOD-03. SOMATIC MUTATIONS OF CHROMATIN REGULATOR Kmt2d IN CEREBELLAR PRECURSORS INFLUENCES SHH-MEDULLOBLASTOMA TUMORIGENESIS". Neuro-Oncology 21, Supplement_6 (noviembre de 2019): vi263. http://dx.doi.org/10.1093/neuonc/noz175.1102.

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Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, is a classic example of dysregulation of developmental pathways leading to tumorogenesis. Despite advancements in multi-modal therapies, most patients suffer from long-term neurocognitive and neuroendocrine disabilities. The Sonic Hedgehog subgroup of MB (SHH-MB) accounts for ~30% of all cases and originates from ATOH1+ cerebellar granule cell precursors (GCPs). Experimental data in mice has shown that activating mutations in the SHH pathway induce tumors only in rare GCPs, suggesting that additional mutations and epigenetic changes are required to influence tumor progression. The KMT2D gene, encoding the histone-lysine N-methyltransferase 2D, is amongst the ten most frequently mutated genes in MB, with somatic mutations seen in ~15% of all SHH-MB patients. We developed sporadic mouse models of SHH-MB with a low penetrance to enable studies of secondary mutations (Tan, PNAS, 2018). Immunofluorescence staining for KMT2D on early-stage SHH-MB lesions, mid-stage and late-stage tumors revealed that a subset of lesions/tumors (16/98) do not express KMT2D and are negative for H3K4me3. Interestingly, P53 and KMT2D expression showed a positive correlation in ~94% of tumors/lesions and NeuN and KMT2D showed a positive correlation in ~92% of tumors/lesions. In order to determine the roles for KMT2D in GCP proliferation and differentiation, and uncover whether and how KMT2D promotes SHH-MB tumorigenesis, we are using genetic mouse-models whereby Kmt2d is heterozygously or homozygously deleted alone, or in conjunction with activation of the SHH pathway. Mice with SHH-MB tumors expressing SmoM2 and a loss of Kmt2d develop aggressive tumors at high penetrance, with metastatic leptomeningeal spread in the brain stem and spinal cord. Thus, loss of Kmt2d increases SHH-MB tumor progression and leads to malignancy. Ongoing studies are determining how the chromatin landscape and gene expression are changed when Kmt2d is deleted in GCPs.

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Kramer, K., S. Modak, B. H. Kushner, M. Souweidane, S. Wolden, J. Humm, P. Zanzonico, P. Smith-Jones, S. Larson y N. Cheung. "Metastatic neuroblastoma (NB) to the central nervous system (CNS): Improved outcome with combined modality including 131-I-8H9 or 131-I-3F8 radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF)". Journal of Clinical Oncology 25, n.º 18_suppl (20 de junio de 2007): 2022. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2022.

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2022 Background: NB metastatic to the CNS (NB-CNS) is difficult to control. We describe a salvage regimen incorporating intra- Ommaya RIT delivered to the CSF. Methods: 37 patients (pts) with NB-CNS (parenchymal masses and/or leptomeningeal [LM] carcinomatosis) treated at MSKCC from 1988 through 2006 were reviewed. Nine (group #1) of 37 pts developed NB-CNS metastasis (median age 3.8 years) and were treated with a salvage regimen: resection of parenchymal masses, 2160 cGy craniospinal irradiation (CSI), intravenous irinotecan and oral temozolomide, and RIT with 131I-8H9 and or 131I-3F8 targeting tumor associated antigens on phase I/II studies. Immunotherapy (intravenous anti-GD2 monoclonal antibody 3F8 plus subcutaneous GM-CSF) was also given for systemic control. Survival was compared to the other 28 (group #2) pts who developed NB-CNS (median age 4.2 years) treated with combinations of surgery, chemotherapy, and radiation but without CSI + RIT. Results: All 37 pts had high risk disease at initial diagnosis of NB. 9 of 9 group #1 pts had marrow and/or bony involvement; 6 of 9 had MYCN amplification and 5 of 9 had serum LDH >1500 U/ml. All had intensive chemotherapy and radiotherapy prior to CNS relapse. Despite this, the CNS salvage regimen was well-tolerated. Myelosuppression following CSI and chemotherapy was common; 2 pts received stem cell support. All 9 pts in the RIT group are alive and well, disease-free at 3+, 11+, 15+, 18+, 18+, 20+, 22+, 31+, 42+ months since CNS relapse. In contrast, pts in group #2 had a median time to death of 5.5 months, (p<0.0001) for survival by Kaplan-Meier analysis. Conclusion: Similar to CNS metastases in most other solid tumors, conventional therapies have been ineffective for NB-CNS. The addition of RIT using 131I-3F8 or 131I-8H9 is well-tolerated and improves the prognosis for these high risk patients. No significant financial relationships to disclose.

