RESUMEN
CCR5-tropic simian/human immunodeficiency viruses (SHIV) with clade C transmitted/founder envelopes represent a critical tool for the investigation of HIV experimental vaccines and microbicides in nonhuman primates, although many such isolates lead to spontaneous viral control post infection. Here, we generated a high-titer stock of pathogenic SHIV-C109p5 by serial passage in two rhesus macaques (RM) and tested its virulence in aged monkeys. The co-receptor usage was confirmed before infecting five geriatric rhesus macaques (four female and one male). Plasma viral loads were monitored by reverse transcriptase-quantitative PCR (RT-qPCR), cytokines by multiplex analysis, and biomarkers of gastrointestinal damage by enzyme-linked immunosorbent assay. Antibodies and cell-mediated responses were also measured. Viral dissemination into tissues was determined by RNAscope. Intravenous SHIV-C109p5 infection of aged RMs leads to high plasma viremia and rapid disease progression; rapid decrease in CD4+ T cells, CD4+CD8+ T cells, and plasmacytoid dendritic cells; and wasting necessitating euthanasia between 3 and 12 weeks post infection. Virus-specific cellular immune responses were detected only in the two monkeys that survived 4 weeks post infection. These were Gag-specific TNFα+CD8+, MIP1ß+CD4+, Env-specific IFN-γ+CD4+, and CD107a+ T cell responses. Four out of five monkeys had elevated intestinal fatty acid binding protein levels at the viral peak, while regenerating islet-derived protein 3α showed marked increases at later time points in the three animals surviving the longest, suggesting gut antimicrobial peptide production in response to microbial translocation post infection. Plasma levels of monocyte chemoattractant protein-1, interleukin-15, and interleukin-12/23 were also elevated. Viral replication in gut and secondary lymphoid tissues was extensive.IMPORTANCESimian/human immunodeficiency viruses (SHIV) are important reagents to study prevention of virus acquisition in nonhuman primate models of HIV infection, especially those representing transmitted/founder (T/F) viruses. However, many R5-tropic SHIV have limited fitness in vivo leading to many monkeys spontaneously controlling the virus post acute infection. Here, we report the generation of a pathogenic SHIV clade C T/F stock by in vivo passage leading to sustained viral load set points, a necessity to study pathogenicity. Unexpectedly, administration of this SHIV to elderly rhesus macaques led to extensive viral replication and fast disease progression, despite maintenance of a strict R5 tropism. Such age-dependent rapid disease progression had previously been reported for simian immunodeficiency virus but not for R5-tropic SHIV infections.
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Infecciones por VIH , VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Replicación Viral , Animales , Femenino , Masculino , Proteínas Adaptadoras Transductoras de Señales/inmunología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Envejecimiento , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Quimiocina CCL2/inmunología , Quimiocina CCL2/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/patología , Progresión de la Enfermedad , VIH/clasificación , VIH/crecimiento & desarrollo , VIH/patogenicidad , VIH/fisiología , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Infecciones por VIH/virología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucinas/inmunología , Interleucinas/metabolismo , Intestinos/virología , Tejido Linfoide/virología , Macaca mulatta/inmunología , Macaca mulatta/metabolismo , Pase Seriado , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/clasificación , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Virus de la Inmunodeficiencia de los Simios/fisiología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Carga Viral , Tropismo Viral , Virulencia , Receptores CCR5/metabolismoRESUMEN
AIMS: The discovery of somatic genetic alterations established many histiocytic disorders as haematologic neoplasms. We aimed to investigate the demographic characteristics and additional haematologic cancers of patients diagnosed with histiocytic disorders in The Netherlands. METHODS AND RESULTS: We retrieved data on histiocytosis patients from the Dutch Nationwide Pathology Databank (Palga). During 1993 to 2022, more than 4000 patients with a pathologist-assigned diagnosis of a histiocytic disorder were registered in Palga. Xanthogranulomas were the most common subtype, challenging the prevailing assumption that Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder. LCH and juvenile xanthogranuloma (JXG) had a peak incidence in the first years of life; males were overrepresented among all histiocytosis subgroups. 118 patients had a histiocytic disorder and an additional haematologic malignancy, including 107 (91%) adults at the time of histiocytosis diagnosis. In 16/118 patients, both entities had been analysed for the same genetic alteration(s). In 11 of these 16 patients, identical genetic alterations had been detected in both haematologic neoplasms. This included two patients with PAX5 p.P80R mutated B cell acute lymphoblastic leukaemia and secondary histiocytic sarcoma, further supporting that PAX5 alterations may predispose (precursor) B cells to differentiate into the myeloid lineage. All 4/11 patients with myeloid neoplasms as their additional haematologic malignancy had shared N/KRAS mutations. CONCLUSIONS: This population-based study highlights the frequency of xanthogranulomas. Furthermore, our data add to the growing evidence supporting clonal relationships between histiocytic/dendritic cell neoplasms and additional myeloid or lymphoid malignancies. Particularly adult histiocytosis patients should be carefully evaluated for the development of these associated haematologic cancers.
