•This Clinical Practice Guideline provides key recommendations on the management of bone sarcomas.•Recommendations have been agreed following a consensus meeting of representatives from ESMO, ...EURACAN, GENTURIS and ERNPaedCan.•Authorship includes a multidisciplinary group of experts from different institutions and countries worldwide.
There are some lines of evidence suggesting a potential role of immunotherapy for treating patients with osteosarcomas.
This was an open-label, multicentre, phase 2 study of pembrolizumab in ...combination with metronomic cyclophosphamide in patients with advanced osteosarcomas. All patients received 50 mg b.i.d. of cyclophosphamide one week on and one week off and 200 mg of intravenous pembrolizumab (every 3 weeks). There was a dual primary end-point, encompassing both the non-progression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. An objective response rate of 20% and/or a 6-month non-progression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from the patients' tumour samples.
Between October 13 2015 and July 3 2017, 17 patients were included. Fifty were assessable for the efficacy end-point. Four patients experienced tumour shrinkage, resulting in a partial response (PR) in one patient (6.7%). The 6-month non-progression rate was 13.3% (95% confidence interval CI: 1.7–40.5). The most frequent adverse events were grade I or II nausea, anaemia, anorexia and fatigue. programmed death-ligand 1 (PD-L1) expression rate was low, observed in only 2 cases of 14 with available tumour material. The only patient who experienced PR had a PD-L1–negative tumour.
Programmed cell death 1 (PD-1) inhibition has limited activity in osteosarcomas. Further studies investigating PD-1 inhibitor in combination with agents modulating the microenvironment are warranted.
This study is registered with ClinicalTrials.gov, number NCT02406781.
•We report here the results of PD-1 targeting in patients with advanced osteosarcomas.•This therapeutic strategy has only modest activity.•Further studies should explore combination strategies reprogramming the microenvironment.
An auxetic material is one with a negative Poisson’s ratio and has the property of widening when stretched or narrowing when compressed in contrast to conventional materials. Typical auxetic ...materials include modified polymeric foams (
Lakes, 1987), regular honeycombs, polypropylene fibres and certain crystal structures. Auxetic materials benefit from enhanced mechanical properties. These benefits include improved indentation resistance, enhanced shear moduli and fracture toughness
Evans and Alderson (2000).
While modelling granular materials,
Bathurst and Rothenburg (1988a,b) noted the theoretical possibility of a negative Poisson’s ratio if the constitutive grains had unconventional interactive properties. These unconventional interactive properties are that the tangential interaction should be stiffer than the normal interaction. In this work, a 2D unit cell has been designed with just such an unconventional interaction so that a 2D granular material can be constructed with negative Poisson’s ratio. Theoretical calculations of such a granular assembly are made using mean strain assumptions and first order heterogeneity calculations. These are compared to 2D discrete element simulations, finite element simulations and Bathurst and Rothenburg’s original result.
Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by ...expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE).
129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety.
A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed.
Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies.
ClinicalTrials.gov: NCT01387555
To identify coping strategies and socio-demographics impacting satisfaction with life and quality of life in Crohn's disease (CD).
402 patients completed the Patient Harvey-Bradshaw Index, Brief COPE ...Inventory, Satisfaction with Life Scale (SWLS), Short Inflammatory Bowel Disease Questionnaire (SIBDQ). We performed structural equation modeling (SEM) of mediators of quality of life and satisfaction with life.
The cohort comprised: men 39.3%, women 60.1%; P-HBI 4.75 and 5.74 (p = 0.01). In inactive CD (P-HBI≤4), both genders had SWLS score 23.8; men had SIBDQ score 57.4, women 52.6 (p = 0.001); women reported more use of emotion-focused, problem-focused and dysfunctional coping than men. In active CD, SWLS and SIBDQ scores were reduced, without gender differences; men and women used coping strategies equally. A SEM model (all patients) had a very good fit (X2(6) = 6.68, p = 0.351, X2/df = 1.114, SRMR = 0.045, RMSEA = 0.023, CFI = 0.965). In direct paths, economic status impacted SWLS (β = 0.39) and SIBDQ (β = 0.12), number of children impacted SWLS (β = 0.10), emotion-focused coping impacted SWLS (β = 0.11), dysfunctional coping impacted SWLS (β = -0.25). In an indirect path, economic status impacted dysfunctional coping (β = -0.26), dysfunctional coping impacted SIBDQ (β = -0.36). A model split by gender and disease activity showed that in active CD economic status impacted SIBDQ in men (β = 0.43) more than women (β = 0.26); emotional coping impacted SWLS in women (β = 0.36) more than men (β = 0.14).