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Kaspers, Gertjan, Ron Mathot, Satianand Ramnarain, Denise Niewerth, Franco Locatelli, Eveline S. J. M. De Bont, Franca Fagioli, Pierre Rohrlich, Arend von Stackelberg y Michel Zwaan. "Pharmacokinetic Results Of a Feasibility and Phase II Study (ITCC 021) On Bortezomib (BTZ) In Pediatric Relapsed ALL: Lack Of Significant Penetration Of BTZ In The Cerebrospinal Fluid". Blood 122, n.º 21 (15 de noviembre de 2013): 1439. http://dx.doi.org/10.1182/blood.v122.21.1439.1439.

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Abstract Prognosis of refractory and relapsed ALL is poor and improvement requires the introduction of agents with a new mechanism of action. Bortezomib (BTZ) as a proteasome inhibitor is such an agent, and was safe as single agent in phase I studies in children (Blaney 2004; Horton 2007). Messinger et al. (2012) reported a single-arm study that BTZ can be combined safely with conventional drugs; the combination was remarkably effective. BTZ results in sensitization of malignant cells to anticancer agents, both in vitro for leukemias as well as for multiple myeloma patients. In patients with ALL, this effect regarding glucocorticoids has not been addressed yet. It also has not been studied whether BTZ reaches the cerebrospinal fluid (CSF), which is relevant in pediatric leukemias in view of the frequent leptomeningeal involvement. In the setting of the lack of clinical experience with BTZ in children in Europe, we developed a European multicentre feasibility/phase II study in refractory or relapsed ALL, in which all patients get BTZ (NTR 1881, EUDRaCT 2009-014037-25, ITCC 021). A randomisation is done for BTZ to start “early”, on day 1 of treatment, or “late”, on day 8 of treatment. Bortezomib is given as iv push for 4 doses at 1.3 mg/m2/dose, thus in group “early” on days 1, 4, 8 and 11 and in group “late” on days 8, 11, 15 and 18. In addition, all patients receive dexamethasone (10 mg/m2/day in 3 doses for 2 weeks, orally or iv) and vincristine (1.5 mg/m2/dose with a maximum of 2 mg as 1-hour infusion on days 8 and 15), and one intrathecal administration of methotrexate (dose age-adjusted) on day 1. Eligible patients have 2nd or greater relapsed ALL, 1st relapsed ALL after allogeneic stem cell transplantation (allo-SCT) in 1st complete remission (CR1), or refractory 1st relapsed ALL, bone marrow involvement and at least 100 leukemic cells per ul blood. Exclusion criteria includes symptomatic CNS leukemia, among other