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1.
J Pediatr Hematol Oncol ; 44(6): 305-312, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35137727

ABSTRACT

BACKGROUND: We investigated whether surveillance imaging had an impact on post-relapse survival in patients with rhabdomyosarcoma (RMS). We hypothesized that relapse detected by imaging (group IM) would be associated with longer survival compared with relapse detected with a clinical sign or symptom (group SS). MATERIALS AND METHODS: We performed an observational multi-institutional study in 127 patients with relapsed RMS comparing overall survival (OS) after relapse using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Relapse was detected in 60 (47%) group IM and 67 (53%) SS patients. Median follow-up in survivors was 4 years (range 1.0 to 16.7 y). Four-year OS rates were similar between group IM (28%, 95% confidence interval [CI]: 14%-40%) and SS (21%, 95% CI: 11%-31%) ( P =0.14). In multivariable analyses accounting for institution, age at diagnosis, time to relapse, risk group at diagnosis, and primary site, not receiving chemotherapy (hazard ratio [HR]: 6.8, 95% CI: 2.8-16.6), radiation (HR: 3, 95% CI: 1.7-5.3), or surgery (HR: 2.8, 95% CI: 1.6-4.8) after relapse were independently associated with poor OS. CONCLUSION: These results on whether surveillance imaging provides survival benefit in patients with relapsed RMS are inconclusive. Larger studies are needed to justify current surveillance recommendations. Chemotherapy, radiotherapy and surgery to treat recurrence prolong OS.


Subject(s)
Rhabdomyosarcoma , Diagnostic Imaging , Humans , Neoplasm Recurrence, Local , Proportional Hazards Models , Retrospective Studies , Rhabdomyosarcoma/diagnostic imaging , Rhabdomyosarcoma/therapy , Rhabdomyosarcoma, Embryonal
2.
Cancer Immunol Res ; 7(9): 1396-1400, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31383651

ABSTRACT

High-grade malignant peripheral nerve sheath tumors (MPNST) have a poor prognosis with limited responsiveness to systemic therapy. We document a case of a complete metabolic response to pembrolizumab monotherapy in metastatic disease. Tumor molecular profiling identified programmed-death ligand-1 (PD-L1) positivity. This characteristic provided a rationale for immune-checkpoint therapy. Treatment with pembrolizumab resulted in a complete metabolic response after four cycles of therapy. Patients with PD-L1-positive, metastatic MPNST may be candidates for immune-checkpoint therapy, which may produce a durable complete remission. Future study of anti-PD-1/PD-L1 therapy is warranted.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Energy Metabolism/drug effects , Nerve Sheath Neoplasms/drug therapy , Nerve Sheath Neoplasms/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Antineoplastic Agents, Immunological/pharmacology , Biopsy , Gene Expression Profiling , Humans , Male , Neoplasm Staging , Nerve Sheath Neoplasms/diagnosis , Positron Emission Tomography Computed Tomography , Tomography, X-Ray Computed , Treatment Outcome , Young Adult
3.
JAMA Oncol ; 5(6): 777-778, 2019 Jun 01.
Article in English | MEDLINE | ID: mdl-30998811
4.
J Adolesc Young Adult Oncol ; 8(2): 217-220, 2019 04.
Article in English | MEDLINE | ID: mdl-30335538

ABSTRACT

Hepatic late effects are not commonly reported in survivors of childhood leukemia. Four young male patients with acute lymphoblastic leukemia (ALL) were diagnosed with bleeding esophageal varices (EVs) during or shortly after completion of maintenance chemotherapy. EVs were identified from 0 to 60 months after completion of leukemia therapy. All four patients were men between 20 to 24 years old. Hematemesis was the most common presenting symptom. Associated features included splenomegaly, cytopenias, azole therapy, alcohol use, and hepatic iron overload. EVs may be an under-recognized complication of ALL therapy, with adolescent and young adult males at highest risk.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Esophageal and Gastric Varices/chemically induced , Maintenance Chemotherapy/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Adult , Esophageal and Gastric Varices/pathology , Humans , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Young Adult
5.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Article in English | MEDLINE | ID: mdl-28748602

