Arndt, Carola

ABSTRACT Purpose We studied histologic Ewing sarcoma (ES) tumor response at local control surgery to explore associations between histologic response and chemotherapy practice changes over time and confirm its prognostic significance in the modern era. Methods We reviewed clinical data for 126 patients with ES treated at Mayo Clinic from 1977 to 2022, analyzing the percentage necrosis as a prognostic factor across chemotherapy regimens (including modern interval‐compressed VDC‐IE). Results In the historical cohort, 5‐year event‐free survival (EFS) and overall survival (OS) for patients with ≤5% versus greater than 5% viable tumor were 76% versus 59% ( p = 0.01) and 83% versus 62% ( p = 0.01). Review of 104 specimens by two pathologists identified the percentage remaining viable tumor as more reproducible than the percentage necrosis and/or fibrosis. On multivariable analysis of patients with localized disease ( n = 87), pelvic tumors and greater than 5% viable tumor remained independent risk factors for poor survival (EFS: hazard ratio [HR] 3.1, p < 0.01; OS: HR 2.1, p = 0.048). The modern cohort consisted of 22 patients. No patients with tumor size less than 8 cm at diagnosis and 100% necrosis after surgery had events; four of seven with tumors greater than 8 cm had events despite 100% necrosis. Conclusions Our results validate the historical threshold of greater than 5% viable tumor with older chemotherapy regimens but not with modern interval‐compressed VDC‐IE. In addition, inter‐rater reliability for the percentage viable is more reproducible than the percentage necrosis. Although numbers are small, tumors less than 8 cm with no viable tumor appear to be a favorable subgroup and suggest risk stratification using a combination of tumor size and any viable tumor should be evaluated in ES.

ABSTRACT Background Rhabdomyosarcoma is the most common soft tissue sarcoma in pediatrics and infants are reported to have inferior outcomes. ARST1431 recommended delayed primary excision (DPE) while discouraging radiation (RT) deviations. This analysis compared outcomes among very young and older patients in this study. Procedures Demographic and tumor characteristics were summarized using frequencies and percentages. Local failure (LF) frequency was summarized by age group, RT, and DPE status. Event‐free survival (EFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared between age groups using the log‐rank test. Results Of 296 patients, 48 (16.2%) were <24 months: 14 (4.7%) < 12 months, 34 (11.5%) 12–24 months–compared with 248 (83.8%) ≥24 months. DPE was performed in: 7 (50%), <12 months; 9 (26%), 12–24 months; 56 (22%), ≥24 months. RT was given to 9 (64%), 27 (79%), and 195 (79%) of <12, 12–24, and >24 months, respectively. LF in DPE+RT was 8.3% and 6.1%, < 24 months and ≥ 24 months, respectively, compared to 29.3% and 20.5% for RT without DPE. The 4‐year EFS did not vary: 56% (95% CI = 26.5, 86.0), 68% (95% CI = 51.2, 84.1), and 61% (95% CI = 54.2, 68.3) <12, 12–24, and >24 months old, respectively. Conclusions Outcomes in younger children are comparable to older children with local failure more common in those without DPE. Optimization of local control will be important for future studies. Trial Registration Number NCT02567435

Neuroblastoma is the most common extracranial solid tumor diagnosed in children. This inaugural version of the NCCN Guidelines for Neuroblastoma provides recommendations for the diagnosis, risk classification, and treatment of neuroblastoma. The information in these guidelines was developed by the NCCN Neuroblastoma Panel, a multidisciplinary group of representatives with expertise in neuroblastoma, consisting of pediatric oncologists, radiologists, pathologists, surgeons, and radiation oncologists from NCCN Member Institutions. The evidence-based and consensus recommendations contained in the NCCN Guidelines are intended to guide clinicians in selecting the most appropriate treatments for their patients with this clinically heterogeneous disease.

PURPOSE Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.

AbstractInfantile myofibromatosis (IM) is characterized by solitary musculoskeletal nodules presenting during infancy but can manifest as multiple lesions with visceral involvement. Multicentric IM with visceral involvement carries a high risk of mortality and there is no consensus on treatment. We present a case of a patient with multicentric IM and pulmonary involvement who progressed on several chemotherapeutic regimens and subsequently had a complete response to sorafenib and later imatinib. This report describes the novel use of sorafenib and imatinib to treat generalized IM and the role of continued tyrosine kinase inhibitor therapy to maintain remission.

AbstractBackgroundVaginal/uterine rhabdomyosarcoma (VU RMS) is one of the most favorable RMS sites. To determine the optimal therapy, the experience of four cooperative groups (Children's Oncology Group [COG], International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Group [MMT], Italian Cooperative Soft Tissue Sarcoma Group [ICG], and European pediatric Soft tissue sarcoma Study Group [EpSSG]) was analyzed.ProcedureFrom 1981 to 2009, 237 patients were identified. Median age (years) at diagnosis differed by tumor location; it was 1.9 for vagina (n = 160), 2.7 for uterus corpus (n = 26), and 13.5 for uterus cervix (n = 51). Twenty‐eight percent of patients received radiation therapy (RT) as part of primary therapy (23% COG, 27% MMT, 46% ICG, and 42% EpSSG), with significant differences in the use of brachytherapy between the cooperative groups (23% COG, 76% MMT, 64% ICG, and 88% EpSSG).ResultsTen‐year event‐free (EFS) and overall survival (OS) were 74% (95% CI, 67–79%) and 92% (95% CI, 88–96%), respectively. In univariate analysis, OS was inferior for patients with uterine RMS and for those with regional lymph node involvement. Although EFS was slightly lower in patients without initial RT (71% without RT vs. 81% with RT; P = 0.08), there was no difference in OS (94% without RT vs. 89% with RT; P = 0.18). Local control using brachytherapy was excellent (93%). Fifty‐one (51.5%) of the 99 survivors with known primary therapy and treatment for relapse were cured with chemotherapy with or without conservative surgery.ConclusionsAbout half of all patients with VU RMS can be cured without systematic RT or radical surgery. When RT is indicated, modalities that limit sequelae should be considered, such as brachytherapy.