factors. It is planned to have 24 fully evaluable patients. This interim analysis is limited to a description of pharmacokinetic (PK) data, especially concerning the CSF. As per June 1, 2013 a total of 14 patients has been enrolled, 9 boys and 5 girls, median 8.7 years of age (range, 1.6-16.2). Most had 2nd relapsed ALL (n=9), others 1st relapsed ALL following allo-SCT in CR1 (n=3) or refractory 1st relapsed ALL (n=2). Regarding PK in the peripheral blood, there was remarkable intra- and inter-individual variability in peak plasma concentrations, between patients ranging from 4.7 to 2920 ng/ml 15 minutes after the first administration of BTZ, median 12.4 ng/ml (18.7 ng/ml in the group with BTZ “early”, 12.1 ng/ml in the group with BTZ “late”). Peak levels after the fourth administration were higher, median 41.1 ng/ml (29.5 ng/ml in the group with BTZ “early” and 158.9 ng/ml in the group with BTZ “late”). There was a 10-fold interindividual variation in the area-under the concentration versus time curve until 72 h (AUC[0-72h]) after administration. Median ratio of AUC[0-72h] fourth dose / AUC[0-72h] first dose was 2.7 (range 0.9 – 9.3), which is indicative of accumulation. In all patients, PK of BTZ was studied in the CSF 15 minutes after administration of the first and third dose (group “early” only) of BTZ, as well as 4 days (group “late”) or one week (group “early”) after the last administration. In general, no BTZ was detected with a lower detection limit of 0.1 ng/ml. In 4 patients some BTZ was detected in CSF, at 0.2 – 0.4 – 1.7 - 5.2 ng/ml. Of potential interest, the latter patient also had the highest peak plasma level of BTZ (2920 ng/ml) and the highest AUC. Future analyses in the complete cohort of 24 randomised patients will focus on more extensive population PK and pharmacodynamic analyses, as well as on efficacy of BTZ. The higher peak plasma levels after the fourth dose suggest decreased clearance (especially in the group which received bortezomib “late”), which indeed has been reported in adults and which requires careful monitoring of toxicity over time. Mean peak plasma concentrations in adults were reported to be 173 ng/ml, and thus seem higher. Meanwhile, BTZ does not or hardly penetrate the cerebrospinal fluid and is unlikely to be a drug that significantly adds to the treatment of leptomeningeal involvement in leukemia. Financially supported by the Dutch Foundation Children Cancer-free. Disclosures: Off Label Use: bortezomib in pediatric relapsed acute lymphoblastic leukemia.

