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Journal of Cytology 2024
PubMed: 38282810
DOI: 10.4103/joc.joc_65_23 -
Medicine Jan 2024With the advancement of diagnostic technology, true acute undifferentiated leukemia (AUL) is becoming more rare, and AUL with extramedullary sarcoma has not been... (Review)
Review
BACKGROUND
With the advancement of diagnostic technology, true acute undifferentiated leukemia (AUL) is becoming more rare, and AUL with extramedullary sarcoma has not been reported.
CASE PRESENTATION
This article reports a case of AUL with extramedullary sarcoma. Flow cytometric analysis of the bone marrow and lymph nodes indicated that the tumor cells of both were of the same origin and mainly expressed stem cell markers and CD7, no myeloid-specific markers, T-lymphoblastic-related markers, and B-lymphoblastic-related markers. Although the priming regimen combined with azacitidine was ineffective, complete remission was achieved by switching to azacitidine combined with HIA (homoharringtonine, idarubicin plus Ara-C).
CONCLUSION
To diagnosis de novo acute leukemia with extensive and comprehensive cellular immune maker detection is available and credible, the expression of a single relatively nonspecific myeloid antigen as a immune maker to detect AUL or AUL associated with sarcoma is precise and effective in our case, which patient was benefit from HIA regiment.
Topics: Humans; Sarcoma, Myeloid; Leukemia, Myeloid, Acute; Leukemia; Bone Marrow; Acute Disease; Azacitidine
PubMed: 38277531
DOI: 10.1097/MD.0000000000036948 -
BioRxiv : the Preprint Server For... Jan 2024Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist...
Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy (RT) in transplanted tumors, but the mechanism(s) remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and two doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to RT + CpG, we performed bulk RNA-seq, single-cell RNA-seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and interferon-γ. CpG + RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG + RT, TCR clonality analysis suggests an increase in clonal T-cell dominance. Collectively, these findings demonstrate that RT + CpG significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft tissue sarcoma.
PubMed: 38260522
DOI: 10.1101/2024.01.03.573968 -
Acta Neuropathologica Communications Jan 2024Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at...
Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at extramedullary sites, and primarily involve the skin and soft tissue of middle-aged adults. ES may be concomitant with or secondary to myeloid neoplasms (mostly acute myeloid leukemia (AML)) or in isolated cases (de novo) without infiltration of the bone marrow by blasts. ES share cytogenetic and molecular abnormalities with AML, including RUNX1T1 fusions. Some of these alterations seem to be correlated with particular sites of involvement. Herein, we report an isolated erythroblastic sarcoma with NFIA::RUNX1T1 located in the central nervous system (CNS) of a 3-year-old boy. Recently, two pediatric cases of CNS MS with complete molecular characterization have been documented. Like the current case, they concerned infants (2 and 3 years-old) presenting a brain tumor (pineal involvement) with leptomeningeal dissemination. Both cases also harbored a NFIA::RUNX1T3 fusion. ES constitutes a diagnostic challenge for neuropathologists because it does not express differentiation markers such as CD45, and may express CD99 which could be confused with CNS Ewing sarcoma. CD43 is the earliest pan-hematopoietic marker and CD45 is not expressed by erythroid lineage cells. E-cadherin (also a marker of erythroid precursors) and CD117 (expressed on the surface of erythroid lineage cells) constitute other immunhistochemical hallmarks of ES. The prognosis of patients with ES is similar to that of other patients with AML but de novo forms seem to have a poorer prognosis, like the current case. To conclude, pediatric ES with NFIA::RUNX1T1/3 fusions seem to have a tropism for the CNS and thus constitute a potential pitfall for neuropathologists. Due to the absence of circulating blasts and a DNA-methylation signature, the diagnosis must currently be made by highlighting the translocation and expression of erythroid markers.
Topics: Child, Preschool; Humans; Infant; Male; Middle Aged; Bone Marrow; Central Nervous System Neoplasms; Leukemia, Myeloid, Acute; NFI Transcription Factors; RUNX1 Translocation Partner 1 Protein; Sarcoma; Sarcoma, Myeloid
PubMed: 38243303
DOI: 10.1186/s40478-023-01708-5 -
Cancer Immunology, Immunotherapy : CII Jan 2024Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint...
BACKGROUND
Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy.
METHODS
This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Baseline and on-treatment plasma and PBMC samples were analyzed by multiplex protein assay and mass cytometry, respectively.
RESULTS
In this Phase 1B study (NCT02298959), ten patients with advanced PD-1-resistant melanoma were treated with a combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg), administered intravenously every 2 weeks. Two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. Changes in plasma analytes such as platelet-derived growth factor and PD-L1 were explored, indicating potential alterations in myeloid cell function. Higher levels of circulating CXCL10 in non-responding patients may reflect pro-tumor activity. Specific subsets of γδ T cells were associated with poor clinical outcomes, suggesting impaired γδ T-cell function in non-responding patients.
CONCLUSIONS
Although limited by sample size and follow-up, these findings highlight the potential of the combination of ziv-aflibercept antiangiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment and the need for further research to improve outcomes in anti-PD-1-resistant melanoma.
TRIAL REGISTRATION NUMBER
NCT02298959.
Topics: Humans; Melanoma; Leukocytes, Mononuclear; Vascular Endothelial Growth Factor A; Recombinant Fusion Proteins; Receptors, Vascular Endothelial Growth Factor; Antibodies, Monoclonal, Humanized
PubMed: 38236249
DOI: 10.1007/s00262-023-03593-2 -
Asian Journal of Surgery Apr 2024
Topics: Humans; Sarcoma, Myeloid; Urinary Bladder; Urinary Bladder Neoplasms; Sarcoma; Pelvis
PubMed: 38212222
DOI: 10.1016/j.asjsur.2023.12.074 -
Cancer Biology & Therapy Dec 2024CD73 is a cell surface 5'nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody...