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Neoplasias Hematológicas , Histiocitosis de Células de Langerhans , Adulto , Masculino , Humanos , Histiocitosis de Células de Langerhans/epidemiología , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , Histiocitos/patología , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Células Dendríticas/patología , DemografíaRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that is highly aggressive with a poor prognosis. There is no standard treatment for BPDCN. Although conventional chemotherapies are usually sensitive in the initial therapy, relapse and drug resistance are inevitable within a short duration. Targeted therapies have enlightened new prospects for the treatment of BPDCN, especially for those in a frail state and intolerable to standard chemotherapies or hematopoietic stem cell transplantation. Here, we report an 82-year-old man diagnosed with cutaneous-limited BPDCN. Considering the old age and limited involvement of the tumor, we reduced the dosage of venetoclax. His skin lesions subsided significantly after 1 cycle of azacytidine (100 mg d1-7) combined with reduced doses of venetoclax (200 mg d1-14). The reduction in the dose of venetoclax avoided severe myelosuppression while achieving satisfactory outcomes. The patient received 2 cycles of therapy with no skin lesions re-occurred for 7 months before relapsing.
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Compuestos Bicíclicos Heterocíclicos con Puentes , Neoplasias Hematológicas , Trastornos Mieloproliferativos , Neoplasias Cutáneas , Sulfonamidas , Masculino , Humanos , Anciano de 80 o más Años , Azacitidina/uso terapéutico , Células Dendríticas/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Hematológicas/terapia , Trastornos Mieloproliferativos/patologíaRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare malignancy derived from plasmacytoid dendritic cells, can mimic both acute leukemia and aggressive T-cell lymphoma. Therapy of this highly aggressive hematological disease should be initiated as soon as possible, especially in light of novel targeted therapies that have become available. However, differential diagnosis of BPDCN remains challenging. This retrospective study aimed to highlight the challenges to timely diagnoses of BPDCN. We documented the diagnostic and clinical features of 43 BPDCN patients diagnosed at five academic hospitals from 2001-2022. The frequency of BPDCN diagnosis compared to AML was 1:197 cases. The median interval from the first documented clinical manifestation to diagnosis of BPDCN was 3 months. Skin (65%) followed by bone marrow (51%) and blood (45%) involvement represented the most common sites. Immunophenotyping revealed CD4 + , CD45 + , CD56 + , CD123 + , HLA-DR + , and TCL-1 + as the most common surface markers. Overall, 86% (e.g. CD33) and 83% (e.g., CD7) showed co-expression of myeloid and T-cell markers, respectively. In the median, we detected five genomic alterations per case including mutational subtypes typically involved in AML: DNA methylation (70%), signal transduction (46%), splicing factors (38%), chromatin modification (32%), transcription factors (32%), and RAS pathway (30%), respectively. The contribution of patients (30%) proceeding to any form of upfront stem cell transplantation (SCT; autologous or allogeneic) was almost equal resulting in beneficial overall survival rates in those undergoing allogeneic SCT (p = 0.0001). BPDCN is a rare and challenging entity sharing various typical characteristics of other hematological diseases. Comprehensive diagnostics should be initiated timely to ensure appropriate treatment strategies.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Neoplasias Cutáneas , Humanos , Estudios Retrospectivos , Leucemia Mieloide Aguda/patología , Médula Ósea/patología , Antígenos HLA-DR , Trastornos Mieloproliferativos/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/metabolismo , Células Dendríticas/patología , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/genéticaRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy which characteristically expresses an atypical phenotype including CD123+, CD56+, and CD4+. We are aimed to investigate the clinical and prognostic characteristics of AML patients exhibiting BPDCN-like immunophenotype and provide additional insights