Reconstruction of maxillary defects following tumor extirpation is challenging because of combined aesthetic and functional roles of the maxilla. One-stage reconstruction combining osseous free flaps ...with immediate osseointegrated implants are becoming the standard for mandibular defects, and have similar potential for maxillary reconstruction.
A woman with maxillary Ewing sarcoma successfully treated at age 9 with neoadjuvant chemotherapy, right hemimaxillectomy, and obturator prosthetic reconstruction presented for definitive reconstruction, complaining of poor obturator fit, and hypernasality. Her reconstruction was computer-simulated by a multidisciplinary team, consisting of left hemi-Lefort I advancement and right maxillary reconstruction with a free fibula flap with immediate osseointegrated implants and dental prosthesis.
Full dental restoration, midface projection, and oral fistula corrections were achieved in 1 operative stage using this approach.
This patient demonstrates a successful approach for maxillary reconstruction using computer-planned orthognathic surgery with free fibula reconstruction and immediate osseointegrated implants with dental prosthesis.
Desmoplastic small round cell tumor (DSRCT) is characterized by the
t(11;22) (p13:q12) translocation. Few additional putative drivers have been identified, and research has suffered from a lack of ...model systems. Next-generation sequencing (NGS) data from 68 matched tumor-normal samples, whole-genome sequencing data from 10 samples, transcriptomic and affymetrix array data, and a bank of DSRCT patient-derived xenograft (PDX) are presented.
fusions were noted to be simple, balanced events. Recurrent mutations were uncommon, but were noted in
(3%),
(6%),
(5%), and
(3%), and recurrent loss of heterozygosity (LOH) at 11p, 11q, and 16q was identified in 18%, 22%, and 34% of samples, respectively. Comparison of tumor-normal matched versus unmatched analysis suggests overcalling of somatic mutations in prior publications of DSRCT NGS data. Alterations in fibroblast growth factor receptor 4 (
) were identified in 5 of 68 (7%) of tumor samples, whereas differential overexpression of
was confirmed orthogonally using 2 platforms. PDX models harbored the pathognomic
fusion and were highly representative of corresponding tumors. Our analyses confirm DSRCT as a genomically quiet cancer defined by the balanced translocation, t(11;22)(p13:q12), characterized by a paucity of secondary mutations but a significant number of copy number alterations. Against this genomically quiet background, recurrent activating alterations of
stood out, and suggest that this receptor tyrosine kinase, also noted to be highly expressed in DSRCT, should be further investigated. Future studies of DSRCT biology and preclinical therapeutic strategies should benefit from the PDX models characterized in this study. IMPLICATIONS: These data describe the general quiescence of the desmoplastic small round cell tumor (DSRCT) genome, present the first available bank of DSRCT model systems, and nominate
as a key receptor tyrosine kinase in DSRCT, based on high expression, recurrent amplification, and recurrent activating mutations.
Background
Children, adolescents, and young adults treated for Ewing sarcoma (ES) are at risk for disease‐related and treatment‐related complications. We aimed to describe early and late overall ...mortality, cause‐specific mortality, and key adverse health outcomes in a large, single‐institutional cohort of patients with ES.
Methods
Patients with ES diagnosed at age less than 40 years and treated at Memorial Sloan Kettering between 1974 and 2012 were included. Overall survival was estimated using Kaplan–Meier methods. Cox proportional hazards were used to examine the association of clinical and pathologic variables with overall survival. Cause‐specific mortality was evaluated with the cumulative incidence function accounting for competing risks.
Results
Three hundred patients with ES (60.3% male; median age at diagnosis: 16.8 years range: 0.3–39; 30.0% with metastatic disease at diagnosis) were followed for a median of 7.8 years (range: 0.2–37). Five‐year overall survival was 65.2% (95% confidence interval 95% CI, 59.8–71.1%) for the entire cohort; 78.6% for those with localized disease; 40.1% for those with isolated pulmonary metastases; and 28.1% for those with extrapulmonary metastases. In multivariable analysis, older age at diagnosis, minority race/ethnicity, and metastatic disease at diagnosis were associated with inferior survival. Ten‐year cumulative incidence of relapse/progression was 40.1%, with eight late relapses occurring at a median of 6.3 years after diagnosis (range: 5–14). Seventeen patients developed subsequent neoplasms (treatment‐related myelodysplastic syndrome/acute myelogenous leukemia = 9; solid tumors = 6; nonmelanoma skin cancer NMSC = 4). Excluding NMSC and melanoma in situ, the cumulative incidence of subsequent malignant neoplasms at 25 years was 15% (95% CI, 4.8–25.1%).
