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In Vivo (Athens, Greece) 2022Concomitant immunity (CIM) is a phenomenon that elicits an antitumor response not sufficient enough to destroy the primary tumor but prevents a secondary implant from...
BACKGROUND/AIM
Concomitant immunity (CIM) is a phenomenon that elicits an antitumor response not sufficient enough to destroy the primary tumor but prevents a secondary implant from growing and spreading. This study aimed to develop a method of identification of serum tumoricidal factors released into circulation during CIM and to compare the CIM-related effect to the effect elicited by the cytotoxic drug doxorubicin.
MATERIALS AND METHODS
SL2 tumor-bearing mice were studied at three time points - day 4, day 7, and day 11 following i.p. 5×10 cell implantation. Hematological effects and thymocyte immunophenotyping (CD4/CD8) data were compared to the effects induced by intravenous 10 mg/kg doxorubicin (DOX) administration to intact DBA 2 mice. The level of plasma colony stimulating factor-granulocyte macrophage (CSF-GM) was evaluated by ELISA.
RESULTS
Identical thymus histopathology and an extent of double-positive CD4+CD8+ subset depletion was found in day 11 tumor-bearing mice (TBM-11) and in DOX-administered animals. TBM-11 exhibited a leukemoid reaction with an increase in monocyte and granulocyte counts. Conversely, DOX administration was followed by severe leukocytopenia at the 72-h time point. No increase in CSF-GM was observed in mice with or without a leukemoid reaction.
CONCLUSION
The complexity of CIM can be examined by tracking alterations in the most fragile cortical CD8+CD4+ double positive population. Thymocyte apoptosis induced by DOX and TBM-11 might be associated with different mechanisms. TBM-11 did not exhibit severe myelotoxicity as DOX did. CIM-related serum factors can be assessed and screened via thymocyte subset analysis.
Topics: Animals; Antineoplastic Agents; Doxorubicin; Granulocyte-Macrophage Colony-Stimulating Factor; Leukemoid Reaction; Mice; Mice, Inbred DBA
PubMed: 35478153
DOI: 10.21873/invivo.12808 -
Innere Medizin (Heidelberg, Germany) Dec 2022Paraneoplastic leukocytosis in solid tumors is associated with poor prognosis. While mild leukocytosis is common, paraneoplastic hyperleukocytosis is extremely rare. The...
Paraneoplastic leukocytosis in solid tumors is associated with poor prognosis. While mild leukocytosis is common, paraneoplastic hyperleukocytosis is extremely rare. The case of a 73-year-old male diagnosed with an adenocarcinoma of the lung and a peak white blood cell count of 178,000/µl is reported. The patient succumbed to the disease after two cycles of immunochemotherapy only 2 months after first hospital admission. Specific treatment options are still under investigation and have not been reported in clinical use.
Topics: Male; Humans; Aged; Leukocytosis; Lung Neoplasms; Leukocyte Count; Lung
PubMed: 36149442
DOI: 10.1007/s00108-022-01407-8 -
Cureus Sep 2022Leukocytosis is defined by an increased WBC count in the peripheral blood. This can be caused by many pathologies from benign conditions such as stress, infection, and...
Leukocytosis is defined by an increased WBC count in the peripheral blood. This can be caused by many pathologies from benign conditions such as stress, infection, and inflammation or malignant origins such as leukemia. Although leukocytosis is regularly encountered clinically and has many etiologies making a definitive diagnosis, at times, may be difficult. A case of severe leukocytosis requires careful consideration of symptoms and confirmation with serial complete blood count (CBC) testing before pursuing further invasive testing such as bone marrow biopsy. Here, we report the case of a 78-year-old male patient who, after a cardiac arrest, presented with reactive hyperleukocytosis mimicking acute monocytic leukemia.
PubMed: 36299948
DOI: 10.7759/cureus.29508 -
Cureus May 2021Pulmonary malignancies are known to have high prevalence and mortality. They are associated with different paraneoplastic syndromes, especially pulmonary carcinomas,...
Pulmonary malignancies are known to have high prevalence and mortality. They are associated with different paraneoplastic syndromes, especially pulmonary carcinomas, because they are more common than pulmonary sarcomas. We present a case of a 56-year-old African American male who was admitted to our institution with a three-month history of a dry cough, progressive shortness of breath, and two to three days of right arm swelling. He had extreme leukocytosis (WBC count of 106,500 cells/mm). Computed tomography (CT) scan of the thorax demonstrated an irregular, thick-walled 14-cm lung mass occupying the middle and upper hemithorax. CT-guided biopsy of the mass confirmed the diagnosis of lung sarcoma.
PubMed: 34150398
DOI: 10.7759/cureus.15047 -
Hematology. American Society of... Dec 2022Children with Down syndrome (DS) have a greater than 100-fold increased risk of developing acute myeloid leukemia (ML) and an approximately 30-fold increased risk of...