for risk stratification of AML. A total of 241 newly diagnosed AML patients were enrolled in this retrospective study and categorized into BPDCN-like positive (n = 125)/negative (n = 116) groups, determined by the present with CD123+ along with either CD56+ or CD4+, or both. Subsequently, an analysis was conducted to examine the general clinical characteristics, genetic profiles, and prognosis of the two respective groups. Patients with BPDCN-like immunophenotype manifested higher frequencies of acute myelomonocytic leukemia and acute monoblastic leukemia. Surprisingly, the presence of the BPDCN-like immunophenotype exhibited an inverse relationship with CEBPA bZIP mutation. Notably, patients with BPDCN-like phenotype had both worse OS and EFS compared to those without BPDCN-like phenotype. In the CN-AML subgroups, the BPDCN-like phenotype was associated with worse EFS. Similarly, a statistically significant disparity was observed in both OS and EFS within the favorable-risk subgroup, while only OS was significant within the adverse-risk subgrouMoreover, patients possessing favorable-risk genetics without BPDCN-like phenotype had the longest survival, whereas those who had both adverse-risk genetics and BPDCN-like phenotype exhibited the worst survival. Our study indicated that BPDCN-like phenotype negatively associated with CEBPA bZIP mutation and revealed a significantly poor prognosis in AML. Moreover, the 2022 ELN classification, in combination with the BPDCN-like phenotype, may better distinguish between different risk groups.
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Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Neoplasias Cutáneas , Humanos , Estudios Retrospectivos , Subunidad alfa del Receptor de Interleucina-3 , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Pronóstico , Enfermedad Aguda , Trastornos Mieloproliferativos/patología , Neoplasias Cutáneas/patología , Células Dendríticas/patología , Mutación , Proteínas Potenciadoras de Unión a CCAAT/genéticaRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.
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Busulfano , Células Dendríticas , Trasplante de Células Madre Hematopoyéticas , Tiotepa , Acondicionamiento Pretrasplante , Vidarabina , Humanos , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Células Dendríticas/patología , Tiotepa/administración & dosificación , Tiotepa/uso terapéutico , Masculino , Busulfano/administración & dosificación , Busulfano/uso terapéutico , Persona de Mediana Edad , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/patología , Femenino , Trasplante Homólogo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , AloinjertosRESUMEN
BACKGROUND: Dendritic cells participate in the pathophysiology of lupus erythematosus (LE), which are studied in systemic and cutaneous forms; however, little is known about their oral manifestations. METHODS: The expressions of dendritic cell markers (including CD1a, CD21, CD123, and langerin) were investigated by immunohistochemistry technique. Sixty intraoral and lower lip LE lesions, and additional 10 control samples were collected from 2003 to 2019. They were topographically analyzed in the epithelium (EP), lamina propria (LP), epithelial junction (JUN), and deep perivascular (PV) areas. RESULTS: The expression of CD1a was decreased in the EP (p = 0.003) and increased in the deep PV area (p = 0.002). Langerin immunostaining showed no significant decrease in EP (p = 0.944); however, it increased in LP (p = 0.012) and JUN (p = 0.006). CD21 was expressed in only two specimens (EP, p = 0.012; LP, p < 0.001; deep PV area, p = 0.018). CD123 expression increased in all topographies (EP, p < 0.005; LP, p < 0.001, JUN, p < 0.001; deep PV, p < 0.001). The comparison between vermilion and intraoral mucosa LE lesions suggested that sun-exposed sites showed higher expression of CD123 (EP, p = 0.024; LP, p = 0.047; JUN, p = 0.001). CONCLUSIONS: CD1a, langerin, and CD123 expressions were detected coincidently surrounding the inflammatory infiltrate in oral LE, suggesting that these cells may play an important role in immune response. Interestingly, plasmacytoid dendritic cells showed increased CD123 expression in sun-exposed site lesions, which point out a possible function in their pathogenesis. Further studies are needed to confirm this hypothesis.