CD73 is a cell surface 5'nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade. Our results highlight improved survival in syngeneic tumor models of colorectal cancer (CT26 and MC38) and sarcoma (MCA205). This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil+Oxaliplatin (5FU+OHP). We hypothesize that the improved responses are tumor microenvironment (TME)-driven, as suggested by the lack of anti-CD73 enhanced cytopathic effects mediated by 5FU+OHP on cell lines . Pharmacodynamic analysis, using imaging mass cytometry and RNA-sequencing, revealed noteworthy changes in specific cell populations like cytotoxic T cells, B cells and NK cells in the CT26 TME. Transcriptomic analysis highlighted treatment-related modulation of gene profiles associated with an immune response, NK and T-cell activation, T cell receptor signaling and interferon (types 1 & 2) pathways. Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy.
Topics: Animals; Mice; Antibodies, Monoclonal; Sarcoma; Immunosuppressive Agents; Adenosine; Fluorouracil; Tumor Microenvironment
PubMed: 38206570
DOI: 10.1080/15384047.2023.2296048 -
Case Reports in Oncology 2024Myeloid sarcoma (MS) is also known as chloroma, extramedullary acute myeloid leukemia (AML), or granulocytic sarcoma. MS is a rare extramedullary infiltration of myeloid...
INTRODUCTION
Myeloid sarcoma (MS) is also known as chloroma, extramedullary acute myeloid leukemia (AML), or granulocytic sarcoma. MS is a rare extramedullary infiltration of myeloid cells, most commonly collecting in the skin and causing a small number of localized lesions. It is strongly associated with AML; however, MS more commonly occurs after diagnosis of AML is previously established or after previous treatment of AML.
CASE PRESENTATION
This case describes a patient with an atypical presentation of MS with no known history of AML and up to 18 lesions identified on CT scan that were previously being monitored for months by her primary care physician. She presented with sepsis attributed to choledocholithiasis versus bacteremia from scattered abscesses versus osteomyelitis of her left knee; nonetheless, lactic acid failed to improve after common bile duct stent with biliary sphincterotomy/dilation or with incision and drainage and empiric antibiotics. Core needle biopsy of her left abdominal sidewall was eventually positive for MS, but she unfortunately developed multiorgan failure with symptomatic hypercalcemia refractory to treatment and ultimately decided to go to comfort care rather than pursue further workup and treatment. Although bone marrow biopsy was ultimately not performed to rule out synchronous AML, this is likely a case of isolated MS due to her scattered skin lesions being present for months prior to hospitalization and acute illness.
CONCLUSION
This case highlights the importance of maintaining MS in the differential diagnosis and the importance of early diagnostic core needle biopsy for patients with persistent skin lesions of unknown origin.
PubMed: 38188484
DOI: 10.1159/000535600 -
Biomedicine & Pharmacotherapy =... Feb 2024Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as "undruggable". KRAS mutations frequently occur in multiple... (Review)
Review
Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as "undruggable". KRAS mutations frequently occur in multiple human cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning as a "molecule switch" determining the activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, KRAS alteration also exhibits an unique immune signature characterized by elevated PD-L1 level and high tumor mutational burden(TMB). KRAS mutation shape an immune suppressive microenvironment by impeding effective T cells infiltration and recruiting suppressive immune cells including myeloid-derived suppressor cells(MDSCs), regulatory T cells(Tregs), cancer associated fibroblasts(CAFs). In immune checkpoint inhibitor(ICI) era, NSCLC patients with mutated KRAS tend to be more responsive to ICI than patients with intact KRAS. The hallmark for KRAS mutation is the existence of multiple kinds of co-mutations. Different types of co-alterations have distinct tumor microenvironment(TME) signatures and responses to ICI. TP53 co-mutation possess a "hot" TME and achieve higher response to immunotherapy while other loss of function mutation correlated with a "colder" TME and a poor outcome to ICI-based therapy. The groundbreaking discovery of KRAS G12C inhibitors significantly improved outcomes for this KRAS subtype even though efficacy was limited to NSCLC patients. KRAS G12C inhibitors also restore the suppressive TME, creating an opportunity for combinations with ICI. However, an inevitable challenge to KRAS inhibitors is drug resistance. Promising combination strategies such as combination with SHP2 is an approach deserve further exploration because of their immune modulatory effect.
Topics: Animals; Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mutation; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Tumor Microenvironment
PubMed: 38171240
DOI: 10.1016/j.biopha.2023.116058 -
Cureus Nov 2023Acute myeloid leukemia (AML) is the most prevalent form of leukemia in adults, with rising global incidence rates. AML usually presents with non-specific clinical...
Acute myeloid leukemia (AML) is the most prevalent form of leukemia in adults, with rising global incidence rates. AML usually presents with non-specific clinical features such as pallor, fever, and bleeding. This case report discusses a unique presentation of AML, where a 25-year-old female with a history of hypertension presented with unilateral facial swelling, chest pain, and shortness of breath. Radiologic investigations revealed a mediastinal mass encasing the superior vena cava (SVC), confirming the suspicion of SVC syndrome. Upon testing with a biopsy, the mass was found to be composed of immature myeloid cells confirming the diagnosis of myeloid sarcoma-associated AML. The patient's treatment involved a combination of surgical debridement, induction chemotherapy, supportive care, and management of complications. This case highlights that despite its common occurrence, AML may present with atypical clinical manifestations such as SVC syndrome, posing challenges in its diagnosis and timely management.
PubMed: 38161934
DOI: 10.7759/cureus.49616