OBJECTIVES: Next-generation sequencing (NGS) has the potential to transform the paradigm for diagnosing and treating cancer. Widespread adoption is predicated on demonstrating the clinical ...utility/clinical impact of NGS and developing evidence-based reimbursement policies. A review of clinical utility, coverage and reimbursement from third-party payers was conducted in a cohort of pediatric oncology patients as part of a clinical NGS program. METHODS: NGS was performed in a CLIA-certified laboratory at Columbia University Medical Center. Testing included whole-exome sequencing (WES) of matched tumor-normal tissue, transcriptome analysis and copy number variation. WES of patient-parent DNA was performed when a constitutionally encoded disease or syndrome was suspected. Targeted sequencing of 48 or 467 cancer-associated genes was used when tumor tissue was limited. RESULTS: 105 patients received NGS (WES: n=82, 78%; targeted panels: n=23, 22%). Clinical utility/clinical impact was demonstrated in 62/105 patients (59%); druggable targets (17/62), diagnostic/prognostic (26/62); other clinically-impactful findings (19/62). WES identified 54/62 (87%) of the clinically-impactful findings. 78 patients (74%) received partial reimbursement. In 16/27 patients denied coverage (59%), a clinically-actionable result was found. Reimbursement was provided by commercial plans to 35/52 patients (67%) and to 43/50 patients (86%) by managed-government plans. Government plans provided no coverage for 3 patients. Insurers without a specific coverage plan or considered NGS "experimental", denied coverage for all or part of testing. On average, insurers reimbursed 33% of the total NGS service charges: 30% (range, 0-89%) from commercial plans; 37% (range, 0-61%) from managed-government plans. The average reimbursement was: $3,426 (range, $750-$7,227) for WES; $837 (range, $82-$l,399) for targeted 48-gene panel sequencing and $2,586 (range, $444-$4,149) for targeted 467-gene panel sequencing. CONCLUSIONS: NGS provided clinically-impactful information for 59% of patients but only one-third of charges for testing were reimbursed by insurers. Evidence-based reimbursement policies are needed to promote the adoption of NGS technologies that benefits patients into clinical practice.
Much evidence supports an important role for the inducible enzyme cyclooxygenase-2 (COX-2) in tumor angiogenesis. Previous studies have focused on the role of COX-2 in stimulating endothelial ...proliferation, with blockade of this enzyme impairing endothelial homeostasis. However, recent data suggest that COX-2 also regulates molecules implicated in endothelial trafficking with pericytes/vascular mural cells (VMC), an interaction crucial to vessel stability. We investigated the role of COX-2 in vascular assembly by testing the effect of the specific COX-2 inhibitor SC-236 in an orthotopic xenograft model of human Wilms' tumor. Tumor growth was significantly suppressed by SC-236 (78% at day 28, 55% at day 35). Perfusion studies and immunostaining showed a marked decrease in vasculature, particularly in small vessels. Specifically, SC-236 inhibited participation of VMC in xenograft vessels. SC-236-treated tumors developed segmentally dilated, architecturally erratic tumor vessels with decreased nascent pericytes and scant mature VMC. Although vascular endothelial growth factor expression was unchanged, expression of the chemokine receptor CXCR4 was decreased in tumor vessels, consistent with defective homing of vascular progenitor cells. Vascular expression of phosphorylated platelet-derived growth factor receptor-beta was also diminished, indicating impaired VMC-endothelial trafficking. Consistent with the key role of this interaction in vessel homeostasis, vascular cells in SC-236-treated tumors displayed markedly diminished phosphorylated Akt, indicating disrupted survival signaling. These results show that SC-236 causes defective vascular assembly by attenuating incorporation of VMC into tumor vessels, impairing endothelial survival, and raise the possibility that blockade of COX-2 may provide therapeutic synergies with antiangiogenic molecules that more selectively target endothelial cells.