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Células Dendríticas , Lupus Eritematoso Sistémico , Humanos , Células Dendríticas/patología , Inmunohistoquímica , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Lupus Eritematoso Sistémico/patología , Piel/patologíaRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignant hematologic neoplasm arising from plasmacytoid dendritic cells. It is a very rare tumor that constitutes less than 0.1% of all hematologic malignancies. Most patients with BPDCN present clinically with cutaneous lesions as the first sign of disease. Immunophenotypic variability with aberrant marker profiles has been reported. We report a case of a transcription factor 4 (TCF-4) + BPDCN, with negative CD56 expression in an 85-year-old woman with multiple skin nodules. A punch biopsy revealed a diffuse, monomorphous, and non-epidermotropic cell infiltrate involving the entire dermis. The infiltrate was composed of intermediate-sized cells with immunoblastoid morphology, which is an unusual morphologic variant. The neoplastic cells were strongly positive for CD45 and co-expressed CD4, CD123, TCF-4, BCL-2, and CD10. The Ki-67 proliferative rate was very high (90%). Negative immunostains included CD56, an unusual finding in BPDCN. This case illustrates the challenges encountered in the diagnosis of this entity, particularly in unusual morphologic variants and phenotypes. The elucidation of molecular signatures and development of targeted therapies for its management have been recently introduced and differ from acute myeloid leukemias. Hence, accurate diagnosis of BPDCN is critical for dermatopathologists.
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Neoplasias Hematológicas , Neoplasias Cutáneas , Femenino , Humanos , Anciano de 80 o más Años , Neoplasias Cutáneas/patología , Neoplasias Hematológicas/patología , Piel/patología , Células Dendríticas/patología , BiopsiaRESUMEN
ABSTRACT: Cutaneous malignant squamomelanocytic tumor (SMT) is a rare neoplasm comprising 2 distinct cell populations of squamous cell carcinoma and a second component of either benign or malignant melanocytes. SMT most often presents as a keratotic papule in areas of chronic sun exposure, typically on the head or neck of middle-aged and elderly-aged, White male patient populations. In recent years, there has been an increase in case reports, including a review article published in 2023, identifying a total of 37 cases published in the literature. There are only 3 reported cases in the literature with spindled or dendritic cells in the melanocytic component, as most have been of the epithelioid subtype. Despite the increasing prevalence, the origin and pathophysiology is poorly understood. We report 2 cases of SMT with dendritic melanocytes that are centered around a hair follicle, proposing the theory that these 2 distinct cell types may arise from the hair follicles.
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Carcinoma de Células Escamosas , Células Dendríticas , Melanocitos , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Masculino , Melanocitos/patología , Carcinoma de Células Escamosas/patología , Células Dendríticas/patología , Anciano , Folículo Piloso/patología , Persona de Mediana Edad , Anciano de 80 o más AñosRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological malignancy derived from the precursors of plasmacytoid dendritic cells. Although disease awareness has increased over time, BPDCN represents a rare disease with an aggressive clinical course and a dismal prognosis. Due to the overlap in clinical and histological features with a large spectrum of inflammatory and neoplastic diseases, BPDCN is difficult to diagnose. Furthermore, given the rarity of the disease, treatment options for BPDCN are limited, sometimes changing by practitioner and hospitals. Treatment options range from conventional chemotherapy to the recently approved biologic agent tagraxofusp and stem cell transplantation. Therefore, a multidisciplinary approach with coordination among dermatologists, pathologists, and hematologists is ultimately imperative to reach the correct diagnosis and management of BPDCN.
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Células Dendríticas , Neoplasias Hematológicas , Neoplasias Cutáneas , Humanos , Células Dendríticas/patología , Neoplasias Hematológicas/patología , Neoplasias Cutáneas/patología , PronósticoRESUMEN
The 5th edition of the World Health Organization classification of hematolymphoid tumors (WHO Blue Book) is soon to be published. Significant revisions have been made in the chapters on histiocytic/dendritic cell neoplasms and stroma-derived neoplasms of lymphoid tissues, leading to the reclassification and renaming of specific diseases. This article provides a concise interpretation and summary of these updates, highlighting the differences from the fourth edition. Pertinent changes from clinical pathological diagnosis to treatment and prognosis are explored, with an emphasis on recent advancements in molecular genetics. Newly introduced disease classifications are discussed, and the section on follicular dendritic cell sarcoma contributed by the author is detailed to assist readers in quickly understanding and assimilating the new classification standards.
