Strategies to implement and execute precision oncology

Anti-cancer treatment has come a long way, and there probably is a long way to go before we can offer every patient a therapy that works, is safe, and affordable. Many paths may be pursued to ultimately achieve this goal, and precision oncology could be one of them: by matching treatment to specific characteristics of a patient, his or her tumor, and its micro-environment, higher response rates may be achieved whilst toxicity and unnecessary costs could be avoided. This thesis discusses several biomarker-based strategies to tailor treatment to specific tumor- or patient-characteristics, ultimately aimed at improving outcomes for individual patients. Part II is dedicated to tumor micro-environment, and how it may be employed to counteract chemotherapy resistance. It describes two prospective studies, both build on the observation that (A) mesenchymal stem cells (MSCs) mediate platinum-induced chemoresistance in mice, and that (B) indomethacin prevented this type of chemoresistance. Present research has demonstrated that translation to human cancer patients is safe and probably worthwhile, given that patients with advanced cancer have higher levels of circulating MSCs; especially once they have received systemic anti-cancer treatment. Part III focusses on biomarkers for targeted- and immunotherapy. It describes the set-up and first results of the Drug Rediscovery Protocol (DRUP), a nationwide, prospective, multi-drug and pan-tumor trial aimed at identifying new tumor type/molecular variant-combinations that are sensitive to approved anti-cancer drugs. Analysis of the first ~500 clinical case submissions showed that there are many patients (>50% in our dataset) whose molecular tumor profile can potentially be targeted by an already available anti-cancer drug, to which these patients would otherwise not have access. So far, one cohort (nivolumab for patients with MSI tumors) has completed accrual: clinical benefit was observed in twenty patients (67%), including eleven patients (37%) with an objective response. Yet, outside the context of clinical trials, most of these patients do currently not have access to nivolumab treatment. Negotiations with Dutch health authorities are therefore ongoing. Ideally, this will lead to nivolumab-reimbursement under the condition that further / confirmatory data will be gathered (“coverage with evidence development”). If successful, other DRUP cohorts will hopefully follow. Part IV discusses two aspects of precision oncology in daily practice. First, the relationship between somatic mutations and treatment consequences is complex and can’t be fully captured by most currently used gene panels. Adequate interpretation of extensive tumor sequencing, on the other hand, requires expertise from clinical, pathological, biological, genetical and technical perspective. A new type of tumor board is therefore rising: the multidisciplinary genetic- or Molecular Tumor Board (MTB). Three recommendations were formulated that may serve as a roadmap for successful MTB implementation. We feel that standardization of MTB practice would not only prevent variation in quality of care, but would also help to move the emerging field of tumor sequencing forward. Second, the need for cross-disciplinary evidence development is addressed: anti-cancer treatment options now range from systemic therapies, to interventional radiology, and so forth. Evidence directly comparing across these modalities, however, is scarce

Sterfte aan kanker en andere chronische aandoeningen: kenmerken in 2006 en trends vanaf 1996.