ABSTRACT

BACKGROUND: The combination of vincristine, irinotecan, and temozolomide (VIT) is often used to treat children and adolescents with relapsed rhabdomyosarcoma (RMS); however, the outcome of these patients has not been previously described. PROCEDURES: We sought to determine the response rate (RR) and progression-free survival (PFS) for patients with relapsed RMS treated with VIT by retrospective review of patients treated at five tertiary care hospitals. Prior treatment with irinotecan was permitted. RESULTS: Among 19 patients with a median age of 8 years (range 2-17 years), 12 (63%) were males and 12 (63%) had embryonal histology. Median time to relapse from initial diagnosis was 16 months (range 2.8-45 months). VIT was used as first, second, third, or fourth line of therapy in four (21%), seven (37%), six (32%), and two (10%) patients, respectively. Four patients received VIT as adjuvant therapy following radiation and/or surgery. Therefore, among 15 evaluable patients, the best response to VIT was 0 (complete response, CR), 0 (partial response, PR), 4 (stable disease, SD), and 11 (progressive disease, PD) for an overall clinical benefit rate (CR + PR + SD) of 26.7% (95% CI: 7.8-55.1%). After a median follow-up of 8 months, 2 (10%) patients were alive without disease, 3 (16%) were alive with disease, and 14 (74%) patients died of PD. PFS at 3 months was 23% (95% CI: 5.7-46.7%). CONCLUSIONS: VIT therapy in combination with adequate local control is associated with some disease control in patients with first relapse RMS and may be another reasonable option to offer patients as salvage therapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/mortality , Rhabdomyoma/drug therapy , Rhabdomyoma/mortality , Adolescent , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Child , Child, Preschool , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Disease-Free Survival , Female , Follow-Up Studies , Humans , Irinotecan , Male , Survival Rate , Temozolomide , Vinculin/administration & dosage
6.
Pediatr Blood Cancer ; 63(2): 202-5, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26376023

ABSTRACT

BACKGROUND: Patients with rhabdomyosarcoma (RMS) who complete therapy typically undergo 4 years of surveillance imaging despite lack of evidence that this improves outcomes. We compared overall survival (OS) between patients in whom progression or relapse was detected by routine clinical evaluation or by imaging. PROCEDURE: Children with progressive or relapsed RMS treated at Texas Children's Hospital between 1992 and 2012 were identified and their records were reviewed. Survival time after progression or relapse was compared between two groups: (1) patients in whom progression or relapse was suspected on the basis of clinical history, symptoms, laboratory evaluation, or physical exam; and (2) patients whose progression or relapse was initially detected by imaging. RESULTS: Of the 43 children with progressive or relapsed RMS, 26 (60%) had metastatic disease at diagnosis and 19 (44%) had alveolar histology. With a median follow up time of 5 years in six survivors, there was no difference in OS between patients in whom progression or relapse was diagnosed based on imaging (n = 15) or by clinical evaluation (n = 28) (3-year OS 20% vs. 11%, respectively, P = 0.38). Disease extent, primary site, and risk group at diagnosis were associated with survival after progression or relapse. CONCLUSIONS: Routine surveillance imaging practice should be critically reviewed for children with RMS. Although our findings must be validated by larger studies, they do have substantive implications. Reduced imaging tailored to the risk and pattern of recurrence, associated risks and cost could improve patient quality of life and decrease health-care expenditure without compromising outcome.


