搜索结果：Stem cell reports

Over the past three decades, advances in human pluripotent stem cell (hPSC) technologies, including induced pluripotent stem cells, gene editing, and 2D/3D models, have transformed biomedical research. These powerful tools have revolutionized disease modeling, drug discovery, and the development of advanced therapy medicinal products (ATMPs), while driving the establishment of stem cell core facilities. By providing specialized expertise, standardized workflows, and access to advanced technologies, these facilities support both fundamental and translational research, promote rigor and reproducibility, and foster collaboration. This manuscript highlights their role as hubs of excellence and discusses current challenges and future opportunities for the global stem cell community.

Integrating acellular scaffolds with cell-laden hydrogels holds great potential for engineering soft tissue constructs with structural integrity and uniform cellular distribution. However, achieving sustained and viable tissue regeneration remains a challenge due to poor nutrient diffusion and vascularization in bulk hydrogels. We propose to incorporate cell-laden microgels into polymeric scaffolds to engineer highly-permeable living constructs for vascularized adipose tissue regeneration. The cell-laden microgels, with the size ranging from 200 μm to 600 μm, are produced by electrospraying, coated with fibrin precursors, and embedded in a polymeric scaffold to form a mechanically robust construct with interconnected microporous structures. The microgels with a size of ∼200 μm exhibited better mass diffusion, improving viability and proliferation of encapsulated adipose tissue-derived stem cells compared with the bulk hydrogel. Human umbilical vein endothelial cells can be further introduced into the voids among the cell-laden microgels to form a pre-vascularized cellular network inside the assembled constructs. In vivo, the permeable living constructs can effectively maintain their original shape, significantly enhance tissue infiltration, promote vascularization, and alleviate hypoxia, thereby facilitating adipose tissue regeneration. The scaffold-assisted cell-laden microgel assembly strategy provides new insights into engineering living constructs with a structurally stable, permeable microenvironment for vascularized tissue regeneration. STATEMENT OF SIGNIFICANCE: This work reports a scaffold-assisted strategy for assembling ADSC-laden electrosprayed microgels within a 3D-printed polymeric scaffold to create a mechanically robust yet permeable living construct for vascularized adipose tissue regeneration. The inherent inter-microgel voids in the assembled living constructs facilitate mass diffusion, thereby enhancing cell viability and proliferation compared with those in bulk hydrogel. To create a pre-vascularized living construct, HUVECs are introduced into the voids among the cell-laden microgels, which form an endothelial network among the microgels and promote ADSC differentiation. Owing to their structural stability and high permeability, the engineered living constructs can maintain a designated regeneration volume upon in vivo implantation, with improved vessel and tissue ingrowth and reduced hypoxia, further enhancing adipogenesis.

Acidophil stem cell-like pituitary neuroendocrine tumors are uncommon PIT1-lineage tumors with heterogeneous morphology and immunophenotypes. Their distinction from other PIT1-lineage tumors and from tumors with additional gonadotroph-lineage-marker expression remains challenging. We retrospectively analyzed three surgically resected acidophil stem cell-like PitNETs. Clinical, endocrine, radiological, operative, histological, immunohistochemical, and follow-up data were reviewed. In cases 2 and 3, spatially matched serial sections were used to assess the relationship between PIT1 and SF1 expression. All patients were male and aged 17-48 years. The tumors showed PIT1 and PRL expression with variable GH expression. Case 1 showed LH positivity but was SF1-negative. Cases 2 and 3 showed SF1 positivity but were negative for FSH and LH. Spatially matched serial sections in cases 2 and 3 demonstrated PIT1-positive and SF1-positive nuclei in morphologically corresponding tumor-cell areas across consecutive serial sections, supporting PIT1/SF1 lineage-marker co-expression. All tumors showed radiological and/or intraoperative evidence of local invasiveness. The Knosp grades were bilateral grade 3 in case 1, grade 4 in case 2, and grade 1 in case 3. Early postoperative MRI showed no visible residual tumor in all cases. At the last available MRI follow-up, no recurrence or progression was identified after 14.7, 51.3, and 57.6 months in cases 1, 2, and 3, respectively. Acidophil stem cell-like PitNETs may show heterogeneous PIT1/SF1 or LH lineage-marker expression. Spatially matched serial-section analysis supports PIT1/SF1 co-expression in a subset of tumors; however, the biological significance and classification implications of this pattern require further study. Integrated interpretation of morphology, transcription factors, hormones, cytokeratin pattern, endocrine findings, radiological invasiveness, and longitudinal follow-up is essential.

