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Background In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES. Methods Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2‐6 [D2‐6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re‐escalation in cohort C. In arm 2, patients were assigned to NIR (days 1‐7 [D1‐7]) and escalating doses of IRN (D2‐6). Results From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose‐limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1‐7 plus TMZ at 30 mg/m2 every day on D2‐6 (arm 1) or NIR at 100 mg every day on D1‐7 plus IRN at 20 mg/m2 every day on D2‐6 (arm 2). One confirmed partial response was observed in arm 2; the median progression‐free survival was 9.0 weeks (95% CI, 7.0‐10.1 weeks) and 16.3 weeks (95% CI, 5.1‐69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP‐ribose) activity was 89% (range, 83%‐98%). Conclusions The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple‐combination study of NIR, IRN, and TMZ has commenced., Preclinical evaluations have identified the EWS‐FLI1 translocation, pathognomonic of Ewing sarcoma, as a predictive factor of response to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors with synergistic cell death in vivo with DNA damaging agents. This phase 1 study examines the dosing and safety of a combination of the PARP inhibitor niraparib with temozolomide or irinotecan.

The largest whole genome sequencing (WGS) endeavour involving cancer and rare diseases was initiated in the UK in 2015 and ran for 5 years. Despite its rarity, sarcoma ranked third overall among the number of patients' samples sent for sequencing. Herein, we recount the lessons learned by a specialist sarcoma centre that recruited close to 1000 patients to the project, so that we and others may learn from our experience. WGS data was generated from 597 patients, but samples from the remaining approximately 400 patients were not sequenced. This was largely accounted for by unsuitability due to extensive necrosis, secondary to neoadjuvant radiotherapy or chemotherapy, or being placed in formalin. The number of informative genomes produced was reduced further by a PCR amplification step. We showed that this loss of genomic data could be mitigated by sequencing whole genomes from needle core biopsies. Storage of resection specimens at 4 °C for up to 96 h overcame the challenge of freezing tissue out of hours including weekends. Removing access to formalin increased compliance to these storage arrangements. With over 70 different sarcoma subtypes described, WGS was a useful tool for refining diagnoses and identifying novel alterations. Genomes from 350 of the cohort of 597 patients were analysed in this study. Overall, diagnoses were modified for 3% of patients following review of the WGS findings. Continued refinement of the variant‐calling bioinformatic pipelines is required as not all alterations were identified when validated against histology and standard of care diagnostic tests. Further research is necessary to evaluate the impact of germline mutations in patients with sarcoma, and sarcomas with evidence of hypermutation. Despite 50% of the WGS exhibiting domain 1 alterations, the number of patients with sarcoma who were eligible for clinical trials remains small, highlighting the need to revaluate clinical trial design.

Bone tumors are a group of histologically diverse diseases that occur across all ages. Two of the commonest, osteosarcoma (OS) and Ewing sarcoma (ES), are regarded as characteristic adolescent and young adult (AYA) cancers with an incidence peak in AYAs. They are curable for some but associated with unacceptably high rates of treatment failure and morbidity. The introduction of effective new therapeutics for bone sarcomas is slow, and to date, complex biology has been insufficiently characterized to allow more rapid therapeutic exploitation. This review focuses on current standards of care, recent advances that have or may soon change that standard of care and challenges to the expert clinical research community that we suggest must be met.

Primary malignant bone sarcomas (MBS) are rare and there are few studies examining their incidence and outcome. Here, the incidence and survival of all subtypes of MBS registered in England between 1979 and 2007 were analysed from patient registry data held by the National Cancer Intelligence Network (NCIN). Over 11,002 new cases of MBS were registered, an average of 379 per year. There was no change in incidence demonstrated over the study period (p = 0.08). Although a peak incidence is observed in adolescence, approximately half of MBS are diagnosed in patients over 50 years. An improvement in outcome of MBS was observed between those patients registered from 1979 to 1983 and 1983 to 1987 (p0.0001), but there has been no improvement since. In the most recent period studied (patients diagnosed 1998-2002) 5-year survival was 55% in Ewing sarcoma, 70% in chondrosarcoma, 56% in chordoma and 43% in osteosarcoma. Patients diagnosed with osteosarcoma over the age of 40 years or with a non-extremity tumour have a significantly inferior outcome; 22% 5-year survival40 years compared with 53%40 years (p0.0001) and 16% non-extremity tumour compared to 48% extremity tumour (p0.0001). This population-based study has allowed us to confidently define the English incidence and survival rates of both the commoner bone tumours such as osteosarcoma, and rarer entities such as chordoma as well as groups with inferior outcome. The lack of significant improvement over recent decades for these diseases is cause for concern and further research.

The combination of bortezomib and rituximab was evaluated in patients with mantle cell lymphoma (MCL), follicular lymphoma (FL) and Waldenstrom macroglobulinaemia (WM), in a Phase I and later, a randomized Phase II study. In the randomized study, 42 patients with recurrent/refractory disease received either: bortezomib 1·3 mg/m2 on days 1, 4, 8 and 11 of a 3-week cycle with rituximab 375 mg/m2 on day 1 (21 patients) or: bortezomib 1·6 mg/m2 and rituximab on days 1, 8, 15 and 22 of a 5-week cycle (with rituximab being given only in cycles 1 and 4).Twenty-eight patients were withdrawn (toxicity 16, progression 7, and ‘patient choice’ 5). The main toxicities were neurological, gastro-intestinal and haematological. The overall response rate was 28/42(67%) and by histology: MCL 11/19, FL 8/15, and WM 9/10. Ten of 28 responding patients remained progression-free at 1–3·5 years. Toxicity and efficacy were equivalent between the two groups. The combination has significant toxicity but is effective, particularly in patients with WM.

Long-term disease-free survival in patients with localised osteosarcoma treated in large multicentre randomised trials is over 50%. Most relapses occur early, usually within 2-3 years. Relapse after 5 years is uncommon and has been infrequently described. Eight patients with osteosarcoma treated at The London Bone and Soft Tissue Tumour Service since 1986 developed recurrence of disease after 5 years, the latest 14 years after the initial diagnosis. Five patients developed pulmonary metastases, two patients isolated bone metastases and one patient intra-abdominal metastases. Although a second complete remission was achieved in six patients, four patients relapsed again, all with pulmonary metastases. Two patients had coexistent brain metastases. one of those with a second recurrence has achieved a further complete remission and remains well 50 months after the most recent treatment. A second patient is disease-free 24 months after complete excision of an isolated pulmonary metastasis and one further patient is disease-free 6 months after chemotherapy and pneumonectomy for pleural and pulmonary metastases. Five patients have died of disease with a median survival from the date of relapse of 17 months (2-68 months). Current data looking at long-term outcome of patients with osteosarcoma is limited. Reports of late relapse are rare as numbers are small, thus long-term surveillance of patients is essential. It is possible that sites of relapse are more unusual, and more extensive staging may be necessary when late relapse occurs. (C) 2004 Wiley-Liss, Inc.