96 research outputs found
Chemotherapy-Induced Neuronal Maturation in Sinonasal Teratocarcinosarcoma—a Unique Observation
Sinonasal teratocarcinosarcoma (SNTCS) is a rare and highly malignant tumour with combined features of a teratoma and carcinosarcoma. We report the first case of a SNTCS in 23 year old male treated with neo-adjuvant chemotherapy followed by cranio-facial resection. The resection specimen displayed cellular maturation in the neuroectodermal component. The patient presented with a short history of nasal obstruction, epistaxis and headache. On imaging, a bone destroying lesion of left paranasal sinuses and nasal cavity was identified. The diagnosis of SNTCS could be offered only on the third biopsy which showed heterogeneous admixture of primitive neuroectodermal, epithelial and mesenchymal elements. An adequate sampling with high index of suspicion is needed to catch hold this rare tumor. Tumor was excised after 4 cycles of neo-adjuvant chemotherapy. On microscopic examination, it showed similar epithelial and mesenchymal components as the pretreatment biopsies. However, the primitive neuroectodermal component displayed extensive neuronal maturation. The undifferentiated neuroectodermal cells were completely absent in the post chemotherapy specimen. This case throws light on the morphologic evidence of chemotherapy induced maturation in the neuroectodermal component within SNTCS, an event hitherto not reported in the literature in case of SNTCS
Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes—an international multicentre retrospective study
Background Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to noncancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population
Disparate In Vivo Efficacy of FTY720 in Xenograft Models of Philadelphia Positive and Negative B-lineage Acute Lymphoblastic Leukemia
Most patients with acute lymphoblastic leukemia (ALL) respond well to standard chemotherapy-based treatments. However a significant proportion of patients, particularly adult patients, relapse with the majority dying of leukemia. FTY720 is an immunosuppressive drug that was recently approved for the treatment of multiple sclerosis and is currently under pre-clinical investigation as a therapy for a number of hematological malignancies. Using human ALL xenografts in NOD/SCIDγc−/− mice, we show for the first time that three Ph+ human ALL xenografts responded to FTY720 with an 80±12% (p = 0.048) reduction in overall disease when treatment was commenced early. In contrast, treatment of mice with FTY720 did not result in reduced leukemia compared to controls using four separate human Ph− ALL xenografts. Although FTY720 reactivated PP2A in vitro, this reactivation was not required for death of Ph− ALL cells. The plasma levels of FTY720 achieved in the mice were in the high nanomolar range. However, the response seen in the Ph+ ALL xenografts when treatment was initiated early implies that in vivo efficacy may be obtained with substantially lower drug concentrations than those required in vitro. Our data suggest that while FTY720 may have potential as a treatment for Ph+ ALL it will not be a useful agent for the treatment of Ph− B-ALL
Mammalian Target of Rapamycin (mTOR) Activity Dependent Phospho-Protein Expression in Childhood Acute Lymphoblastic Leukemia (ALL)
Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25–30% of
patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central
mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL.
However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent
phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL
patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited
increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor
4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of
chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for
p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed
patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to
identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic
cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments
Hamartomas, teratomas and teratocarcinosarcomas of the head and neck: Report of 3 new cases with clinico-pathologic correlation, cytogenetic analysis, and review of the literature
<p>Abstract</p> <p>Background</p> <p>Germ-cell tumors (GCT) are a histologically and biologically diverse group of neoplasms which primarily occur in the gonads but also develop at different extragonadal sites in the midline of the body. The head and neck region including the upper respiratory tract is a very rare location for such tumors in both children and adults, which can cause diagnostic and therapeutic difficulties.</p> <p>Methods</p> <p>We describe here two new cases of multilineage tumors including sinonasal teratocarcinosarcoma [SNTCS], and congenital oronasopharyngeal teratoma (epignathus) and compare their features with those of a new case of a rare salivary gland anlage tumor [SGAT], an entity for which the pathogenesis is unclear (i.e. hamartoma versus neoplasm). We correlate their presenting clinico-pathological features and compare histologic and cytogenetic features in an attempt to elucidate their pathogenesis and biologic potentials.</p> <p>Results and discussion</p> <p>Cytogenetic analysis revealed chromosomal abnormalities only in the case of SNTCS that showed trisomy 12 and 1p deletion. Both cytogenetic abnormalities are characteristically present in malignant germ cell tumors providing for the first time evidence that this rare tumor type indeed might represent a variant of a germ cell neoplasm. The SGAT and epignathus carried no such cytogenetic abnormalities, in keeping with their limited and benign biologic potential.</p> <p>Conclusion</p> <p>The comparison of these three cases should serve to emphasize the diversity of multilineage tumors (hamartomas and GCT) of the upper respiratory tract in regards to their biology, age of presentation and clinical outcomes. Malignant tumors of germ cell origins are more likely to affect adults with insidious symptom development, while benign tumors can nevertheless cause dramatic clinical symptoms which, under certain circumstances, can be fatal.</p