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Larrouquere, L., S. Berthier, E. Col, C. Lefebvre, C. Cottet-Rousselle, B. Chovelon, C. Garrel, J. Boutonnat, P. Faure y F. Hazane-Puch. "P11.33 Characterization of a new patient-derived metastatic glioblastoma cell line and response to sodium selenite anticancer agent: in vitro results and preclinical data in mice". Neuro-Oncology 21, Supplement_3 (agosto de 2019): iii50. http://dx.doi.org/10.1093/neuonc/noz126.179.

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Abstract BACKGROUND Glioblastoma (GBM) are very heterogeneous, organized in a hierarchical pattern, including cancer stem cells (CSC), and are responsible for development, maintenance, and cancer relapse. Therefore, it is relevant to establish new GBM cell lines with CSC characteristics to develop new treatments. MATERIAL AND METHODS A new human GBM cell line, named R2J, was established from the cerebro-spinal fluid of a patient affected by GBM with leptomeningeal metastasis. Cells were cultured both in monolayer and in spheres in a medium without serum and characterized before being implanted into the striatum of nude mice. The tumor progression was followed by MRI and brains were collected to perform IHC analyses. Sodium selenite (SS), previously described for its anticancer potential in GBM cell lines, was tested in the R2J cells prior to delimitate its toxicity and absorption in Balb/c mice. To be achieved, we tested different doses of SS (2.25, 4.5, 6.75 and 10.125 mg/kg-dissolve in water-) given orally for 5 days followed by a wash-out of 2 days followed by 5 supplementary days. At the end of this protocol, mice were sacrificed to collect blood, brain, kidney, liver and lungs. We evaluated the behavior and the weight of the mice along the study and we performed biochemical measurements including the dosage of selenium (Se) in blood and organs by ICP-MS. RESULTS R2J cells displays an abnormal karyotype and about 2% of the population is able to form self-renewable spheres in a define medium. Original tumor, R2J cells cultured in monolayer (2D) and in spheres showed a persistence expression of CD44, CD56 (except in monolayer), EGFR, Ki67, Nestin, and vimentin. The R2J cell line is tumorigenic and possesses CSC properties. We tested in vitro the anticancer effects of sodium selenite (SS) compared to temozolomide (TMZ). SS was absorbed by R2J cells, was cytotoxic, induced an oxidative stress, and arrested cell growth in G2M before inducing both necrosis and apoptosis via caspase-3. SS also changed dimethyl-histone-3-lysine-9 (H3K9m2) levels and reduced histone deacetylase (HDAC) activity, suggesting anti-invasiveness potential. Mouse orthotopic xenografts of R2J cells were able to form tumor within 14 days, even when implanted at 1000 cells as spheres. IHC revealed a persistent CD56 and nestin expression as in the parental tumor. After the period of treatment with SS, mice lost about 5% of their weight at 6.75 mg/kg. Se concentration significantly increased in plasma in a dose dependent manner, in kidney (at 2.25 mg/kg), in liver (at 4.5mg/kg), in brain and lung (at 6.75 mg/kg). CONCLUSION This study highlights the value of this new GBM cell line for preclinical modeling and allowed us to test SS as a potential anticancer agent. All these data plus the fact that Se crosses the blood brain barrier are the first step to further investigations in orthotopic patient-derived glioblastoma xenografts in mice.

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Nishihori, Taiga, Jun Zhou, Kenneth H. Shain, Rachid Baz, Melissa Alsina, Daniel Sullivan, Ryan Hillgruber, Elizabeth M. Sagatys, Lynn C. Moscinski y Ling Zhang. "Cerebrospinal Fluid (CSF) Involvement By Plasma Cell Dyscrasias – Single Center Experience". Blood 124, n.º 21 (6 de diciembre de 2014): 5686. http://dx.doi.org/10.1182/blood.v124.21.5686.5686.