Secondary central nervous system involvement by extranodal NK/T-cell lymphoma is rare and presents significant diagnostic challenges, particularly in immune compromised patients. We report a case of a 29-year-old man with chronic active Epstein-Barr virus infection and prior extranodal NK/T-cell lymphoma status post allogeneic hematopoietic stem cell transplantation who presented with a new-onset seizure and a ring-enhancing intracranial lesion. Initial imaging findings closely mimicked cerebral toxoplasmosis, leading to empiric antimicrobial therapy and delayed diagnosis. Despite treatment, the lesion demonstrated rapid progression, prompting stereotactic biopsy, which revealed Epstein-Barr virus-positive extranodal T-cell lymphoma with a pathogenic STAT3 p.Y640F activating mutation. This case highlights the substantial radiographic overlap between central nervous system lymphoma and infectious etiologies in immunosuppressed patients, where conventional imaging modalities may lack specificity. The presence of an aggressive molecular profile, including STAT3 activation, likely contributed to rapid disease progression and poor prognosis. This report underscores the importance of maintaining a high index of suspicion for lymphoma in patients with progressive intracranial lesions unresponsive to empiric therapy and emphasizes the critical role of early tissue diagnosis to guide appropriate management.

Stem-cell-based human embryo models offer an ethically tractable platform for studying early human development. This study employs somitoids, three-dimensional models of human somitogenesis, to investigate how transcriptional programs and culture conditions influence somite formation and segmentation. We show that pre-differentiation culture medium impacts the developmental potential of induced pluripotent stem cells (iPSCs), with StemFit medium and Matrigel embedding outperforming mTeSR Plus medium in generating robust somite-like structures. Strikingly, these differences arise despite only subtle changes in transcriptomic and time-resolved proteomic profiles. P300-based proximity labeling also reveals a largely overlapping set of chromatin-associated regulators across iPSC conditions. In somitoids, enhancer-associated profiling highlights factors linked to somitogenesis, including MESP2 and TBX6. Knockout of three identified regulators, BPTF, RBPJ, and CITED2, demonstrate their essential roles in somite formation. Together, these findings highlight how culture conditions and enhancer-associated networks influence early human development and demonstrate somitoids as a scalable system for functional genomics.

Human herpesvirus 7 (HHV-7) encephalitis commonly occurs in immunocompromised individuals and has a poor prognosis. We here reported 3 cases of HHV-7 encephalitis following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with typical neurological symptoms, including altered consciousness and epileptic seizures, and conducted a systematic review of the literature to identify clinical characteristics and management strategies in these patients. Cerebrospinal fluid next-generation sequencing (NGS) was the key evidence that led to their diagnosis. Foscarnet and cidofovir appeared effective, particularly with at least four weeks of treatment. All three patients showed at least partial improvement in neurological symptoms. Furthermore, a systematic search was conducted in PubMed, Google Scholar, and Web of Science to identify related cases. Clinical presentation, diagnostic findings, treatment strategies, and outcomes were analyzed. A total of 10 publications were included, together with our 3 cases, comprising 7 cases of HSCT recipients for detailed analysis. Our study suggested that early recognition and prompt antiviral therapy are critical for improving prognosis. Further exploration is needed regarding risk factors and treatment strategies.

A 65-year-old woman was diagnosed with myelodysplastic syndrome following the detection of pancytopenia, and allogeneic hematopoietic stem cell transplantation was planned. No HLA-matched related or unrelated donor was available. Anti-HLA antibody screening showed broad, high mean fluorescence intensity (MFI) antibodies against HLA-A, -B, -C, and -DR. The maximum MFI was 21,919, and high-MFI donor-specific antibodies (DSA) against HLA-haploidentical related donors were detected. Because reduced-intensity conditioning and graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide were planned, donor selection prioritized avoidance of DSA over HLA compatibility. Consequently, peripheral blood stem cell transplantation was performed from an unrelated donor with two HLA mismatches. Engraftment was achieved promptly, and neither acute nor chronic GVHD developed. The patient remains in complete remission at nine months after transplantation.