Children with Down syndrome (DS) have a greater than 100-fold increased risk of developing acute myeloid leukemia (ML) and an approximately 30-fold increased risk of acute lymphoblastic leukemia (ALL) before their fifth birthday. ML-DS originates in utero and typically presents with a self-limiting, neonatal leukemic syndrome known as transient abnormal myelopoiesis (TAM) that is caused by cooperation between trisomy 21-associated abnormalities of fetal hematopoiesis and somatic N-terminal mutations in the transcription factor GATA1. Around 10% of neonates with DS have clinical signs of TAM, although the frequency of hematologically silent GATA1 mutations in DS neonates is much higher (~25%). While most cases of TAM/silent TAM resolve without treatment within 3 to 4 months, in 10% to 20% of cases transformation to full-blown leukemia occurs within the first 4 years of life when cells harboring GATA1 mutations persist and acquire secondary mutations, most often in cohesin genes. By contrast, DS-ALL, which is almost always B-lineage, presents after the first few months of life and is characterized by a high frequency of rearrangement of the CRLF2 gene (60%), often co-occurring with activating mutations in JAK2 or RAS genes. While treatment of ML-DS achieves long-term survival in approximately 90% of children, the outcome of DS-ALL is inferior to ALL in children without DS. Ongoing studies in primary cells and model systems indicate that the role of trisomy 21 in DS leukemogenesis is complex and cell context dependent but show promise in improving management and the treatment of relapse, in which the outcome of both ML-DS and DS-ALL remains poor.
Topics: Infant; Infant, Newborn; Child; Humans; Child, Preschool; Down Syndrome; Leukemoid Reaction; GATA1 Transcription Factor; Leukemia, Myeloid, Acute; Mutation
PubMed: 36485097
DOI: 10.1182/hematology.2022000395 -
Anaerobe Oct 2022Paeniclostridium sordellii is a pathogen that causes rapidly fatal infections characterized by severe edema, extreme leukemoid reaction and lack of an innate immune...
OBJECTIVE
Paeniclostridium sordellii is a pathogen that causes rapidly fatal infections characterized by severe edema, extreme leukemoid reaction and lack of an innate immune response. We recently identified a metalloproteinase of P. sordellii-1 (Mcs1) that cleaves human vascular cell adhesion molecule 1, an adhesion molecule important to hematopoietic precursor retention and leukocyte diapedesis. In the current study, we further characterize Mcs1 activity and investigate its role in pathogenesis.
METHODS
Mcs1 peptide cleavage sequence and activity conditions were identified using a semi-quantitative fluorescence-based reporter assay. Additional host targets for Mcs1 protease activity were tested and confirmed by gel electrophoreses and western blots. Finally, Mcs1 knock out (ΔMcs1) and complemented (cMcs1) strains were developed for assessment in our animal model of myonecrosis.
RESULTS
Data show that Mcs1 prefers aliphatic amino acid residues, I or L, especially when adjacent to negatively charged or noncharged-polar residues. In vitro, Mcs1 cleaved or partially cleaved human cell adhesion molecules, E-selectin and intracellular adhesion molecule-1 (ICAM-1), and mediators of innate immune infection defense, complement protein-3 and antimicrobial peptide LL-37. In vivo, infection with the ΔMcs1 P. sordellii strain had little effect on animal survival, tissue destruction or circulating white blood cell counts compared to wild type and cMcs1 strains.
CONCLUSIONS
Similar to proteolytic virulence factors from other pathogens, Mcs1 is a promiscuous protease that cleaves multiple human-host factors. Despite minimal impact of Mcs1 on the murine model of P. sordellii infection, it is worth considering its role in humans and other animal models.
Topics: Animals; Humans; Mice; Clostridium sordellii; Disease Models, Animal; Peptide Hydrolases; Virulence Factors; Clostridium Infections; Bacterial Proteins
PubMed: 34688909
DOI: 10.1016/j.anaerobe.2021.102468 -
Leukemia Research Reports 2020Acute myeloid leukemia (AML) is defined by the presence of ≥ 20% myeloblasts in the blood or bone marrow. Spontaneous remission (SR) of AML is a rare event, with few...
Acute myeloid leukemia (AML) is defined by the presence of ≥ 20% myeloblasts in the blood or bone marrow. Spontaneous remission (SR) of AML is a rare event, with few cases described in the literature. SR is generally associated with recovery from an infectious or immunologic process, and more recently possibly with clonal hematopoiesis. We review the literature and assess the trends associated with SR, and report a new case of a 58-year-old man with a morphologic diagnosis of AML associated with a severe gastrointestinal (GI) tract infection. The patient had an NF1 variant that was previously unreported in AML as the only clonal abnormality. After treatment of the infection, the increased blast population subsided with no leukemia-directed therapy, and the patient has remained in a continuous, spontaneous complete remission for > 2 years.
PubMed: 32477862
DOI: 10.1016/j.lrr.2020.100204 -
EJNMMI Research Feb 2020The undifferentiated embryonic sarcoma of the liver (UESL) is a rare, aggressive tumor mainly affecting children. Since UESL has no specific clinical symptoms or imaging...