Abstract only
10012
Background: Sorafenib, an oral multitargeted kinase inhibitor, is indicated for treatment of adults with refractory renal cell or hepatocelluar carcinoma. We performed a phase I ...trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib in children with refractory solid tumors. Methods: Sorafenib was administered q12h for 28 consecutive day cycles. Cohorts of 3–12 patients were enrolled at 105, 130, 150, 200, and 250 mg/m
2
/dose dose levels. Results: 34 eligible pts 16M, median age 14.6 yrs, (range, 5–21) with osteosarcoma (n = 8), rhabdomyosarcoma (n = 3), other sarcomas (n = 13), hepatoblastoma (n = 3), or other solid tumors (n = 7) received 1–22 cycles (median 2). Grade 3 dose-limiting toxicity (DLT) occurred in 4/6 pts at the starting dose (150 mg/m
2
) and included hypertension (n = 1), rash/urticaria (n = 1), back pain (n = 1), thrombocytopenia (n = 1) and ALT/AST (n = 1). No DLTs were observed at 105 (n = 6) or 130 (n = 3) mg/m
2
, and the dose was re-escalated to 150 mg/m
2
with modified eligibility criteria (normal ALT) and revised guidelines for grading and management of hypertension. Gr 3 DLTs occurred in 1/6 pts (lipase) at 150 mg/m
2
and 2/2 pts (hyponatremia, hand-foot syndrome) at 250 mg/m
2
. At 200 mg/m
2
only 1/6 pts experienced DLT (gr 3 ALT). No objective responses were observed, but 2 pts had tumor shrinkage. Sorafenib AUC did not increase proportionally with dose - the mean AUC
0–24h
was similar at 150 mg/m
2
(28±24 μg · h/mL, n = 9) and 200 mg/m
2
(28±17 μg · h/mL, n = 4). T
max
was prolonged and variable (10±11 h, n = 19). Plasma VEGFR (n = 13) decreased from 9.9±1.6 ng/mL at baseline to 8.3±1.7 ng/mL by d 28 (p < 0.001). Conclusions: The MTD of sorafenib in children with solid tumors is 200 mg/m
2
, similar to the adult recommended dose (400 mg).
No significant financial relationships to disclose.
When first conceived, antiangiogenic therapy for cancer offered the possibility of universal efficacy, low toxicity, and little possibility of resistance. Blockade of the vascular endothelial growth ...factor (VEGF) pathway has yielded the most promising results both in animal models and in patients. However, resistance to VEGF blockade has been found even when given in combination with chemotherapy or other antiangiogenic agents. This resistance is associated with remodeled vasculature and with increased expression of angiogenic factors, such as PDGF-B and angiopoietin-1, which may contribute to vessel stabilization. Future efforts must be directed towards the identification of factors associated with vascular remodeling in order to improve the efficacy of antiangiogenic therapy.
Current Issues in Wilms Tumor Management Grundy, Paul; Perlman, Elizabeth; Rosen, Nancy S. ...
Current problems in cancer,
09/2005, Letnik:
29, Številka:
5
Journal Article
Background
Generalized lymphatic anomaly (GLA) and Gorham–Stout disease (GSD) are rare complicated lymphatic malformations that occur in multiple body sites and are associated with significant ...morbidity and mortality. Treatment options have been limited, and conventional medical therapies have been generally ineffective. Emerging data suggest a role for sirolimus as a treatment option for complex lymphatic anomalies.
Procedure
Disease response was evaluated by radiologic imaging, quality of life (QOL), and clinical status assessments in children and young adults with GLA and GSD from a multicenter systematic retrospective review of patients treated with oral sirolimus and the prospective phase 2 clinical trial assessing the efficacy and safety of sirolimus in complicated vascular anomalies (NCT00975819). Sirolimus dosing regimens and toxicities were also assessed.
Results
Eighteen children and young adults with GLA (n = 13) or GSD (n = 5) received oral sirolimus. Fifteen patients (83%) had improvement in one or more aspects of their disease (QOL 78%, clinical status 72%, imaging 28%). No patients with bone involvement had progression of bone disease, and the majority had symptom or functional improvement on sirolimus. Improvement of pleural and pericardial effusion(s) occurred in 72% and 50% of affected patients; no effusions worsened on treatment.
Conclusions
Sirolimus appears effective at stabilizing or reducing signs/symptoms of disease in patients with GLA and GSD. Functional impairment and/or QOL improved in the majority of individuals with GLA and GSD with sirolimus treatment.
Activating mutations in NOTCH1 are present in over 50% of human T-cell lymphoblastic leukemia (T-ALL) samples and inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSI) has emerged as a ...potential therapeutic strategy for the treatment of this disease. Here, we report a new human T-cell lymphoma line CUTLL1, which expresses high levels of activated NOTCH1 and is extremely sensitive to gamma-secretase inhibitors treatment. CUTLL1 cells harbor a t(7;9)(q34;q34) translocation which induces the expression of a TCRB-NOTCH1 fusion transcript encoding a membrane-bound truncated form of the NOTCH1 receptor. GSI treatment of CUTLL1 cells blocked NOTCH1 processing and caused rapid clearance of activated intracellular NOTCH1. Loss of NOTCH1 activity induced a gene expression signature characterized by the downregulation of NOTCH1 target genes such as HES1 and NOTCH3. In contrast with most human T-ALL cell lines with activating mutations in NOTCH1, CUTLL1 cells showed a robust cellular phenotype upon GSI treatment characterized by G1 cell cycle arrest and increased apoptosis. These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs. Leukemia (2006) 20, 1279-1287. doi: 10.1038/sj.leu.2404258; published online 11 May 2006 Keywords: T-cell lymphoblastic leukemia, NOTCH1, cell line
PDF
