Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial)

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09697-9

In situ TEM observation of the Boudouard reaction: multi-layered graphene formation from CO on cobalt nanoparticles at atmospheric pressure

Using a MEMS nanoreactor in combination with a specially designed in situ Transmission Electron Microscope (TEM) holder and gas supply system, we imaged the formation of multiple layers of graphene encapsulating a cobalt nanoparticle, at 1 bar CO:N2 (1:1) and 500 °C. The cobalt nanoparticle was imaged live in a TEM during the Boudouard reaction. The in situ/operando TEM studies give insight into the behaviour of the catalyst at the nanometer-scale, under industrially relevant conditions. When switching from Fischer-Tropsch syngas conditions (CO:H2:N2 1:2:3 at 1 bar) to CO-rich conditions (CO:N2 1:1 at 1 bar), we observed the formation of multi-layered graphene on Co nanoparticles at 500 °C. Due to the high temperature, the surface of the Co nanoparticles facilitated the Boudouard reaction, causing CO dissociation and the formation of layers of graphene. After the formation of the first patches of graphene at the surface of the nanoparticle, more and more layers grew over the course of about 40 minutes. In its final state, around 10 layers of carbon capped the nanoparticle. During this process, the carbon shell caused mechanical stress in the nanoparticle, inducing permanent deformation. © The Royal Society of Chemistry 2017

Healthcare Costs of Metastatic Cutaneous Melanoma in the Era of Immunotherapeutic and Targeted Drugs

Immunotherapeutic and targeted drugs improved survival of patients with metastatic melanoma. There is, however, a lack of evidence regarding their healthcare costs in clinical practice. The aim of our study was to provide insight into real-world healthcare costs of patients with metastatic cutaneous melanoma. Data were obtained from the Dutch Melanoma Treatment Registry for patients who were registered between July 2012 and December 2018. Mean total/monthly costs per patient were reported for all patients, patients who did not receive systemic therapy, and patients who received systemic therapy. Furthermore, mean episode/monthly costs per line of therapy and drug were reported for patients who received systemic therapy. Mean total/monthly costs were € 89,240/€ 6809: € 7988/€ 2483 for patients who did not receive systemic therapy (n = 784) and € 105,078/€ 7652 for patients who received systemic therapy (n = 4022). Mean episode/monthly costs were the highest for nivolumab plus ipilimumab (€ 79,675/€ 16,976), ipilimumab monotherapy (€ 79,110/€ 17,252), and dabrafenib plus trametinib (€ 77,053/€ 12,015). Dacarbazine yielded the lowest mean episode/monthly costs (€ 6564/€ 2027). Our study showed that immunotherapeutic and targeted drugs had a large impact on real-world healthcare costs. As new drugs continue entering the treatment landscape for (metastatic) melanoma, it remains crucial to monitor whether the benefits of these drugs outweigh their costs

The PRO-RCC study:a long-term PROspective Renal Cell Carcinoma cohort in the Netherlands, providing an infrastructure for ‘Trial within Cohorts’ study designs

BACKGROUND: Ongoing research in the field of both localized, locally advanced and metastatic renal cell carcinoma has resulted in the availability of multiple treatment options. Hence, many questions are still unanswered and await further research. A nationwide collaborative registry allows to collect corresponding data. For this purpose, the Dutch PROspective Renal Cell Carcinoma cohort (PRO-RCC) has been founded, for the prospective collection of long-term clinical data, patient reported outcome measures (PROMs) and patient reported experience measures (PREMs).METHODS: PRO-RCC is designed as a multicenter cohort for all Dutch patients with renal cell carcinoma (RCC). Recruitment will start in the Netherlands in 2023. Importantly, participants may also consent to participation in a 'Trial within cohorts' studies (TwiCs). The TwiCs design provides a method to perform (randomized) interventional studies within the registry. The clinical data collection is embedded in the Netherlands Cancer Registry (NCR). Next to the standardly available data on RCC, additional clinical data will be collected. PROMS entail Health-Related Quality of Life (HRQoL), symptom monitoring with optional ecological momentary assessment (EMA) of pain and fatigue, and optional return to work- and/or nutrition questionnaires. PREMS entail satisfaction with care. Both PROMS and PREMS are collected through the PROFILES registry and are accessible for the patient and the treating physician.TRIAL REGISTRATION: Ethical board approval has been obtained (2021_218) and the study has been registered at ClinicalTrials.gov (NCT05326620).DISCUSSION: PRO-RCC is a nationwide long-term cohort for the collection of real-world clinical data, PROMS and PREMS. By facilitating an infrastructure for the collection of prospective data on RCC, PRO-RCC will contribute to observational research in a real-world study population and prove effectiveness in daily clinical practice. The infrastructure of this cohort also enables that interventional studies can be conducted with the TwiCs design, without the disadvantages of classic RCTs such as slow patient accrual and risk of dropping out after randomization.</p