Conclusion
Patients with ES are at high risk for relapse/progression and second cancers.
18-fluorodeoxyglucose positron emission tomography (PET) is already an integral part of staging in rhabdomyosarcoma. We investigated whether primary-site treatment response characterized by serial ...PET imaging at specific time points can be correlated with local control.
We retrospectively examined 94 patients with rhabdomyosarcoma who received initial chemotherapy 15 weeks (median) before radiotherapy and underwent baseline, preradiation, and postradiation PET. Baseline PET standardized uptake values (SUVmax) and the presence or absence of abnormal uptake (termed PET-positive or PET-negative) both before and after radiation were examined for the primary site. Local relapse-free survival (LRFS) was calculated according to baseline SUVmax, PET-positive status, and PET-negative status by the Kaplan-Meier method, and comparisons were tested with the log-rank test.
The median patient age was 11 years. With 3-year median follow-up, LRFS was improved among postradiation PET-negative vs PET-positive patients: 94% vs 75%, P=.02. By contrast, on baseline PET, LRFS was not significantly different for primary-site SUVmax≤7 vs >7 (median), although the findings suggested a trend toward improved LRFS: 96% for SUVmax≤7 vs 79% for SUVmax>7, P=.08. Preradiation PET also suggested a statistically insignificant trend toward improved LRFS for PET-negative (97%) vs PET-positive (81%) patients (P=.06).
Negative postradiation PET predicted improved LRFS. Notably, 77% of patients with persistent postradiation uptake did not experience local failure, suggesting that these patients could be closely followed up rather than immediately referred for intervention. Negative baseline and preradiation PET findings suggested statistically insignificant trends toward improved LRFS. Additional study may further understanding of relationships between PET findings at these time points and outcome in rhabdomyosarcoma.
The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this pilot study, we explore the sensitivity of various targeted and whole-genome NGS ...platforms in order to assess the best genomic approach of using liquid biopsy in future prospective clinical trials. Moreover, we investigate 35 paired primary/relapsed RMS from two contributing institutions, 18 fusion-positive (FP-RMS) and 17 fusion-negative RMS (FN-RMS) by either targeted DNA or whole exome sequencing (WES). In 10 cases, circulating tumor DNA (ctDNA) from multiple timepoints through clinical care and progression was analyzed for feasibility of liquid biopsy in monitoring treatment response/relapse. ctDNA alterations were evaluated using a targeted 36-gene custom RMS panel at high coverage for single-nucleotide variation and fusion detection, and a shallow whole-genome sequencing for copy number variation. FP-RMS have a stable genome with relapse, with common secondary alterations CDKN2A/B, MYCN, and CDK4 present at diagnosis and impacting survival. FP-RMS lacking major secondary events at baseline acquire recurrent MYCN and AKT1 alterations. FN-RMS acquire a higher number of new alterations, most commonly SMARCA2 missense mutations. ctDNA analyses detect pathognomonic variants in all RMS patients within our collection at diagnosis, regardless of type of alterations, and confirmed at relapse in 86% of FP-RMS and 100% FN-RMS. Moreover, a higher number of fusion reads is detected with increased disease burden and at relapse in patients following a fatal outcome. These results underscore patterns of tumor progression and provide rationale for using liquid biopsy to monitor treatment response.
To examine patterns of failure in patients with parameningeal rhabdomyosarcoma (PM-RMS) treated with intensity modulated radiation therapy (IMRT).
Forty-seven patients with PM-RMS received ...chemotherapy and IMRT for definitive treatment. The median age was 9 years (range, 0.5-35 years). The high-risk features were as follows: 40% alveolar histology, 72% group III and 26% group IV disease, 57% either intracranial extension (ICE) (n=25) or cranial neuropathy (n=21). The median time to RT from the start of chemotherapy was 15 weeks (range, 2-54 weeks). Patients received 50.4 Gy in 1.8-Gy fractions to the primary tumor by use of IMRT. Thirteen patients aged≥14 years with alveolar histology received 36 Gy prophylactic nodal irradiation (PNI) to bilateral cervical nodes. Events were defined as local, regional (nodal), central nervous system (CNS), or distant failures.