Hepatic graft-versus-host disease (GVHD) is a rare but life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT). Steroid-refractory hepatic GVHD carries a high risk of mortality with limited salvage options. Liver transplantation after HSCT poses unique challenges due to dual alloimmunity and is rarely pursued, particularly in pediatric patients. We report a pediatric patient with steroid-refractory chronic hepatic GVHD successfully treated with living donor liver transplantation (LDLT) from a parental donor. A 13-year-old male underwent allogeneic HSCT for idiopathic severe aplastic anemia and developed progressive chronic hepatic GVHD characterized by ductopenia and severe cholestasis. His disease was refractory to corticosteroids and multiple additional therapies, including ruxolitinib, mesenchymal stromal cells, infliximab, sirolimus, anti-thymocyte globulin, alpha-1 antitrypsin, cyclophosphamide, and emapalumab. His course was complicated by Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorder (PTLD), successfully treated with rituximab. Fifteen months after HSCT, and seven months after clearance of EBV viremia, he underwent LDLT from a parental donor. Donor selection preserved the option for future donor-derived EBV-specific cytotoxic T lymphocyte therapy if needed. Eleven months following LDLT, the patient remains clinically well, with normal liver function, sustained full donor chimerism, and no evidence of recurrent GVHD or PTLD. LDLT may represent a viable option in select pediatric patients with irreversible chronic hepatic GVHD. This case underscores the importance of early multidisciplinary planning and highlights the absence of liver-specific biomarkers or targeted therapies to guide management. Dedicated research into preventive and regenerative strategies is warranted.

The profound challenge in treating glioblastoma (GBM) stems from a confluence of obstacles. The formidable blood-brain barrier (BBB) limits drug access, while the tumor's inherent inter- and intra-tumoral heterogeneity, profound immunosuppression, invasive growth, and frequent recurrence all contribute to dismal prognoses and severely hamper therapeutic efficacy. Extracellular vesicles (EVs), naturally occurring nano-sized messengers between cells, offer a novel therapeutic avenue by addressing these key obstacles. Their inherent ability to cross the BBB, deliver diverse cargo, and modulate the immune system positions them as promising vehicles for targeted drug delivery, immunotherapy, and even cancer vaccination. This review explores the therapeutic potential of various EV subtypes, including those derived from dendritic cells, T cells, brain endothelial cells, and mesenchymal stem cells, emphasizing their unique properties and preclinical successes in GBM models. We discuss current engineering strategies to enhance EV targeting, delivery, and therapeutic efficacy, alongside the emerging potential of EV-based cancer vaccines for GBM. Finally, we address the challenges and future directions of EV-based therapies for GBM, including standardized isolation and characterization protocols, scalable production, and rigorous safety assessments. Despite these challenges, the burgeoning field of EV research holds immense promise for transforming GBM treatment paradigms and improving patient outcomes.

Aplastic anemia (AA) rarely coexists with intestinal Behçet disease (iBD), and the post-partum period may further complicate its expression. Managing refractory iBD with recurrent perforation on a background of long-standing AA is challenging, and evidence on optimal treatment is limited. A 42-year-old woman with non-severe aplastic anemia (NSAA) diagnosed in 2005 (AA duration ≈ 20 years) developed recurrent fever, oral ulcers, and penetrating ulcers of the ileocaecum and terminal ileum shortly after cesarean delivery in June 2019, with one episode of vulvar ulceration. Histology showed transmural vasculitis with focal obliterative endarteritis, confirming iBD; HLA-B51 was negative. Pre-transplant marrow was markedly hypocellular without dysplasia, and karyotype (46,XX), flow cytometry, myelodysplastic syndrome/AML and myeloproliferative neoplasm gene panels, and paroxysmal nocturnal hemoglobinuria screening were all negative, supporting acquired AA rather than hypoplastic myelodysplastic syndrome. Despite corticosteroids, tacrolimus, tofacitinib, and tocilizumab, she sustained 2 intestinal perforations (May and September, 2023). As iBD was refractory and AA had progressed to very severe AA, she underwent human leukocyte antigen (HLA)-matched sibling peripheral-blood allogeneic hematopoietic stem cell transplantation (allo-HSCT) in June 2024 with fludarabine/busulfan/cyclophosphamide/ anti-thymocyte globulin conditioning. Neutrophil and platelet engraftment occurred around D+11 and D+15, with 100% donor chimerism at D+16 and no acute or chronic graft-versus-host disease; only transient, self-limiting cytomegalovirus (CMV) and Epstein-Barr virus DNAemia occurred, without CMV disease or post-transplant lymphoproliferative disorder. Blood counts recovered progressively, with hemoglobin 127 grams/L and platelets 118 × 109/L at the last follow-up (≈12 months), only mild residual cytopenia, transfusion independence, and sustained remission of iBD on maintenance immunosuppression. She then returned to work and was lost to follow-up. This case suggests that allo-HSCT may be an effective option for selected patients with AA and refractory iBD, achieving sustained remission of both the marrow failure and the intestinal disease. As this is a single case with limited follow-up (≈12 months), longer follow-up and additional cases are needed.