Thuis sterven In 2006 is 32% van de mensen met kanker of andere chronische aandoeningen thuis gestorven; 27% stierf in het ziekenhuis, 25% in het verpleeghuis en 15% elders. Dat is opmerkelijk omdat in de wetenschappelijke literatuur de plaats van sterven meer en meer als een belangrijke kwaliteitsindicator voor goede palliatieve zorg wordt gezien. Thuis sterven stelt mensen in staat zo lang mogelijk de regie te behouden over hun eigen leven. Onderzoek uit 2005 liet zien dat 73% van de algemene bevolking thuis de beste plaats vindt om te sterven voor mensen die ongeneeslijk ziek zijn. Ook terminale patiënten zelf geven veelal aan thuis te willen sterven. Zorgvraag Het Ministerie van VWS heeft palliatieve zorg als belangrijk speerpunt. Net als in vorige kabinetsperiodes wordt palliatieve zorg gezien als zorg die waar mogelijk thuis gegeven moet worden en anders zo ‘thuis’ mogelijk. Met subsidie van het ministerie van VWS deed het NIVEL onderzoek naar de niet-acute sterfte in Nederland op basis van gegevens van het CBS. Doel van het onderzoek was inzicht te krijgen in hoe de sterfte aan kanker en andere chronische aandoeningen zich ontwikkelt en wat voor consequenties dat kan hebben voor de vraag naar palliatieve zorg. Opname Het aandeel patiënten dat in een ziekenhuis sterft lijkt iets te zijn afgenomen, het aandeel dat sterft in een verpleeghuis is iets toegenomen, stelt NIVEL-onderzoeker Anneke Francke: “Toch sterft nog steeds bijna eenderde in het ziekenhuis. Dit impliceert dat patiënten in de palliatieve fase nog zijn opgenomen. Het is bekend dat er thuis in de laatste week soms nog crisissituaties ontstaan, doordat de symptomen te ernstig worden en onvoldoende kunnen worden bestreden of de mantelzorg het niet meer aankan. Extra aandacht voor ondersteuning van mantelzorgers is dus essentieel.” Allochtoon sterft liever in het ziekenhuis Bijna 90% van de overledenen had een Nederlandse herkomst, 8% was westers allochtoon, 2% niet-westers allochtoon. Niet-westerse allochtonen overlijden even vaak thuis als autochtone Nederlanders. Maar zij overlijden relatief vaak in het ziekenhuis en weinig in een verpleeg- of verzorgingshuis. Francke: “Dit hangt deels samen met de leeftijdsopbouw, voor een ander deel waarschijnlijk met het feit dat veel mensen uit bijvoorbeeld Turkije en Marokko negatief oordelen over opname in een verpleeg- of verzorgingshuis. In deze culturen is het voor velen een schande om oudere familieleden te laten opnemen. Een ziekenhuisopname heeft echter een medische noodzaak en wordt niet primair gezien als vervanging van familiezorg. Wat sterven in het ziekenhuis acceptabeler maakt.” Niet acute sterfte In 2006 stierven rond 135.000 Nederlanders. Ruim de helft (54%) overleed als gevolg van een chronische ziekte. Van deze groep overleden veertigduizend mensen aan kanker, 29.000 aan CVA (acute sterfte niet meegerekend), COPD, dementie, hartfalen en diabetes. Van alle niet-acuut overledenen was bijna driekwart minstens zeventig jaar. Vraag naar palliatieve zorg In 2000 deed het NIVEL een vergelijkbaar onderzoek. Toen werd voorspeld dat in de komende jaren de niet-acute sterfte met ongeveer 1% per jaar zou toenemen. Wat betekende dat de vraag naar palliatieve zorg ook met ongeveer 1% per jaar zou toenemen. Uit het huidige onderzoek blijkt dat er sprake is van een stijging van 0,7% per jaar ten opzichte van 1996

Dying from cancer or other chronic diseases in the Netherlands: ten-year trends derived from death certificate data.

BACKGROUND: For the further development of palliative care, it is relevant to gain insight into trends in non-acute mortality. The aim of this article is twofold: (a) to provide insight into ten-year trends in the characteristics of patients who died from cancer or other chronic diseases in the Netherlands; (b) to show how national death statistics, derived from physicians' death certificates, can be used in this type of investigations. METHODS: Secondary analysis of data from 1996 to 2006 on the "primary" or "underlying" cause of death from official death certificates filled out by physicians and additional data from 2003 to 2006 on the place of death from these certificates. RESULTS: Of the 135,000 people who died in the Netherlands in 2006, 77,000 (or 57%) died from a chronic disease. Cancer was the most frequent cause of death (40,000). Stroke accounted for 10,000 deaths, dementia for 8,000 deaths and COPD and heart failure each accounted for 6,000 deaths. Compared to 1996, the number of people who died from chronic diseases has risen by 6%. Of all non-acute deaths, almost three quarters were at least 70 years old when they died. Almost one third of the people died at home (31%), 28% in a hospital, 25% in a nursing home and 16% somewhere else. CONCLUSIONS: Further investments to facilitate dying at home are desirable. Death certificate data proved to be useful to describe and monitor trends in non-acute deaths. Advantages of the use of death certificate data concern the reliability of the data, the opportunities for selection on the basis of the ICD-10, and the availability and low cost price of the data.(aut. ref.

