Summary Local treatment of metastases such as metastasectomy or radiotherapy remains controversial in the treatment of metastatic renal cell carcinoma. To investigate the benefits and harms of ...various local treatments, we did a systematic review of all types of comparative studies on local treatment of metastases from renal cell carcinoma in any organ. Interventions included metastasectomy, radiotherapy modalities, and no local treatment. The results suggest that patients treated with complete metastasectomy have better survival and symptom control (including pain relief in bone metastases) than those treated with either incomplete or no metastasectomy. Nevertheless, the available evidence was marred by high risks of bias and confounding across all studies. Although the findings presented here should be interpreted with caution, they and the identified gaps in knowledge should provide guidance for clinicians and researchers, and directions for further research.
Osteosarcoma (OS), chondrosarcoma, and chordoma are characterized by multiple challenges to the investigator, clinician, and patient. One consequence of their rarity among sarcomas, as well as their ...biologic and clinical heterogeneity, is that management guidelines are inadequate to inform the range of individual patient-treatment decisions from diagnosis, approaches to surgery, chemotherapy, radiotherapy, treatment of recurrence, palliative care, and quality of survivorship. Of high-grade sarcomas, OSs are among the most curable, with more than two-thirds of patients with localized disease likely to achieve long-term survival. Neoadjuvant chemotherapy comprising cisplatin, doxorubicin, and methotrexate with intercalated surgery is the standard of care for resectable OS in those younger than 40 years. Outcomes for OS presenting with unresectable metastases or recurrent disease, or in those older than 40 years are generally poor. Overall results have improved little for all patients with OS, and new treatments are needed. Surgical resection remains the cornerstone of management for chondrosarcoma and chordoma. However, the application of new biologic insights to therapeutic development indicates that improved treatments may soon be routine for patients with chondrosarcoma and chordoma for whom surgery alone is inadequate. For all these uncommon diseases, patients should be offered specialist expert care delivered by experienced multidisciplinary teams in high-volume centers.
Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease ...monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.
The objective of this study was to investigate potential correlations between pathologic fractures (PFs) and prognosis of patients with primary central high-grade osteosarcoma of the extremities.
We ...retrospectively analyzed 2,847 patients registered in the Consecutive Cooperative Osteosarcoma Study Group database with primary central high-grade osteosarcoma of the extremities, treated between 1980 and 2010. Intended treatment included pre- and postoperative chemotherapy and surgery. Univariable and multivariable survival analyses were performed for all patients and then differentiated for adult and pediatric (≤ 18 years at time of diagnosis) patients.
A total of 2,193 patients were ≤ 18 years of age; 11.3% of all patients had PFs. In the overall cohort, presence of PF correlated significantly with tumor site, histologic subtype, relative tumor size, and primary metastases, but not with body mass index or local surgical remission. In univariable analysis, 5-year overall survival (OAS) of patients with and without PF was 63% versus 71%, respectively (
= .007), and 5-year event-free survival (EFS) was 51% versus 58% (
= .026). In pediatric patients, OAS and EFS did not differ significantly between patients with and without PF. In adults, 5-year OAS in patients with and without PF was 46% versus 69% (
< .001), and 5-year EFS was 36% versus 56% (
< .001). In multivariable analysis, PF was not a statistically significant factor for OAS or EFS in the total cohort or in pediatric patients. In adult patients, PF remained an independent prognostic factor for OAS (
= .013; hazard ratio HR, 1.893). It was not a significant prognostic factor for EFS (
= .263; HR, 1.312).
In this largest study to date with extremity osteosarcomas, we observed the occurrence of PF to correlate with inferior OAS expectancies in adult but not in pediatric patients.
Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker ...of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP-RAC1-JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca
-CaMKII-NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.
Abstract Background Patients with bone metastases from advanced cancer often experience skeletal-related events (SRE), which cause substantial pain and morbidity. Denosumab, a fully human monoclonal ...antibody that inhibits RANK Ligand (RANKL), is a novel bone-targeted agent with a distinct mechanism of action relative to the bisphosphonate zoledronic acid, for prevention of SRE. This pre-planned analysis evaluates the efficacy and safety of denosumab versus zoledronic acid across three pivotal studies. Methods Patient-level data from three identically designed, randomised, double-blind, active-controlled, phase 3 trials of patients with breast cancer, prostate cancer, other solid tumours or multiple myeloma were combined. End-points included time to first SRE, time to first and subsequent (multiple) SRE, adverse events, time to disease progression and overall survival. Findings Denosumab was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21 months, reducing the risk of a first SRE by 17% (hazard ratio, 0.83 95% confidence interval (CI): 0.76–0.90; P < 0.001). Efficacy was demonstrated for first and multiple events and across patient subgroups (prior SRE status; age). Disease progression and overall survival were similar between the treatments. In contrast to zoledronic acid, denosumab did not require monitoring or dose modification/withholding based on renal status, and was not associated with acute-phase reactions. Hypocalcaemia was more common for denosumab. Osteonecrosis of the jaw occurred at a similar rate ( P = 0.13). Conclusion Denosumab was superior to zoledronic acid in preventing SRE with favourable safety and convenience in patients with bone metastases from advanced cancer.
Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with ...chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.
Osteosarcoma is the most common bone cancer in children and adolescents. Although 70% of patients with localized disease are cured with chemotherapy and surgical resection, patients with metastatic ...osteosarcoma are typically refractory to treatment. Numerous lines of evidence suggest that cytotoxic T lymphocytes (CTLs) limit the development of metastatic osteosarcoma. We have investigated the role of PD-1, an inhibitory TNFR family protein expressed on CTLs, in limiting the efficacy of immune-mediated control of metastatic osteosarcoma. We show that human metastatic, but not primary, osteosarcoma tumors express a ligand for PD-1 (PD-L1) and that tumor-infiltrating CTLs express PD-1, suggesting this pathway may limit CTLs control of metastatic osteosarcoma in patients. PD-L1 is also expressed on the K7M2 osteosarcoma tumor cell line that establishes metastases in mice, and PD-1 is expressed on tumor-infiltrating CTLs during disease progression. Blockade of PD-1/PD-L1 interactions dramatically improves the function of osteosarcoma-reactive CTLs in vitro and in vivo, and results in decreased tumor burden and increased survival in the K7M2 mouse model of metastatic osteosarcoma. Our results suggest that blockade of PD-1/PD-L1 interactions in patients with metastatic osteosarcoma should be pursued as a therapeutic strategy.
Osteosarcoma (OSA) is the most common form of malignant bone cancer in children and dogs, although the disease occurs in dogs approximately 10 times more frequently than in people. Multidrug ...chemotherapy and aggressive surgical techniques have improved survival; however, new therapies for OSA are critical, as little improvement in survival times has been achieved in either dogs or people over the past 15 years, even with significant efforts directed at the incorporation of novel therapeutic approaches. Both clinical and molecular evidence suggests that human and canine OSA share many key features, including tumor location, presence of microscopic metastatic disease at diagnosis, development of chemotherapy-resistant metastases, and altered expression/activation of several proteins (e.g. Met, ezrin, phosphatase and tensin homolog, signal transducer and activator of transcription 3), and p53 mutations, among others. Additionally, canine and pediatric OSA exhibit overlapping transcriptional profiles and shared DNA copy number aberrations, supporting the notion that these diseases are similar at the molecular level. This review will discuss the similarities between pediatric and canine OSA with regard to histology, biologic behavior, and molecular genetic alterations that indicate canine OSA is a relevant, spontaneous, large animal model of the pediatric disease and outline how the study of naturally occurring OSA in dogs will offer additional insights into the biology and future treatment of this disease in both children and dogs.
Due to its indolent clinical behaviour, the treatment paradigm of atypical cartilaginous tumours (ACTs) in the long bones is slowly shifting from intralesional resection (curettage) and local ...adjuvants, towards active surveillance through wait-and-scan follow-up. In this retrospective cohort study performed in a tertiary referral centre, we studied the natural behaviour of ACT lesions by active surveillance with MRI. Clinical symptoms were not considered in the surveillance programme.
The aim of this study was to see whether active surveillance is safe regarding malignant degeneration and local progression. In total, 117 patients were evaluated with MRI assessing growth, cortical destruction, endosteal scalloping, periosteal reaction, relation to the cortex, and perilesional bone marrow oedema. Patients received up to six follow-up scans.
At the time of the first follow-up MRI, 8% of the lesions showed growth (n = 9), 86% remained stable (101), and 6% decreased in size (n = 7). During the third follow-up, with a mean follow-up time of 60 months (SD 23), 24 patients were scanned, of whom 13% had lesions that had grown and 13% lesions that had decreased in size. After 96 months (SD 37), at the sixth follow-up MRI, 100% of the lesions remained stable. None of the lesions showed malignant progression and although some lesions grew in size (mean 1 mm (SD 0.8)), no malignant progression occurred.
We conclude that active surveillance with MRI is safe for ACTs in the long bones in the short- and mid-term follow-up.
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