With a median follow-up time of 3.3 years (range, 0.5-12.8 years), 18 patients experienced failure: 5 local, 2 regional, 6 distant, and 7 CNS. The 5-year local failure-free survival was 86%. Age, histology, and time to RT did not influence the risk of local failure. The 5-year regional failure-free survival was 92%: 100% for embryonal and 74% for alveolar (P=.03). However, there were no lymph node failures in patients with alveolar histology who were given PNI. The 5-year CNS failure-free survival was 83%: 100% without and 70% with ICE (P=.01); 95% without and 69% with cranial neuropathy (P=.02). The estimated 5-year event-free survival and overall survival were 61% for group III and 58% for group IV patients.
Distant failure was the most common type of failure among group IV patients. Patients with alveolar histology seem to benefit from PNI. The presence of ICE or cranial neuropathy portends a high risk of CNS failure, the most common pattern of failure among non-group IV patients. These patients may benefit from the addition of novel CNS-directed therapy.
Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown.
We ...evaluated children with osteosarcoma (OS) on two Children's Oncology Group trials with higher dose doxorubicin (375-600 mg/m
) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected.
All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness
scores (
< 0.01) and LV mass
scores (
< 0.01) were significantly smaller than normal for body-surface area in both sexes. The average LV mass
scores were significantly smaller for girls (
< 0.01) and marginally smaller for boys (
= 0.06). Girls had significantly smaller LV end-diastolic dimension
scores normalized to BSA (
< 0.01) compared to healthy controls and had significant increases in NT-proBNP. Four children developed SMNs as first events, a rate similar to historical controls.
Dexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity.
ClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.
To analyze prognostic factors and patterns of failure for rhabdomyosarcoma of the perineal and perianal region (PRMS), with an emphasis on radiation therapy for locoregional control.
Detailed records ...of all 14 patients treated for PRMS at Memorial Sloan-Kettering Cancer Center between 1998 and 2012 were reviewed. The Kaplan-Meier method was used to assess the event-free survival (EFS) and overall survival (OS), and a competing-risks analysis was used to assess the cumulative incidence of local, regional, and distant failures.
Median age was 15.8 years (range, 1.1-31.9 years). High-risk features were identified: 9 of 14 patients (64%) had group 3 disease and 3 of 14 (21%) had group 4; 11 of 14 tumors (78%) were alveolar; 12 of 14 tumors (86%) were ≥5 cm; and 9 of 14 patients (64%) had involved lymph nodes (N1). Of those aged ≥10 years at diagnosis, 9 of 10 (90%) had alveolar histology, all had tumors ≥5 cm, and 8 of 10 (80%) presented with N1 disease. The rates of local, regional, and distant failure at 5 years were 17%, 31%, and 52%, respectively. Although 3 of the 4 patients with regional failure received nodal irradiation, only one of the nodal failures occurred in the radiation therapy field. The 5-year EFS was 33%, and OS was 39%. Age ≥10 years was associated with poor outcomes: EFS was 13% in patients aged ≥10 years, compared with 75% in those aged <10 years (P=.04); the OS was 13% in patients aged ≥10 years, compared with 100% in those aged <10 years (P=.04).
Patients with PRMS, especially those aged ≥10 years, present with poor prognostic features and continue to have poor outcomes. Given the high incidence of regional node recurrence, we recommend prophylactic ilioinguinal lymph node irradiation for all patients aged ≥10 years. For children aged <10 years, nodal evaluation is essential to determine the role for lymph node irradiation.
Alterations of the
tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting ...molecular events are not well defined. Additionally,
alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor MTT). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of
-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis.
We investigated the clinicopathologic and molecular landscape of a cohort of 22
-mutant RMS and a control group of 13
-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing.
Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was
abnormality (36%), being mutually exclusive from
mutations (14%). MTT showed coexisting
and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with
-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic
-mutant ERMS were associated with
alterations.
Patients with NF1-mutant ERMS lacking
alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.
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