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Abstract Introduction: Central nervous system (CNS) involvement by plasma cell dyscrasias (PCD) is uncommon but poses significant clinical challenges and has a dismal prognosis. Lumbar puncture (LP) is typically performed only for patients with neurologic signs or symptoms and data on patients with CNS involvement are rather scarce. Here, we report a retrospective single institution review of clinicopathological features and treatment outcomes in the setting of cerebrospinal fluid (CSF) involvement by PCD. Methods: We identified consecutive patients with plasma cell disorders who had abnormal cytology or flow cytometry results in the CSF in the Department of Hematopathology database at Moffitt Cancer Center from 1997 to 2014. Cytology slides [Wright-Giemsa (WG) and Papanicolaou (Pap) stained preparations] and the corresponding flow cytometry were reviewed to confirm the diagnosis. Four-color flow cytometry was performed using antibodies against CD38, CD138, CD56, CD117, CD19, and cytoplasmic kappa and lambda light chains, withadditional markers added when necessary. Clinical variables were abstracted from the patient medical records. Overall survival was estimated from the time CSF involvement was identified using the Kaplan-Meier method. Results: Sixty-seven Pap-stained cytology smeas/cytospins and WG stained cytospins from 65 patients who underwent LP for clinical suspicion of CSF involvement were reviewed. Flow cytometry was preformed on 48 cases positive for atypical plasma cells by cytology. Sixteen of 67 (23.9%) were suspicious or diagnostic for PCD (median age of 58 years (range 44 – 75), 56% were male). However, only 4 of 16 cases (25%) were diagnosed as PCD by cytology without additional flow cytometry study. Median tumor load of PCD by flow cytometry was 81% (range 4 - 99%). PCD included 14 patients (88%) with multiple myeloma [MM; 1 patient progressed to secondary plasma cell leukemia (PCL)], 1 with primary PCL, and 1 with Waldenström macroglobulinemia (Neel-Bing syndrome). Of the 14 MM patients, 57% had high-risk disease by cytogenetics/FISH, and immunophenotypes were IgA (50%), IgG (29%), and light chain (21%). All MM patients had Durie-Salmon stage 3 disease. Median number of prior therapies was 2 (1-4), and 44% received stem cell transplant prior to CSF involvement. Median time from diagnosis to CSF involvement was 23 (range, 6 – 78) months. Presenting symptoms included diplopia/vision loss (31%), headache (25%), and leg weakness (cauda equina/cord compression) (19%). Two patients presented with gross orbital involvement and new/enlarging scalp lesions. On radiologic imaging, 5 (31%) had leptomeningeal, 4 (25%) had epi- or extra-dural, and 2 (13%) had dural enhancement/lesions. None had CSF involvement at the time of initial PCD diagnosis. Treatment included intrathecal chemotherapy (methotrexate, cytarabine or triple regimen; 86%), radiation therapy (including whole brain, craniospinal, radiosurgery or involved field; 63%) and systemic chemotherapy (65%). One patient did not receive treatment due to poor performance status. For 5 patients who had repeat CSF analyses, only one had no evidence of disease on cytology but flow cytometry remained positive. Six-month overall survival rate was 20.2% (95% CI 4.4 – 43.5). At the time of data review, only 2 patients were alive. Conclusions: CSF involvement by PCD carries extremely limited prognosis and represents advanced stage of the disease. Patients may be treated with systemic therapy as well as CNS-directed therapy, though the outcomes are dismal. Careful assessment of patients’ neurologic symptoms and low threshold for performing LP is required for early detection of CSF involvement. Application of flow cytometry appears to be a useful tool in the diagnosis of CSF involvement by PCD; improving sensitivity and specificity over cytology alone, particularly when the tumor load is low or cytologically equivocal for atypical plasma cells. Further research is needed to improve the outcomes of these patients. Disclosures No relevant conflicts of interest to declare.

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Nakagomi, Takayuki y Tomohiro Matsuyama. "Leptomeninges: a novel stem cell niche with neurogenic potential". Stem Cell Investigation 3 (31 de marzo de 2017): 22. http://dx.doi.org/10.21037/sci.2017.03.09.

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Durot, Eric, Lukshe Kanagaratnam, Saurabh Zanwar, Elise Toussaint, Efstathios Kastritis, Shirley D'Sa, Miguel Alcoceba et al. "High Frequency of CNS Involvement in Transformed Waldenström Macroglobulinemia". Blood 138, Supplement 1 (5 de noviembre de 2021): 2526. http://dx.doi.org/10.1182/blood-2021-145440.