BACKGROUND
The undifferentiated embryonic sarcoma of the liver (UESL) is a rare, aggressive tumor mainly affecting children. Since UESL has no specific clinical symptoms or imaging characteristics, many cases of UESL are diagnosed late. The paraneoplastic leukemoid reaction (PLR) is a very rare concomitant of oncological patients associated with poor prognosis. This report describes the clinical course of a patient combining these two rare entities and describes the diagnostic challenges and dynamics of paraneoplastic syndrome.
CASE PRESENTATION
We report a case of UESL in a 46-year-old male who became clinically conspicuous due to pronounced B symptoms. CT and MRI showed a suspicious unifocal liver lesion. As the histological analysis of a tissue sample did not reveal a clear result, an 18F-FDG-PET-CT examination was performed. In addition to a high glucose metabolism of the liver lesion, an increased glucose metabolism in the entire bone marrow was observed. This finding was considered as pronounced paraneoplasia and laparotomy with liver segment resection followed. Immediately after resection of the tumor the paraneoplastic symptoms completely declined and the patient showed no signs of recurrence in the 1-year follow-up.
CONCLUSIONS
Although UESL is rare and predominantly affects children, this diagnosis should always be considered for unclear unifocal cystic liver lesions, regardless of the patient's age, as appropriate treatment has a good prognosis.
PubMed: 32072333
DOI: 10.1186/s13550-020-0602-x -
Diagnostics (Basel, Switzerland) Aug 2022Tumor-associated leukocytosis has been associated with poor prognosis in cervical cancer. Leukemoid reaction (i.e., white blood cell count > 40,000/μL) is defined... (Review)
Review
Pathogenic and Prognostic Roles of Paraneoplastic Leukocytosis in Cervical Cancer: Can Genomic-Based Targeted Therapies Have a Role? A Literature Review and an Emblematic Case Report.
Tumor-associated leukocytosis has been associated with poor prognosis in cervical cancer. Leukemoid reaction (i.e., white blood cell count > 40,000/μL) is defined paraneoplastic (PLR) when it occurs in the presence of a cytokine-secreting tumor (CST) without neoplastic bone marrow infiltration. Cervical cancers displaying PLR represent a peculiar entity characterized by a rapidly progressive behavior typically associated with chemo-radioresistance. The present paper aims to review the literature about the pathogenetic mechanisms of PLR and its prognostic role in cervical cancer. Moreover, it reports the emblematic case of a patient with an advanced cervical cancer associated with PLR that was chemotherapy resistant. The patient underwent a palliative cytoreductive surgery of high complexity, obtaining a temporary regression of PLR. The tumor sample stained positive for G-CSF and IL-6, thus indicating a CST. Notably, the tumor genomic analysis revealed a PI3CKA mutation. Therefore, at the instrumental evidence of a rapidly progressive disease relapse, which was accompanied by reappearance of PLR, we started a targeted treatment with a selective PIK3 inhibitor alpesilib combined with the JAK1-2 inhibitor ruxolitinib. We achieved a relief of symptoms and leukocytosis; however, severe side effects necessitated the treatment suspension. In conclusion, as therapeutic strategies for cancer with PLR are scarcely reported in literature, our study could contribute to expand our understanding of the topic and provide a basis for further research.
PubMed: 36010260
DOI: 10.3390/diagnostics12081910 -
Haematologica Apr 2021The megakaryocyte/erythroid Transient Myeloproliferative Disorder (TMD) in newborns with Down Syndrome (DS) occurs when N-terminal truncating mutations of the...
The megakaryocyte/erythroid Transient Myeloproliferative Disorder (TMD) in newborns with Down Syndrome (DS) occurs when N-terminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where in the hemopoietic cellular hierarchy GATA1s exerts its effects to produce this myeloproliferative state. Here, through a detailed examination of hemopoiesis from murine GATA1s ES cells and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur relatively late in hemopoiesis. GATA1s causes an arrest late in erythroid differentiation in vivo, and even more profoundly in ES-cell derived cultures, with a marked reduction of Ter-119 cells and reduced erythroid gene expression. In megakaryopoiesis, GATA1s causes a differentiation delay at a specific stage, with accumulation of immature, kit-expressing CD41hi megakaryocytic cells. In this specific megakaryocytic compartment, there are increased numbers of GATA1s cells in S-phase of cell cycle and reduced number of apoptotic cells compared to GATA1 cells in the same cell compartment. There is also a delay in maturation of these immature GATA1s megakaryocytic lineage cells compared to GATA1 cells at the same stage of differentiation. Finally, even when GATA1s megakaryocytic cells mature, they mature aberrantly with altered megakaryocyte-specific gene expression and activity of the mature megakaryocyte enzyme, acetylcholinesterase. These studies pinpoint the hemopoietic compartment where GATA1s megakaryocyte myeloproliferation occurs, defining where molecular studies should now be focussed to understand the oncogenic action of GATA1s.
Topics: Animals; Cell Differentiation; Down Syndrome; GATA1 Transcription Factor; Humans; Infant, Newborn; Leukemoid Reaction; Megakaryocytes; Mice
PubMed: 32527952
DOI: 10.3324/haematol.2019.244541