AbstractLate‐onset HC is a well‐recognized complication associated with cyclophosphamide/acrolein‐induced toxicity. It poses a management challenge when hyperhydration and bladder irrigation do not result in clinical improvement as desired. The data regarding use of hyperbaric oxygen therapy (HBO2) as an early treatment modality in this clinical setting are limited. We present 2 cases, that were refractory to hyperhydration and bladder irrigation but responded to HBO2. They were treated with 20‐30 daily sessions over weekdays with 100% oxygen for 90 minutes at 2 atmospheric pressure units (2 atm). Both patients reported improved symptoms within the first 15 sessions, and hematuria diminished by 20 sessions. Hyperbaric oxygen is a less invasive, outpatient therapy that is effective for treatment of HC and is tolerated well by young patients.

We report a 9-year-old Chinese girl with congenital thrombotic thrombocytopenic purpura found to be a compound heterozygote for 2 pathogenic variants in the ADAMTS13 gene, including a novel variation. The girl suffered from recurrent, life-threatening episodes of thrombocytopenia and hemolysis, and laboratory testing showed ADAMST13 enzyme activity of <5%. Sequencing of the ADAMTS13 gene revealed a previously reported missense variant, c.1787C>T (p.Ala596Val), and a novel duplication defined as c.1007_1025dup19 (p.Asp343Leufs*53); the duplication is predicted to result in a premature stop codon and protein truncation. We propose that this novel variant is partly responsible for the patient’s early-onset and severe phenotype.

AbstractBackgroundWe sought to determine whether adolescents with metastatic alveolar rhabdomyosarcoma (ARMS) or embryonal RMS (ERMS) had a different event‐free survival (EFS) compared with younger patients, and to identify treatment‐related factors (adverse events, AEs) that may be associated with differences in outcome.MethodsThe prevalence of AEs in adolescents older than 13 years was compared with that in patients less than or equal to 13 years of age (Fisher exact test) in patients enrolled onto ARST0431. EFS by age and histology was compared by log–rank test.ResultsOf 109 patients, 60 (55%) were older than 13 years; they were more likely to have nausea (17 vs. 4%, P = 0.06) and pain (20 vs. 6%, P = 0.05) compared with younger patients. Adolescents were less likely to complete therapy (63 vs. 76%) and more likely to have unplanned dose modifications outside of protocol guidelines (23 vs. 2.7%). The 3‐year EFS was 26% (95% confidence interval [CI]: 15–38) for adolescents compared with 46% (95% CI: 32–60) for those less than or equal to 13 years (P = 0.011). Forty‐two (59%) adolescents with ARMS had a 3‐year EFS of 13% (95% CI: 2–23) compared with 30% (95% CI: 10–51) for those less than or equal to 13 years (P = 0.032). EFS was comparable between older and younger patients with ERMS (64 vs. 55%, P = 0.53).ConclusionsAlthough there was a significant difference in EFS and protocol compliance by age, the differences in age‐related toxicity are unlikely to account for this. Observed differences in pain and nausea by age could be real or be dependent on patient reporting of symptoms. Future studies in RMS should include patient‐reported outcomes to better evaluate health‐related quality of life.

Objectives/HypothesisEvaluate presentation, management, and clinical outcomes of patients with temporal bone Langerhans cell histiocytosis (LCH).Study DesignRetrospective chart review.MethodsReviewed all patients with temporal bone LCH at a tertiary academic referral center between 1978 and 2014. Presentation, disease course, intervention, and clinical outcomes were analyzed.ResultsBetween 1978 and 2014, 29 temporal bones in 20 patients (12 males; median age 32 years, range 1.3–88 years) were diagnosed with temporal bone LCH, representing 4% of all patients diagnosed with LCH at our institution during that time. Twelve (60%) patients presented purely with head and neck disease, nine (45%) with bilateral temporal bone involvement, seven (35%) with intracranial spread, and eight (40%) with multisystem disease. The most common presenting symptoms were otorrhea (n = 11; 55%) and subjective hearing loss (n = 10; 50%). Treatment included primary chemotherapy or radiation alone(n = 7; 35%), local resection alone (n = 2; 10%), and chemotherapy or radiation with surgery(n = 11; 55%). Ten patients suffered local or systemic relapse (50%; median 12 months). Median follow‐up for patients was 31 months. One patient died secondary to pulmonary complications of multisystem LCH.ConclusionsLCH is an uncommon histiocytic disorder with a range of clinical manifestations and disease severity. Otologic involvement is rare, and frequently manifests with symptoms similar to otomastoiditis. Evaluation and close follow‐up of both ears is important. Bilateral simultaneous or sequential LCH can be seen in up to 45% of cases. Patients with temporal bone LCH should be managed by a multidisciplinary team with treatment tailored to the patient. Relapse is more common in patients with multisystem involvement. Even in subjects with isolated otologic involvement, long‐term follow‐up is critical, with relapses occurring years beyond treatment.Level of Evidence4. Laryngoscope, 126:1899–1904, 2016