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Abstract INTRODUCTION Central nervous system (CNS) relapse is a challenging situation in diffuse large B-cell lymphoma (DLBCL). High CNS-International Prognostic Index (IPI), activated B-cell (ABC) subtype and MYD88 L265P mutation, features often found in transformed Waldenström macroglobulinemia (WM), are associated with a higher risk for developing CNS relapse. This study was aimed to describe CNS involvement in a large cohort of transformed WM. METHODS This international multicenter retrospective study included patients with a diagnosis of WM and a concurrent or sequential histological diagnosis of DLBCL. CNS disease was diagnosed by detection of DLBCL cells in the cerebrospinal fluid and/or by brain biopsy. Patients with CNS involvement by lymphoplasmacytic cells (Bing-Neel syndrome) were excluded. Of 254 identified patients with a diagnosis of histological transformation (HT) between 1988 and 2020, 19 were excluded due to lack of data on extranodal involvement. The first part of the analysis focused on baseline CNS involvement. Clinicobiological characteristics were compared between groups using Chi-square or Fisher's exact tests or Mann Whitney tests as appropriate. We analyzed CNS recurrence in the second part of the study. Forty-eight additional patients were excluded due to baseline CNS involvement (n = 25), absence of treatment at HT (n = 14) and lack of details on follow-up (n = 9). Cumulative incidence of CNS relapse was analyzed using competing-risk models that accounted for other events like systemic relapse or death from any cause, reporting sub-hazard ratio (SHR). RESULTS Baseline CNS involvement was present in 25 patients (11%) with transformed WM, including 10 (4%) with parenchymal disease, 10 with leptomeningeal, 4 (2%) with both, and 1 with unspecified CNS involvement. Characteristics associated with baseline CNS involvement were performance status 2-4 (P=0.03) and ≥2 extranodal sites (P=0.02). Median survival after HT was 1 year [0.7-2.5], comparable to the one of patients without CNS disease (1.8 year [1.2-2.6], P=0.74). We observed no difference in survival based on isolated CNS involvement (n = 10) compared to CNS and systemic involvement (n = 15) (P=0.94). Twenty-three CNS relapses occurred (12%). The 2-year and 3-year rates of CNS relapse were 9% (95% CI, 6-14) and 11% (95% CI, 7-16) (Figure 1). The median time to relapse in the CNS was 11 months (95% CI, 7-25). Thirteen CNS recurrences (57%) occurred during the first year of follow-up. Seventy percent were isolated CNS relapses. The location was leptomeningeal in 43% of cases, parenchymal in 35%, both in 17%, and unspecified in 4%. According to CNS-IPI risk groups (data available for 20 patients), 9 patients (45%) belonged to the high-risk group, 10 (50%) to the intermediate-risk group and 1 (5%) to the low-risk group. Prior to CNS relapse, 87% of patients had received rituximab, and 39% had received CNS prophylaxis (30% intrathecal chemotherapy, 4% high-dose methotrexate (HD-MTX), and 4% both). After CNS recurrence, 96% of patients received salvage treatment: combination of HD-MTX and HD-cytarabine (48%), HD-MTX alone (30%), or HD-cytarabine alone (9%). Four patients underwent consolidative autologous stem cell transplantation. The median survival after CNS relapse was 5.6 months. Factors associated with 3-year cumulative incidence of CNS recurrence in univariate analysis were involvement of kidney/adrenal glands (HR, 4.4; P=0.01) and MYD88 L265P mutation (P=0.01) (Figure 2A and B). Of note, among 74 patients (over 187, 40%) with data available for MYD88 mutation status, 11 CNS relapses occurred in patients with MYD88 L265P mutation (n = 54, 20%) whereas no relapse were observed in MYD88 WT cohort (n = 20). A trend toward higher risk of CNS relapse for ≥2 extranodal sites (HR, 2.3, 95% CI 0.98-5.3; P=0.06) was observed. Cumulative incidence according to CNS-IPI risk groups (0% in the low-risk, 9% in the intermediate-risk and 14% in the high-risk group) was not statistically significant (P=0.47). CONCLUSION CNS involvement occurs frequently in transformed WM. Rate of CNS relapse seems similar to DLBCL patients belonged to the CNS-IPI high-risk group. Special attention should be paid to patients with kidney/adrenal involvement and MYD88 L265P mutation. Figure 1 Figure 1. Disclosures Vos: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel reimbursement. Treon: X4: Research Funding; Janssen: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; BMS: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria. Kapoor: Cellectar: Consultancy; Karyopharm: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

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Sahebi, Firoozeh, Amrita Krishnan, Leonardo Farol, Ji-Lian Cai, George Somlo, Leslie Popplewell, R. Spielberger et al. "High Rate of Complete Remission (CR) and Upgraded Response with Weekly Maintenance Bortezomib Post Single Autologous Peripheral Stem Cell Transplant (PSCT) In Patients with Multiple Myeloma. Results of a Phase II Prospective Study". Blood 116, n.º 21 (19 de noviembre de 2010): 2399. http://dx.doi.org/10.1182/blood.v116.21.2399.2399.