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation, and while ruxolitinib, a JAK1/2 inhibitor, is approved for steroid-refractory acute and chronic GVHD, its real-world safety profile requires comprehensive evaluation. Using the FAERS database from Q1 2012 to Q4 2024, 3615 reports listing ruxolitinib as the primary suspect drug for GVHD were selected for multidimensional analysis via four signal detection methods: reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and empirical Bayesian geometric mean. The analysis identified adverse event (AE) signals across 26 system organ classes, with common AE reports including infections and infestations (e.g., pneumonia, cytomegalovirus), blood and lymphatic system disorders (e.g., thrombocytopenia, anemia), and gastrointestinal disorders (e.g., diarrhea). The median time to AE onset was 74 days (IQR 21-197), and 27% of AE reports occurred beyond 180 days after treatment initiation. Subgroup analysis revealed higher frequencies of hematologic AE reports such as cytopenia and thrombocytopenia in acute GVHD, and more undefined disorders in chronic GVHD; designated medical event analysis highlighted significant renal (e.g., acute kidney injury) and hematologic reporting signals. Sensitivity analyses confirmed the robustness of these signals. In conclusion, ruxolitinib demonstrates significant reported AE concerns in GVHD treatment, particularly infections and cytopenias, necessitating vigilant monitoring and long-term pharmacovigilance to optimize its risk-benefit profile.