Gender differences in coping and the impacts of economic status and emotion-focused coping vary with activity of CD. Psychological treatment in the clinic setting might improve satisfaction with life and quality of life in CD patients.
It is well recognised that adolescents and young adults (AYA) with cancer have inequitable access to oncology services that provide expert cancer care and consider their unique needs. Subsequently, ...survival gains in this patient population have improved only modestly compared with older adults and children with cancer. In 2015, the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE) established the joint Cancer in AYA Working Group in order to increase awareness among adult and paediatric oncology communities, enhance knowledge on specific issues in AYA and ultimately improve the standard of care for AYA with cancer across Europe. This manuscript reflects the position of this working group regarding current AYA cancer care, the challenges to be addressed and possible solutions. Key challenges include the lack of specific biological understanding of AYA cancers, the lack of access to specialised centres with age-appropriate multidisciplinary care and the lack of available clinical trials with novel therapeutics. Key recommendations include diversifying interprofessional cooperation in AYA care and specific measures to improve trial accrual, including centralising care where that is the best means to achieve trial accrual. This defines a common vision that can lead to improved outcomes for AYA with cancer in Europe.
•Reflects the ESMO/SIOPE AYA Working Group position regarding current AYA cancer care, challenges and possible solutions.•Key challenges are lack of understanding of AYA cancer biology, access to specialised centres, available clinical trials.•Key recommendations include diversifying interprofessional cooperation in AYA cancer care and measures to improve trial accrual.•This defines a common vision that can lead to improved outcomes for AYA with cancer in Europe.
Osteosarcoma stratification relies on clinical parameters and histological response. We developed a new personalized stratification using less invasive circulating tumor DNA (ctDNA) quantification.
...Plasma from patients homogeneously treated in the prospective protocol OS2006, at diagnosis, before surgery and end of treatment, were sequenced using low-passage whole-genome sequencing (lpWGS) for copy number alteration detection. We developed a prediction tool including ctDNA quantification and known clinical parameters to estimate patients’ individual risk of event.
ctDNA quantification at diagnosis (diagCPA) was evaluated for 183 patients of the protocol OS2006. diagCPA as a continuous variable was a major prognostic factor, independent of other clinical parameters, including metastatic status diagCPA hazard ratio (HR) = 3.5, P = 0.002 and 3.51, P = 0.012, for progression-free survival (PFS) and overall survival (OS). At the time of surgery and until the end of treatment, diagCPA was also a major prognostic factor independent of histological response (diagCPA HR = 9.2, P < 0.001 and 11.6, P < 0.001, for PFS and OS). Therefore, the addition of diagCPA to metastatic status at diagnosis or poor histological response after surgery improved the prognostic stratification of patients with osteosarcoma. We developed the prediction tool PRONOS to generate individual risk estimations, showing great performance ctDNA quantification at the time of surgery and the end of treatment still required improvement to overcome the low sensitivity of lpWGS and to enable the follow-up of disease progression.
The addition of ctDNA quantification to known risk factors improves the estimation of prognosis calculated by our prediction tool PRONOS. To confirm its value, an external validation in the Sarcoma 13 trial is underway.
•ctDNA detection is a non-invasive procedure.•The use of lpWGS is cost-effective.•This procedure represents a considerable step in reducing therapeutic burden and trauma for patients with cancer.•PRONOS is a tool that estimates relapse risk using ctDNA at diagnosis and known clinical risk factor in osteosarcoma.
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