Subject(s)
Diagnostic Imaging , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/mortality , Rhabdomyosarcoma/mortality , Soft Tissue Neoplasms/mortality , Adolescent , Child , Child, Preschool , Disease Progression , Female , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Male , Neoplasm Recurrence, Local/pathology , Retrospective Studies , Rhabdomyosarcoma/pathology , Soft Tissue Neoplasms/pathology , Young Adult
7.
Mol Cancer Res ; 12(6): 953-64, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24651452

ABSTRACT

UNLABELLED: Ewing sarcoma is the second most common bone cancer in pediatric patients. Although the primary cause of death in Ewing sarcoma is metastasis, the mechanism underlying tumor spread needs to be elucidated. To this end, the role of the CXCR4/SDF-1a chemokine axis as a mediator of Ewing sarcoma metastasis was investigated. CXCR4 expression status was measured in primary tumor specimens by immunohistochemical staining and in multiple cell lines by quantitative reverse transcriptase PCR and flow cytometry. Migration and invasion of CXCR4-positive Ewing sarcoma cells toward CXCL12/SDF-1a were also determined. Interestingly, while CXCR4 status was disparate among Ewing sarcoma cells, ranging from absent to high-level expression, its expression was found to be highly dynamic and responsive to changes in the microenvironment. In particular, upregulation of CXCR4 occurred in cells that were subjected to growth factor deprivation, hypoxia, and space constraints. This upregulation of CXCR4 was rapidly reversed upon removal of the offending cellular stress conditions. Functionally, CXCR4-positive cells migrated and invaded toward an SDF-1a gradient and these aggressive properties were impeded by both the CXCR4 small-molecule inhibitor AMD3100, and by knockdown of CXCR4. In addition, CXCR4-dependent migration and invasion were inhibited by small-molecule inhibitors of Cdc42 and Rac1, mechanistically implicating these Rho-GTPases as downstream mediators of the CXCR4-dependent phenotype. IMPLICATIONS: This study reveals the highly plastic and dynamic nature of CXCR4 expression in Ewing sarcoma and supports a model in which stress-induced upregulation of CXCR4 contributes to tumor metastasis to lung and bone marrow, which express high levels of SDF-1a.


Subject(s)
Bone Neoplasms/pathology , Cell Movement/physiology , Receptors, CXCR4/biosynthesis , Sarcoma, Ewing/pathology , Bone Neoplasms/genetics , Bone Neoplasms/metabolism , Cell Growth Processes/physiology , Cell Hypoxia/physiology , Cell Line, Tumor , Chemokine CXCL12/metabolism , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Neoplasm Invasiveness , Receptors, CXCR4/genetics , Sarcoma, Ewing/genetics , Sarcoma, Ewing/metabolism , Stress, Physiological , cdc42 GTP-Binding Protein/metabolism , rac1 GTP-Binding Protein/metabolism
8.
Front Oncol ; 3: 81, 2013.
Article in English | MEDLINE | ID: mdl-23596566

ABSTRACT

Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of putative stem cell origin that predominantly occurs in children and young adults. Although most patients with localized ES can be cured with intensive therapy, the clinical course is variable and up to one third of patients relapse following initial remission. Unfortunately, little is yet known about the biologic features that distinguish low-risk from high-risk disease or the mechanisms of ES disease progression. Recent reports have suggested that putative cancer stem cells exist in ES and may contribute to an aggressive phenotype. The cell surface receptor leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a somatic stem cell marker that functions as an oncogene in several human cancers, most notably colorectal carcinoma. LGR5 is a receptor for the R-spondin (RSPO) family of ligands and RSPO-mediated activation of LGR5 potentiates Wnt/ß-catenin signaling, contributing to stem cell proliferation and self-renewal. Given its presumed stem cell origin, we investigated whether LGR5 contributes to ES pathogenesis. We found that LGR5 is expressed by ES and that its expression is relatively increased in cells and tumors that display a more aggressive phenotype. In particular, LGR5 expression was increased in putative cancer stem cells. We also found that neural crest-derived stem cells express LGR5, raising the possibility that expression of LGR5 may be a feature of ES cells of origin. LGR5-high ES cells showed nuclear localization of ß-catenin and robust activation of TCF reporter activity when exposed to Wnt ligand and this was potentiated by RSPO. However, modulation of LGR5 or exposure to RSPO had no impact on proliferation confirming that Wnt/ß-catenin signaling in ES cells does not recapitulate signaling in epithelial cells. Together these studies show that the RSPO-LGR5-Wnt-ß-catenin axis is present and active in ES and may contribute to tumor pathogenesis.

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