Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group.

BackgroundNew prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays.MethodsA NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome.ResultsThe analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels.ConclusionsNGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes

Alveolar Rhabdomyosarcoma with Regional Nodal Involvement: Results of a Combined Analysis from Two Cooperative Groups

BACKGROUND: Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and European cooperative groups. In order to define the better therapeutic strategy, we analyzed two studies conducted between 2005 and 2016 by the European paediatric Soft tissue sarcoma Study Group (EpSSG) and Children’s Oncology Group (COG). METHODS: We retrospectively identified patients with ARMS-N1 enrolled in either EpSSG RMS2005 or in COG ARST0531. Chemotherapy in RMS2005 comprised IVADo (ifosfamide, vincristine, dactinomycin, doxorubicin), IVA and maintenance (vinorelbine, cyclophosphamide); in ARST0531 it consisted on either VAC (vincristine, dactinomycin, cyclophosphamide) or VAC alternating with VI (vincristine, irinotecan). Local treatment was similar in both protocols. RESULTS: The analysis of the clinical characteristics of 239 patients showed some differences between study groups: in RMS2005, advanced IRS Group and large tumors predominated. There were no differences in outcomes between the two groups: 5-year event-free survival (EFS), 49%(95%CI=39–59) and 44%(95%CI=30–58), and overall survival (OS), 51%(95%CI=41–61) and 53.6%(95%CI=40–68), in RMS2005 and ARST0531, respectively. In RMS2005, EFS of patients with FOXO1-positive tumors was significantly inferior to those FOXO1-negative (49.3% vs 73%, p=0.034). In contrast, in ARST0531, EFS of patients with FOXO1-positive tumors was 45% compared with 43.8% for those FOXO1-negative. CONCLUSIONS: The outcome of patients with ARMS N1 was similar in both protocols. However, patients with FOXO1 fusion-negative tumors enrolled in RMS2005 showed a significantly better outcome, suggesting that different strategies of chemotherapy may have an impact in the outcome of this subgroup of patients

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

Relapsed Rhabdomyosarcoma

Relapsed rhabdomyosarcoma (RMS) represents a significant therapeutic challenge. Nearly one-third of patients diagnosed with localized RMS and over two-thirds of patients with metastatic RMS will experience disease recurrence following primary treatment, generally within three years. Clinical features at diagnosis, including primary site, tumor invasiveness, size, stage, and histology impact likelihood of relapse and prognosis post-relapse. Aspects of initial treatment, including extent of surgical resection, use of radiotherapy, and chemotherapy regimen, are also associated with post-relapse outcomes, as are features of the relapse itself, including time to relapse and extent of disease involvement. Although there is no standard treatment for patients with relapsed RMS, several general principles, including tissue biopsy confirmation of diagnosis, assessment of post-relapse prognosis, determination of the feasibility of additional local control measures, and discussion of patient goals, should all be part of the approach to care. Patients with features suggestive of a favorable prognosis, which include those with botryoid RMS or stage 1 or group I embryonal RMS (ERMS) who have had no prior treatment with cyclophosphamide, have the highest chance of achieving long-term cure when treated with a multiagent chemotherapy regimen at relapse. Unfortunately, patients who do not meet these criteria represent the majority and have poor outcomes when treated with such regimens. For this group, strong consideration should be given for enrollment on a clinical trial

A phase i study of vincristine, irinotecan, temozolomide and bevacizumab (vitb) in pediatric patients with relapsed solid tumors

Background: To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of irinotecan administered in combination with vincristine, temozolomide and bevacizumab in children with refractory solid tumors. Methods: The study design included two dose levels (DL) of irinotecan given intravenously once daily for 5 consecutive days (DL1: 30 mg/m2, and DL2: 50 mg/m2), combined with vincristine 1.5 mg/m2 on days 1 and 8, temozolomide 100 mg/m2 on days 1-5, and bevacizumab 15mg/kg on day 1, administered every 21 days for a maximum of 12 cycles. Results: Thirteen patients were enrolled and 12 were evaluable for toxicity Dose limiting toxicity observed include

Gcn4 is required for the response to peroxide stress in the yeast Saccharomyces cerevisiae

An oxidative stress occurs when reactive oxygen species overwhelm the cellular antioxidant defenses. We have examined the regulation of protein synthesis in Saccharomyces cerevisiae in response to oxidative stress induced by exposure to hydroperoxides (hydrogen peroxide, and cumene hydroperoxide), a thiol oxidant (diamide), and a heavy metal (cadmium). Examination of translational activity indicates that these oxidants inhibit translation at the initiation and postinitiation phases. Inhibition of translation initiation in response to hydroperoxides is entirely dependent on phosphorylation of the α subunit of eukaryotic initiation factor (eIF)2 by the Gcn2 kinase. Activation of Gcn2 is mediated by uncharged tRNA because mutation of its HisRS domain abolishes regulation in response to hydroperoxides. Furthermore, Gcn4 is translationally up-regulated in response to H(2)O(2), and it is required for hydroperoxide resistance. We used transcriptional profiling to identify a wide range of genes that mediate this response as part of the Gcn4-dependent H(2)O(2)-regulon. In contrast to hydroperoxides, regulation of translation initiation in response to cadmium and diamide depends on both Gcn2 and the eIF4E binding protein Eap1. Thus, the response to oxidative stress is mediated by oxidant-specific regulation of translation initiation, and we suggest that this is an important mechanism underlying the ability of cells to adapt to different oxidants

Survival outcomes and surgical morbidity based on surgical approach to pulmonary metastasectomy in pediatric, adolescent and young adult patients with osteosarcoma

Abstract Background Thoracotomy is considered the standard surgical approach for the management of pulmonary metastases in osteosarcoma (OST). Several studies have identified the advantages of a thoracoscopic approach, however, the clinical significance of thoracotomy compared to thoracoscopy is yet to be evaluated in a randomized trial. Aims The primary aim was to determine the survival outcomes in OST patients based on surgical approach for pulmonary metastasectomy (PM) and secondary aim was to assess the post‐operative morbidities of OST PM through various surgical approaches. Materials and Methods We conducted a single institution retrospective study to compare survival outcomes and surgical morbidity according to the surgical approach of the management of pulmonary metastases in patients with OST. Results Sixty‐one patients with OST underwent PM. Twenty‐one patients were metastatic at diagnosis and underwent PM during primary treatment; nine had thoracotomy, six thoracoscopy, and six combined thoracoscopy with thoracotomy (CTT). Forty‐three patients with first pulmonary relapse or progression underwent PM; 18 had thoracotomy, 16 thoracoscopy and nine CTT. There was no difference in survival between surgical approaches. There were significantly more postoperative morbidities associated with thoracotomy for initial PM (pain and postoperative chest tube placement), and for PM at first relapse (pneumothoraces, pain, Foley catheter use and prolonged hospitalizations). Conclusion Our study demonstrates that patients with OST pulmonary metastases have comparable poor outcomes despite varying surgical approaches for PM. There were significantly more postoperative morbidities associated with thoracotomy for PM. Surgical bias and other competing risks could not be assessed given the limitations of a retrospective study and may be addressed in a prospective trial evaluating surgical approach for PM in OST

Libretto-121: A Phase 1/2 Study of Oral Selpercatinib in Pediatric Patients with Advanced Ret-Altered Solid or Primary CNS Tumors

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