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Sarcoma de Células Dendríticas Foliculares , Neoplasias de los Tejidos Blandos , Humanos , Tejido Linfoide/patología , Neoplasias de los Tejidos Blandos/patología , Sarcoma de Células Dendríticas Foliculares/genética , Sarcoma de Células Dendríticas Foliculares/patología , Células Dendríticas/patología , Organización Mundial de la SaludRESUMEN
BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare malignant tumor with a dismal prognosis, with isolated case reports in Chile. The BPDCN can present skin and bone marrow compromise, and its diagnosis is frequently confused with other pathologies. This study aimed to evaluate the clinical and immunophenotypical features of BPDCN in the Chilean population. METHODS: We performed a retrospective study from 2013 to 2021 in clinical records of 2 public Chilean referral hospitals, including ten patients, 80% male, with a median age of 66 years (15-81). RESULTS: The most frequent initial referral diagnoses were T-cell lymphoma (4/10) and acute myeloblastic leukemia (3/10). Seven patients presented skin and bone marrow involvement; we found a lower frequency of adenopathies (5/10), splenomegaly (2/10), and hepatomegaly (2/10). The complete blood count revealed anemia and leukopenia, with blasts in 5/10. Nine patients received induction therapy. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was indicated in 8/10 cases with remission in 5/8, and 1 patient received HyerCVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone, methotrexate, cytarabine) and an allogeneic bone marrow transplant. The median survival was 10 months (95% CI 4.2-15.8 months) with 9/10 deaths. Relapse in the central nervous system was documented in 2 cases. CONCLUSIONS: Our study found that BPDCN, a rare pathology in the Chilean population, shows a similar clinical presentation compared to previous studies. It is susceptible to respond to initial systemic and intrathecal chemotherapy.
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Células Dendríticas , Humanos , Masculino , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Anciano , Chile/epidemiología , Adulto , Adolescente , Anciano de 80 o más Años , Células Dendríticas/patología , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cutáneas/patología , Neoplasias Hematológicas/patología , Vincristina/uso terapéutico , Ciclofosfamida/uso terapéutico , Prednisona/uso terapéuticoAsunto(s)
Células Dendríticas , Factor de Transcripción Ikaros , Humanos , Factor de Transcripción Ikaros/genética , Células Dendríticas/patología , Células Dendríticas/metabolismo , Células Madre Hematopoyéticas/patología , Células Madre Hematopoyéticas/metabolismo , Masculino , Reordenamiento Génico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Femenino , Persona de Mediana EdadAsunto(s)
Células Dendríticas , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Testiculares/patología , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/cirugía , Células Dendríticas/patología , Diagnóstico Diferencial , Niño , Orquiectomía , Neoplasias Hematológicas/patologíaAsunto(s)
Células Dendríticas , Neoplasias Nasales , Proteína EWS de Unión a ARN , Translocación Genética , Humanos , Proteína EWS de Unión a ARN/genética , Células Dendríticas/patología , Femenino , Adulto , Neoplasias Nasales/genética , Neoplasias Nasales/patología , Neoplasias Nasales/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Neoplasias de los Senos Paranasales/genética , Neoplasias de los Senos Paranasales/patología , Cromosomas Humanos Par 22/genética , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión a Calmodulina/metabolismoRESUMEN
Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88-1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73-2.38; p = 0.44). Grade 3-4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed.
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Melanoma , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Supervivencia sin Enfermedad , Adyuvantes Inmunológicos/uso terapéutico , Células Dendríticas/patología , Estadificación de NeoplasiasRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with poor outcomes. The World Health Organization (WHO) redefined BDCN as a distinct disease entity in 2016. BPDCN arises from plasmacytoid dendritic cells, manifesting primarily in the skin, bone marrow, and lymph nodes, occasionally involving the central nervous system (CNS). This presents challenges in diagnosis and treatment, with CNS involvement often overlooked in standard diagnostic workups due to BPDCN's rarity and patients often being neurologically asymptomatic at diagnosis. CNS involvement typically emerges during relapse, yet clinical trials often exclude such cases, limiting our understanding of its development and treatment. Treatment options for CNS involvement include intrathecal (IT) chemotherapies like methotrexate and cytarabine, often in combination with systemic agents. Tagraxofusp and traditional regimens for acute myeloid leukemia show limited success at preventing CNS relapse, prompting exploration of combined therapies like hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD) with venetoclax and adding IT chemotherapy to other backbones. Ongoing clinical trials investigating emerging therapies offer hope despite limited focus on CNS implications. Trials incorporating CNS-involved patients aim to pioneer novel treatment approaches, potentially reshaping BPDCN management. Understanding CNS involvement's complexities in BPDCN remains crucial for tailored treatments and better patient outcomes.