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19:an update from the Dutch Oncology COVID-19 Consortium

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic

Dutch Oncology COVID-19 consortium:Outcome of COVID-19 in patients with cancer in a nationwide cohort study

Aim of the study: Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19. Methods: This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible. Results: Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years). Conclusion: The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered

Het gedrag van een afgezonken tunnel als gevolg van een aardbeving

Een afgezonken tunnel in Griekenland is gebruikt als onderwerp voor een dynamische eindige elementenanalyse om de invloed van de grondsoort en de kracht van de aardbeving op het tunnelgedrag tijdens een aardbeving te bestuderen. De aardbevingsbelasting resulteert in een enorme horizontale tunnelverplaatsing, waarbij de tunnel als een stijf lichaam beweegt. De tunnel lijkt de krachten als gevolg van de dynamische belasting op te kunnen nemen zonder te bezwijken. De grondsoort is van ondergeschikt belang voor het dynamische tunnelgedrag, terwijl de kracht van de aardbeving een grote rol speelt. De resultaten van de numerieke analyse vormen de invoer voor een semi-analytische bepaling van de verwekingsgevoeligheid. Uit de resultaten volgt dat verweking een belangrijk bezwijkmechanisme is. Naast de kracht van de aardbeving blijkt ook de grondslag van grote invloed op de verwekingsgevoeligheid

Nonrandom ventricular rhythm in horses with atrial fibrillation and its significance for patients

RR interval sequences during spontaneous atrial fibrillation in eight horses were analyzed as in previous studies in patients and dogs using histograms and serial autocorrelograms. In patients and dogs with spontaneous atrial fibrillation, ventricular rhythms were always random. In the horses, the histograms were skewed with median RR intervals of approximately 1,000 ms. A striking finding in these animals was the presence of long RR intervals up to 5,000 ms in duration. The shortest RR intervals lasted 400 to 600 ms. In contrast to findings in dogs and patients, the serial autocorrelograms showed periodicity that was reenforced by digitalis (n = 3), but eliminated by quinidine (n = 2) and atropine (n = 2). Quinidine and atropine eliminated the longer RR intervals, whereas digitalis increased the number of long RR intervals. In one horse, it was possible to measure intra-arterial pressure, and large ftuctuations in pressure were observed as the RR intervals varied from over 3,000 to less than 500 ms. It is postulated that these changes in blood pressure are associated with baroreceptor responses that may alter the electrophysiologic behavior of the atria and atrioventricular node. These changes cause the nonrandom patterns of ventricular rhythm in the horse. Because such very long RR intervals do not occur in human beings or dogs during atrial fibrillation, the random ventricular rhythm in these groups is maintained even during digitalis treatment

[Checkpoint inhibitor induced diabetes mellitus]

Item does not contain fulltextBACKGROUND Checkpoint inhibitors are relatively new anti-cancer medicines that activate tumour cell immunity. CASE DESCRIPTION We describe two patients who presented to the emergency department due to severe ketoacidosis, this being the first symptom of diabetes in said patients. A few weeks prior to this, they each commenced treatment with the checkpoint inhibitor pembrolizumab. HbA1c level, assessed in one of the patients, was not elevated upon presentation. CONCLUSION Type 1 diabetes mellitus is a rare, but potentially life-threatening, complication of treatment with checkpoint inhibitors. However, routine measurement of glucose or HbA1c levels is not useful in patients who are treated with checkpoint inhibitors. Both patients and healthcare professionals should be (made) aware of the symptoms of hyperglycaemia, thereby ensuring immediate treatment with insulin in order to prevent severe ketoacidosis