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.
Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two ...formulations of pazopanib was performed in children with STS or other refractory solid tumors.
Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD.
Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41).
Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.
Nutritional status (NS), defined by undernutrition (body mass index BMI <5th percentile) or overnutrition (BMI ≥ 85th percentile), is a poor prognostic indicator in pediatric oncology patients. The ...impact of NS has been primarily studied in hematologic malignancies. This review is intended to summarize literature reporting on the association of NS and treatment-related outcomes in pediatric solid tumors.
We searched four electronic databases from inception through August 2018 without language restriction, and included studies of children with cancers arising from renal, bone, liver, eye, muscle, vascular, germ cell, and neural crest tissues, reporting on NS as a predictor for toxicity, survival or relapse. Due to data heterogeneity and limited availability of studies, formal statistical analysis was not achievable. Descriptive statistics were summarized in table format.
Of 8,991 reports identified, 75 full-text articles were evaluated, 10 of which met inclusion criteria. Up to 62% of patients were over- or undernourished at diagnosis. Abnormal BMI was associated with worse overall survival in Ewing sarcoma (hazard ratio (HR): 3.46, P = .022), osteosarcoma (HR: 1.6, P < .005), and a trend toward poorer overall survival in rhabdomyosarcoma (HR: 1.70, P = .0596). High BMI in osteosarcoma was associated with increased nephrotoxicity (odds ratio: 2.8, P = .01) and postoperative complications. NS was not a significant predictor of outcomes in other included disease categories.
Existing literature supports the prognostic significance of NS in pediatric solid tumor patients and underscores the need for prospective studies to better elucidate underlying physiological changes in this population.
A phase 2 study of the WEE1 inhibitor adavosertib in combination with irinotecan in children demonstrates an intriguing positive signal of efficacy in neuroblastoma, a pediatric tumor characterized ...by replication stress. Further pediatric development of adavosertib and related compounds targeting DNA damage response will be challenged by appropriate patient selection, fit‐for‐filing trial design, and ongoing access to agents, likely to be predicated on success in adult malignancy.
nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients ...with recurrent/refractory solid tumours treated with nab-paclitaxel are reported.
Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).
Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m2 and grade 4 neutropenia >7 days at 270 mg/m2. The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1–2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases high-grade, malignant and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m2. Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST.
nab-Paclitaxel 240 mg/m2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma.
NCT01962103.
2013-000144-26.
•This phase 1 study determined the maximum tolerated dose/recommended phase II dose (RP2D) of nab-paclitaxel in paediatric patients.•The paediatric RP2D is 240 mg/m2 given days 1, 8 and 15 every 4 weeks.•This dose demonstrated preliminary signs of activity and manageable toxicity.•Results warrant the phase II study of nab-paclitaxel in this population.
Kinase fusions have been identified in a growing subset of sarcomas, but a lack of preclinical models has impeded their functional analysis as therapeutic targets in the sarcoma setting. In this ...study, we generated models of sarcomas bearing kinase fusions and assessed their response to molecularly targeted therapy. Immortalized, untransformed human mesenchymal stem cells (HMSC), a putative cell of origin of sarcomas, were modified using CRISPR-Cas9 to harbor a RET chromosomal translocation (HMSC-RET). In parallel, patient-derived models of RET- and NTRK-rearranged sarcomas were generated. Expression of a RET fusion activated common proliferation and survival pathways and transformed HMSC cells. The HMSC-RET models displayed similar behavior and response to therapy as the patient-derived counterparts in vitro and in vivo. Capicua (CIC)-mediated suppression of negative MAPK pathway regulators was identified as a potential mechanism by which these sarcomas compensate for RET or NTRK inhibition. This CIC-mediated feedback reactivation was blocked by coinhibition of the MAPK pathway and RET or NTRK in the respective models. Importantly, the combination of RET and ERK inhibitors was more effective than single agents at blocking tumor growth in vivo. This work offers new tools and insights to improve targeted therapy approaches in kinase-addicted sarcomas and supports upfront combination therapy to prolong responses.
Novel models of kinase-rearranged sarcomas show that MAPK pathway feedback activation dampens responses to tyrosine kinase inhibitors, revealing the potential of combinatorial therapies to combat these tumors.
Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant ...fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.
EZH2 inhibition: it’s all about the context Rosen, Ezra Y; Shukla, Neerav N; Glade Bender, Julia L
JNCI : Journal of the National Cancer Institute,
11/2023, Letnik:
115, Številka:
11
Journal Article
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