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Abstract Abstract 2399 The quality and depth of response particularly achievement of complete remission (CR) have been associated with significant improvement in progression free survival (PFS) and overall survival in multiple myeloma patients undergoing autologous stem cell transplant. Achievement of CR is considered a valid surrogate endpoint for survival in clinical trials for patients with multiple myeloma. We performed a phase II study investigating the role of sequential bortezomib/dexamethasone followed by thalidomide/dexamethasone as maintenance therapy post single autologous PSCT. The objectives were to examine the feasibility, toxicities, CR, PFS and overall survival rates. Within 4–8 weeks of autologous PSCT using melphalan 200mg/m2, pts received weekly bortezomib (bor) at 1.3mg/m2 /wk × 3 weeks with 1 week rest and dexamethasone (dex) at 40mg/d × 4 d for 6 months, followed by thalidomide (thal) at 50 –200mg/d and dexamethasone (dex) at 40mg/dx4 d for 6 more months. Single agent thalidomide was then continued until disease progression. Between March 2008 and June 2010, forty-five pts were enrolled. Median age was 54 years (29-71). Median time from diagnosis was 6.1 mo. (3.5 – 145.9). Disease stage at diagnosis; by Salmon-Durie (I/II/III 2/8/34/1 not available) and by ISS (I/II/III 18/14/8/ 5 not available). Pts received prior induction treatment with thal/dex (15), bortezomib based (27) and lenalidomide based regimens (10). Median B2M at enrollment was 1.8 mg/L (1.05 -5.3). Disease status at enrollment included complete remission (CR) (11), very good partial response (VGPR) (11), partial response (PR) (23). Six pts had chromosome 13 abnormalities (1 pt by karyotype and 5 pts by FISH), 2 pts had t 4;14 (one with concurrent ch 17 p del) and 3 pts had complex cytogenetic abnormalities. Results: Forty-five pts have been enrolled and undergone transplant. Five pts were unable to start planned maintenance therapy due to development of grade II or more neuro toxicities (4), and persistent thrombocytopenia (1) after PSCT. Thirty nine pts started maintenance bor/dex within 4–8 weeks of PSCT. One pt is too early for maintenance therapy. Twenty-five pts have completed the planned 6 months of bor/dex. Ten pts stopped bor/dex because of low WBC (2), PN (4), diagnosis of adrenal cancer (1), myocardial infarction (MI) (1), and relapse (2). Six pts are still receiving maintenance bortezomib. With a median F/U of 8.5 mo. (0.2 -24.0) twelve of 44 evaluable pts (27%) have achieved CR post PSCT and 17 of 33 evaluable pts (51%) have achieved CR after bor/dex on an intention to treat (ITT) analysis. Fifteen of 25 pts (60%) who have completed 6 months of bor/dex have achieved CR. Nine of 25 pts (36%) have upgraded their response with bor/dex. Eight pts (24%) could not complete bortezomib due to toxicities. At one year post PSCT fourteen of 28 evaluable pts (50%) remain in CR. Six pts have relapsed of whom 2 died of relapsed myeloma (leptomeningeal disease 1 pt). One pt experienced MI while receiving bortezomib (grade IV). Grade III toxicities have occurred in 17 pts; low platelet (1), asthenia (2), mood alteration (1), GI (severe constipation due to partial bowel obstruction on thalidomide) (1), skin rash (1), hyperglycemia (1), lymphopenia (10), sinus bradycardia (1), elevated triglyceride (1), DVT (1), low phosphate (3), leukopenia (1), edema (1). Sixteen pts had peripheral neuropathy (PN) grade I prior to start of bortezomib. Only 8 pts have developed new PN on the study and all are grade I-II. No patient has experienced grade III-IV PN. Median bortezomib dose is 1.3 mg /m2 per week. Conclusion: Prolonged weekly bortezomib maintenance therapy is well tolerated and can upgrade response post single autologous PSCT with no severe peripheral neuropathy. Fifty one percent of pts have achieved CR and 36% have upgraded their response after six months of bortezomib/dexamethasone therapy suggesting this is an active maintenance strategy post PSCT. Disclosures: No relevant conflicts of interest to declare.