Background - Globoid cell leukodystrophy or Krabbe disease is a rare condition caused by biallelic pathogenic variants in the GALC gene. Accumulation of the metabolic intermedier galactosyl ceramide and psychosine leads to the death of myelin-producing cells. Demyelination results in large amounts of myelin debries that exceed the clearence capacity of microglial cells and macrophages and cause their transformation into globoid cells.Case presentation - We present the case of a currently 17 months old girl whose motor and cognitive development was noted to be delayed at 4 month of age. She had episodes of febrile enteritis followed by focal seizures and spasms with increasing frequency. Her neurological exam was significant for irritability, lack of eye contact, lethargy, increased limb tone, axial hypotonia, few spontaneous movements, sluggish deep reflexes, frequent myoclonus, and automatisms (chewing motions). The seizures were difficult to control. Her cranial MRI revealed confluent white matter abnormalities in the hemispheral white matter, cerebellum and brainstem suggesting an underlying metabolic abnormality. Whole exome sequencing identified two likely pathogenic variants in trans within the GALC gene, establishing the diagnosis of globoid cell leukodystrophy. At the time of diagnosis, hematopoietic stem cell transplantation (HSCT) was not recommended due to the advanced disease. Antiseizure medications and supportive therapy have been the means of controlling her symptoms.Conclusion - Infantile Krabbe disease is a severe progressive disorder leading to death in 2-3 years. The only currently approved disease modifying therapy is HSCT that is effective only in early stages and is not without risks itself. There are numerous preclinical and clinical studies involving various forms of corrective gene therapy that may halt or reverse the course of this dismal condition. Bevezetés – A globoidsejtes leukodystrophia vagy Krabbe-kór egy olyan ritka betegség, amelyet a GALC gén biallélikus patogén variánsai okoznak. A galaktocerebrozid és pszichozin nevű metabolikus intermedierek felhalmozódása a myelintermelő sejtek pusztulásához vezet. A demyelinisatio során keletkező, nagy mennyiségű myelintörmelék lebontása meghaladja a microglia és makrofág sejtek kapacitását, aminek következtében globoid sejtekké alakulnak át.Esetbemutatás – A tanulmányban egy jelenleg 17 hónapos kislány esetét mutatjuk be, akinél 4 hónapos korban a motoros és kognitív fejlődés elmaradását észlelték. Majd lázas enteritisepizódok jelentkeztek, amelyeket egyre gyakoribbá váló fokális rohamok és görcsök követtek. Neurológiai státuszából kiemelendő a nagyfokú irritabilitás, szemkontaktus hiánya, letargia, fokozott végtagtónus, axiális hipotónia, kevés spontán mozgás, renyhe mélyreflexek, gyakori myoclonusok és automatizmusok (csámcsogás). Rohamai nehezen voltak kontrollálhatóak. Koponya-MRIvizsgálata az agyféltekék fehérállományában, a kisagyban és az agytörzsben konfluens jelzavart mutatott, ami metabolikus rendellenességre utalt. Teljes exomszekvenálás során a GALC génben két, transz pozícióban elhelyezkedő, valószínűleg patogén variánst azonosítottunk, ami megerősítette a globoid-sejtes leukodystrophia diagnózisát. A diagnózis időpontjában a haematopoeticus őssejt-transzplantáció (HSCT) a betegség előrehaladott stádiuma miatt nem volt javasolható. Ezért a tünetek kezelésére antiepilepsziás szereket és sokrétű támogató terápiát alkalmaztunk.Következtetés – A csecsemőkori Krabbekór súlyos, progresszív betegség, amely 2-3 éven belül halálhoz vezet. Jelenleg az egyetlen jóváhagyott betegségmódosító terápia a HSCT, ami csak korai fázisban hatékony, és nem kockázatmentes. Számos preklinikai és klinikai tanulmány van folyamatban különböző génterápiás megközelítésekkel, amelyek megállíthatják vagy visszafordíthatják ennek a súlyos állapotnak a lefolyását.

Mantle cell lymphoma (MCL) remains an incurable B-cell malignancy despite major advances in its therapeutic management. While Bruton tyrosine kinase inhibitors (BTKi) and, more recently, CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy have significantly improved outcomes in relapsed or refractory MCL, relapse after CAR-T therapy is associated with a dismal prognosis and represents a major therapeutic challenge. Here, we report the case of a 43-year-old male diagnosed with stage IV common-type MCL, who achieved long-term complete remission (CR) after treatment with polatuzumab vedotin, rituximab, and bendamustine (Pola-R-Benda) following relapse after CAR-T therapy. The patient had previously received standard first-line immunochemotherapy (R-CHOP alternating with R-DHAP) and autologous stem-cell transplantation, resulting in durable CR, followed by ibrutinib at first relapse in 2017 with sustained remission until 2021. Eleven months after CAR-T therapy with brexucabtagene autoleucel, the patient experienced systemic relapse. Enrollment into a Pola-R-Benda clinical protocol resulted in complete metabolic remission after three cycles, confirmed by positron emission tomography/computer tomography. Treatment was well tolerated except for mild grade 2 diarrhea. The patient remains in ongoing CR >20 months after initiation of Pola-R-Benda. To our knowledge, this is among the first reports of long-term remission with Pola-R-Benda following CAR-T failure in MCL, suggesting that antibody-drug conjugate-based therapy may represent an effective salvage option in this highly refractory clinical setting.