Limited evidence for the effect of sodium fluoride on deterioration of hearing loss in patients with otosclerosis: a systematic review of the literature

OBJECTIVE: To determine the protective effect of sodium fluoride on the deterioration of hearing loss in adult patients with otosclerosis. DATA SOURCES: PubMed, Embase, the Cochrane Library, and CINAHL. STUDY SELECTION: A systematic literature search was conducted. Studies reporting original study data on the deterioration of hearing loss in otosclerosis patients treated with sodium fluoride were included. DATA EXTRACTION: Directness of evidence (DoE) and risk of bias (RoB), using the Cochrane Collaboration's tool for assessing risk of bias, of the selected articles were assessed. Studies with low DoE, high RoB, or both were excluded. Absolute risks, mean deterioration of hearing in decibels, risk differences, and their 95% confidence intervals were extracted from the included studies. DATA SYNTHESIS: Our search yielded 168 original titles, of which, 2 placebo-controlled studies were eligible for data extraction. The results of these 2 studies were conflicting. One of the included studies, with high DoE and moderate RoB, reported an absolute risk reduction for deterioration of hearing loss of 18% [95% CI 17; 19] when treating with sodium fluoride. The other included study, with high DoE and moderate RoB, reported no clinically significant difference in mean deterioration of bone-conduction, air-conduction, or air-bone gap between the sodium fluoride group and the placebo group. CONCLUSION: There is weak evidence from one study with significant limitations that deterioration of hearing loss in otosclerosis patients receiving sodium fluoride treatment is less than in patients treated with a placebo

Rating scale analysis and psychometric properties of the Caregiver Self-Efficacy Scale for Transfers

Parents and caregivers faced with the challenges of transferring children with disability are at risk of musculoskeletal injuries and/or emotional stress. The Caregiver Self-Efficacy Scale for Transfers (CSEST) is a 14-item questionnaire that measures self-efficacy for transferring under common conditions. The CSEST yields reliable data and valid inferences; however, its rating scale structure has not been evaluated for utility. The aims of this study were to evaluate the category response structure of the CSEST, test the utility of a revised rating scale structure, and confirm its psychometric properties. The Rasch Measurement Model was used for all analyses. Subjects included 175 adult caregivers recruited from multiple communities. Results confirm that a revised five-category rating scale structure yields reliable data and valid inferences. Given the relationship between self-efficacy and risk of physical and/or emotional stress, measuring parental self-efficacy for transfers is a proactive process in rehabilitation

Free-Stream Effects on Jet-Installation Noise of a Dual-Stream Engine

An investigation of the effects of free-stream on jet-installation noise is performed using a numerical solver based on the lattice-Boltzmann method. In order to simulate a realistic configuration, a high-lift wing comprised by a main element and a deployed flap (MD30P30N) is placed in the vicinity of a dual-stream engine (GE90-94B). The engine operating parameters are used as inputs to generate realistic exhaust flows. Far-field noise spectra from the isolated and installed jets, obtained through the Ffowcs-Williams and Hawkings analogy, are compared for different polar angles. In the absence of free-stream, the results show a low-frequency noise amplification, occurring mainly upstream of the jet axis. This noise increase is due to a dipole source at the flap trailing-edge, where hydrodynamic waves from the jet scatter as sound to the far-field. With free-stream, the wing produces a downward flow, which deflects the jet plume. There is a consequent change on the shear layer turbulence characteristics, which is responsible for altering the far-field spectral shape and directivity pattern of the overall configuration. Through a wavelet decomposition of the near-pressure field, coherent and chaotic fluctuations are splitted. Near-field spectra show the change in amplitude of fluctuations of coherent structures due to free-stream, which are in agreement with the farfield results.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Wind Energ

Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer

Introduction: In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'.Methods: Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease >= 16 weeks). Patients were enrolled using a Simonlike 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained.Results: Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease >= 16 weeks. The most frequently observed HER2 mutation was p.Y772_A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3-6) and 10 months (95% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed.Conclusion: Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC. (C) 2022 The Authors. Published by Elsevier Ltd

Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer

Introduction: In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'.Methods: Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease >= 16 weeks). Patients were enrolled using a Simonlike 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained.Results: Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease >= 16 weeks. The most frequently observed HER2 mutation was p.Y772_A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3-6) and 10 months (95% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed.Conclusion: Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC. (C) 2022 The Authors. Published by Elsevier Ltd.Experimentele farmacotherapi

Personalised reimbursement: a risk-sharing model for biomarker-driven treatment of rare subgroups of cancer patients

Experimentele farmacotherapi