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Buda, Gabriele, Enrico Orciuolo, Sara Galimberti, Francesco Ghio y Mario Petrini. "VDTPACE As Salvage Therapy For Heavily Pretreated MM Patients". Blood 122, n.º 21 (15 de noviembre de 2013): 5377. http://dx.doi.org/10.1182/blood.v122.21.5377.5377.

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Abstract DTPACE is a combination chemotherapy regimen using dexamethasone, thalidomide and a 4-day (d) continuous infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide. It integrates components of CAD (cyclophosphamide, doxorubicin, dexamethasone) and DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin), both of which were components of the Arkansas Total Therapy 2 (TT2) approach to multiple myeloma (MM) treatment. Most recently, DTPACE has been combined with bortezomib (VDTPACE) as induction and consolidation after tandem transplantation as part of Total Therapy 3 (TT3). Limited experience suggests that DTPACE, reduces disease burden as a salvage regimen for aggressive MM or plasma cell leukaemia (PCL) resistant to conventional therapies. In heavily pretreated myeloma, DTPACE has advantages as it uses a number of agents to which the typical MM patient has not previously been exposed, some of which penetrate the blood brain barrier and thus may be effective for leptomeningeal myeloma. On the contrary not enough data are available about the role of VDTPACE as salvage therapy in MM patients. To this scope, we identifed a total of 16 patients who received VDTPACE for relapsed/refractory MM. All patients were heavily pretreated (median three prior regimens, range 1-6; prior autologous stem cell transplant [ASCT] 38%). Five of these patients (31%) had developed very aggressive MM complications, such as extramedullary disease. The VDTPACE regimen consisted of high-dose dexamethasone (40 mg orally daily for 4 d) and a 4-d continuous infusion of cisplatin (10 mg/sqm/d), doxorubicin (10 mg/sqm/d), cyclophosphamide (400 mg/sqm/d) and etoposide (40 mg/sqm/d). Bortezomib was administered intravenously at 1.0 mg/sqm (d 1,4,8,11) and thalidomide was given orally at 100 mg daily. A total of 4 cycles of VDTPACE were administered every 4-6 weeks. Response was graded using the International Myeloma Working Group uniform response criteria. Overall response rate was 63% (very-good partial response 7%, partial response 56%) with stable disease in an additional 12% of patients. Median progression-free survival (PFS) was 7 months (95% confdence interval [CI]:4.0 - 9.9). VDTPACE is an intensive regimen which was given in our cohort on an inpatient basis because myelotoxicity is common. The rates of grade 3-4 neutropenia (56%) and febrile neutropenia (56%) were high although GCSF support was used routinely as prophylaxis. The most common non-haematological toxicities were grade 1-2 metabolic abnormalities that were easily corrected. VDTPACE is an effective salvage therapy for heavily pretreated MM patients. In the era of new targeted, biologically active agents against MM, there are now many more options for refractory and relapsed disease. Unfortunately, many of these newer agents are costly and awaiting approval in a number of countries. Consequently, alternative therapies are needed. Although the overall response rate of 63% in this poor prognosis cohort is more than promising, the PFS is short, suggesting the best role for VDTPACE is in bridging to defnitive therapy, such as allo-transplantation.Table 1Patients CharacteristicsVTDPACE 16SexMale10(63%)Female6 (37%)Age of diagnosisMedian age60Range50-66MM SubtypeIgA4IgG11LCD1ISSI7II4III5Stage( Durie and Salmon)I2II1III13KaryotypeNormal10Abnormal6 Disclosures: No relevant conflicts of interest to declare.

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