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Cutaneous manifestations of chronic lymphocytic leukemia (CLL) are heterogeneous and may result from leukemic infiltration, secondary malignancies, infectious complications, or reactive inflammatory processes. Reactive angioendotheliomatosis (RAE) is a rare vascular proliferation that has only infrequently been reported in association with hematologic malignancies. We describe a 58-year-old man with high-risk relapsed/refractory CLL harboring TP53 mutation and del(17p) who developed rapidly enlarging, fungating cutaneous lesions involving the right thumb, upper arm, and additional sites despite multiple prior therapies, including fludarabine, cyclophosphamide, rituximab, ibrutinib, and venetoclax. Histopathologic evaluation demonstrated dermal vascular proliferation with endothelial marker positivity (CD31, CD34, ERG, and vimentin), consistent with RAE and without evidence of leukemic infiltration. The lesions were refractory to local supportive measures but showed marked regression following treatment with CD19-directed chimeric antigen receptor (CAR) T-cell therapy using lisocabtagene maraleucel. Notably, cutaneous remission despite persistent measurable residual disease and eventual systemic relapse requiring allogeneic hematopoietic cell transplantation. This discordance suggests that regression of RAE may be mediated through immune modulation and alteration of inflammatory or angiogenic pathways rather than direct elimination of cutaneous leukemia. To our knowledge, this is among the first reports describing resolution of paraneoplastic RAE following CAR T-cell therapy in CLL, and it highlights the broader immunomodulatory effects of cellular immunotherapy beyond direct antitumor activity. The authors have confirmed clinical trial registration is not needed for this submission.

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Successful bone regeneration requires coupled osteogenic and vascular development; however, achieving simultaneous multicellular differentiation within engineered tissues remains challenging. Here, we developed a microRNA (miR)-guided spheroid platform to induce dual osteogenic and endothelial differentiation of human adipose-derived stem cells (hASCs) for vascularized bone regeneration. hASCs were transfected with miR-148b or miR-210 to promote osteogenic and vascular-associated phenotypes, respectively, and assembled into spheroids that were bioprinted within an nHA-containing GelMA microgel environment using aspiration-assisted bioprinting (AAB). The integrated platform combined miR-guided osteogenic and endothelial differentiation, spatially organized AAB-based spheroid assembly, and an nHA-containing GelMA microgel environment to support vascularized bone tissue regeneration. The engineered constructs maintained high cell viability (> 90%) and supported active cell spreading and migration within the microgel matrix, together with increased osteogenic and endothelial gene expression. To further verify their in vivo regenerative potential, the constructs were implanted into mouse critical-size calvarial defects, where those containing miR-transfected hASCs improved bone regeneration, achieving ~91% of defect closure, and promoted the formation of vessel-like CD31-positive structures compared to controls. Together, these findings demonstrate that combining miR-mediated dual-lineage differentiation with spatially organized spheroid assembly and a supportive microgel environment provides a promising strategy for vascularized bone tissue engineering.

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a rare cytotoxic lymphoma with key oncogenic drivers in the JAK/STAT pathway. Also primarily involving the subcutaneous adipose tissue, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is more frequently encountered in scenarios of autoimmune disorders. SPTCL shares clinicopathologic overlap with lupus panniculitis. However, the link between autoimmunity and PCGD-TCL is much less established, particularly in the setting of long-standing, immunosuppressed dermatomyositis (DM). We report two cases of PCGD-TCL arising in women with chronic anti-TIF1-&#x3b3; DM following years of immunosuppressive therapy. Case 1 is a 47-year-old woman with a 19-year history of DM on azathioprine/prednisone who developed rapidly progressive, painful subcutaneous nodules. Incisional biopsy confirmed a TCR-delta+, CD8+ cytotoxic T-cell lymphoproliferative disorder (TCLPD) compatible with PCGD-TCL. She achieved complete remission following pralatrexate and subsequent allogeneic hematopoietic stem cell transplant. Case 2 is a 27-year-old woman with DM on mycophenolate/rituximab who developed subcutaneous nodules with an indolent course and some spontaneous regression. A biopsy revealed a similar panniculitic infiltrate with an atypical TCR-delta+, CD8+ phenotype. Notably, both cases were negative for high-risk JAK/STAT pathway mutations. These cases identify PCGD-TCLPD/TCL as a potential complication of chronic, immunosuppressed DM. The shared, atypical CD8+ immunophenotype and absence of canonical driver mutations suggest a distinct pathogenic mechanism possibly linked to long-term immune modulation. Unlike classic PCGD-TCL, which is characterized by an aggressive course and <&#x2009;2-year median survival, the clinical courses in these two cases were variable, with one requiring transplant and the other showing indolent behavior and responsiveness to therapy.