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Trastornos Mieloproliferativos , Neoplasias Cutáneas , Humanos , Sistema Nervioso Central/patología , Neoplasias Cutáneas/patología , Trastornos Mieloproliferativos/patología , Células Dendríticas/patología , RecurrenciaRESUMEN
BACKGROUND: Histiocytoses are rare disorders characterized by the accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs of children and adults, with a wide range of clinical manifestations, presentations, and histology. The histiocytoses are classified according to the WHO Classification, the last version of which was published in 2022, or according to the Histiocyte Society Classification, with the last version published in 2016. PURPOSE: This text provides an overview of histiocytoses as described in the WHO Classification 2022.
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Organización Mundial de la Salud , Humanos , Histiocitosis/patología , Histiocitosis/clasificación , Histiocitosis/diagnóstico , Neoplasias Hematológicas/clasificación , Neoplasias Hematológicas/patología , Células Dendríticas/patologíaRESUMEN
INTRODUCTION: Diet-induced metabolic syndrome may influence the progression and healing of apical periodontitis (AP). The aim of this study was to evaluate the inflammatory immune response of dendritic cells (DCs) and T helper (Th) cells in normal versus obese mice with AP. METHODS: Twenty male C57BL/6 mice were divided into 2 groups: normal chow (NC) and high-fat diet (HFD) for 12 wk. AP was induced in both groups by creating pulp exposure of the right first maxillary molar to the oral environment. Contralateral first molars from each mouse were used as a control. The animal's body mass was recorded on a weekly basis, and they were euthanized after 30 d. The maxillae were removed and processed for micro-computed tomography (micro-CT), histologic analysis, and immunofluorescence staining for DCs (CD11c), Th17 (IL-17A), and T regulatory cells (FOXP3 and IL-10). Different groups were analyzed by Mann-Whitney U test, Student t test, and ordinary 1-way analysis of variance followed by Tukey's multiple comparisons test. The level of significance (α) was set at 0.05. RESULTS: The HFD group showed larger AP lesions than the NC group from micro-CT analysis. For the NC group, induction of AP significantly increased immune cell infiltration when compared with control. HFD showed increased DCs and Th17 infiltration in the control group without AP. In addition, there was no significant change in the amount of DCs and Th17 in the HFD-AP group when compared with the NC-AP and HFD-control groups. CONCLUSIONS: HFD resulted in an increased immune cell infiltration in the periapical area without AP. Despite the larger AP lesion observed in HFD-AP than that of NC-AP, the amount of infiltrated inflammatory cells did not differ significantly. The results of this study suggest that the DCs and Th17 inflammatory pathways are affected by HFD in the periapical region, but their contribution toward AP complicated by metabolic syndrome requires further investigation.
Asunto(s)
Síndrome Metabólico , Periodontitis Periapical , Ratas , Ratones , Masculino , Animales , Ratas Wistar , Dieta Alta en Grasa/efectos adversos , Microtomografía por Rayos X , Ratones Endogámicos C57BL , Periodontitis Periapical/patología , Células Dendríticas/metabolismo , Células Dendríticas/patologíaRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy of the dendritic cell lineage that affects patients of all ages, though the incidence appears to be highest in patients over the age of 60 years. Diagnosis is based on the presence of plasmacytoid dendritic cell precursors expressing CD123, the interleukin-3 (IL-3) receptor alpha, and a distinct histologic appearance. Timely diagnosis remains a challenge, due to lack of disease awareness and overlapping biologic and clinical features with other hematologic malignancies. Prognosis is poor with a median overall survival of 8 to 14 months, irrespective of disease presentation pattern. Historically, the principal treatment was remission induction therapy followed by a stem cell transplant (SCT) in eligible patients. However, bridging to SCT is often not achieved with induction chemotherapy regimens. The discovery that CD123 is universally expressed in BPDCN and is considered to have a pathogenetic role in its development paved the way for the successful introduction of tagraxofusp, a recombinant human IL-3 fused to a truncated diphtheria toxin payload, as an initial treatment for BPDCN. Tagraxofusp was approved in 2018 by the United States Food and Drug Administration for the treatment of patients aged 2 years and older with newly diagnosed and relapsed/refractory BPDCN, and by the European Medicines Agency in 2021 for first-line treatment of adults. The advent of tagraxofusp has opened a new era of precision oncology in the treatment of BPDCN. Herein, we present an overview of BPDCN biology, its diagnosis, and treatment options, illustrated by clinical cases.