The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells
In Ph-positive (Ph+) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph+ acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγnull (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G0 cells in the CD34+CD38− population compared with the CD34+CD38+ and CD34− populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34+CD38− population than in the other populations. Although slow-cycling G0 cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34+CD38− population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34+ cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph+ leukemia due to quiescence
Identification of Hepatic Niche Harboring Human Acute Lymphoblastic Leukemic Cells via the SDF-1/CXCR4 Axis
In acute lymphoblastic leukemia (ALL) patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc null mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis
Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes:an international multicentre retrospective study
Background: Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to non-cancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population. Methods: We studied patients with underlying malignancies admitted with sepsis to one of 25 paediatric intensive care units (PICUs) participating in two large, multi-centre, observational cohorts from the European SCOTER study (n = 383 patients; study period between January 1, 2018 and January 1, 2020) and the U.S. Novel Data-Driven Sepsis Phenotypes in Children study (n = 1898 patients; study period between January 1, 2012 and January 1, 2018). We independently used latent class analysis (LCA) in both cohorts to identify phenotypes using demographic, clinical, and laboratory data from the first 24 h of PICU admission. We then tested the association of the phenotypes with clinical outcomes in both cohorts. Findings: LCA identified two distinct phenotypes that were comparable across both cohorts. Phenotype 1 was characterised by lower serum bicarbonate and albumin, markedly increased lactate and hepatic, renal, and coagulation abnormalities when compared to phenotype 2. Patients with phenotype 1 had a higher 90-day mortality (European cohort 29.2% versus 13.4%, U.S. cohort 27.3% versus 11.4%, p < 0.001) and received more vasopressor and renal replacement therapy than patients with phenotype 2. After adjusting for severity of organ dysfunction, haematological cancer, prior stem cell transplantation and age, phenotype 1 was associated with an adjusted OR of death at 90-day of 1.9 (1.04–3.34) in the European cohort and 1.6 (1.2–2.2) in the U.S. cohort. Interpretation: We identified two clinically-relevant sepsis phenotypes in paediatric cancer patients that are reproducible across two international, multicentre cohorts with prognostic implications. These results may guide further research regarding therapeutic approaches for these specific phenotypes. Funding: Part of this study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.</p
Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes:an international multicentre retrospective study
Background: Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to non-cancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population. Methods: We studied patients with underlying malignancies admitted with sepsis to one of 25 paediatric intensive care units (PICUs) participating in two large, multi-centre, observational cohorts from the European SCOTER study (n = 383 patients; study period between January 1, 2018 and January 1, 2020) and the U.S. Novel Data-Driven Sepsis Phenotypes in Children study (n = 1898 patients; study period between January 1, 2012 and January 1, 2018). We independently used latent class analysis (LCA) in both cohorts to identify phenotypes using demographic, clinical, and laboratory data from the first 24 h of PICU admission. We then tested the association of the phenotypes with clinical outcomes in both cohorts. Findings: LCA identified two distinct phenotypes that were comparable across both cohorts. Phenotype 1 was characterised by lower serum bicarbonate and albumin, markedly increased lactate and hepatic, renal, and coagulation abnormalities when compared to phenotype 2. Patients with phenotype 1 had a higher 90-day mortality (European cohort 29.2% versus 13.4%, U.S. cohort 27.3% versus 11.4%, p < 0.001) and received more vasopressor and renal replacement therapy than patients with phenotype 2. After adjusting for severity of organ dysfunction, haematological cancer, prior stem cell transplantation and age, phenotype 1 was associated with an adjusted OR of death at 90-day of 1.9 (1.04–3.34) in the European cohort and 1.6 (1.2–2.2) in the U.S. cohort. Interpretation: We identified two clinically-relevant sepsis phenotypes in paediatric cancer patients that are reproducible across two international, multicentre cohorts with prognostic implications. These results may guide further research regarding therapeutic approaches for these specific phenotypes. Funding: Part of this study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.</p
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