Cancer immunotherapy has experienced remarkable advances in the last decades. Striking clinical responses have been achieved for several solid cancers, particularly cancer types with a high... Show moreCancer immunotherapy has experienced remarkable advances in the last decades. Striking clinical responses have been achieved for several solid cancers, particularly cancer types with a high mutation burden, which placed tumour-mutated antigens (neoantigens) centre stage as targets of tumour immunity and cancer immunotherapy. Neoantigens can be presented in complex with HLA molecules on the tumour cell surface, where T cells with the correct specificity can recognize the neoantigen as ‘non-self’ which will trigger killing of the tumour cell by the T cell. In theory, cancers with a low/moderate mutation burden that present neoantigens in complex with HLA class molecules could still be eligible for T cell-mediated immunotherapy. This thesis, describes the finding that neoantigen-specific T cells are present in mismatch-repair proficient (MMR-p) colorectal cancer patients, a low mutation burden cancer type. Moreover, CD39 and CD103 were found as cell surface markers that pinpoint the T cell population that contains the neoantigen-specific T cells. In addition, subsequent metastasis of a melanoma patient cohort were studied and revealed that also at advanced, late-stage disease, neoantigen-directed T cell therapy is, in theory, still applicable. Taken together, the studies reveal potential for the development of neoantigen-directed cancer immunotherapy for a broader patient population. Show less
Bootsma, T.I.; Wal, D. van de; Vlooswijk, C.; Roos, D.C.; Drabbe, C.; Tissier, R.; ... ; Husson, O. 2024
PurposeAdolescent and young adult cancer survivors (AYAs) are at increased risk of long-term and late effects, and experience unmet needs, impacting their health-related quality of life (HRQoL). In... Show morePurposeAdolescent and young adult cancer survivors (AYAs) are at increased risk of long-term and late effects, and experience unmet needs, impacting their health-related quality of life (HRQoL). In order to provide and optimize supportive care and targeted interventions for this unique population, it is important to study HRQoL factors' interconnectedness on a population level. Therefore, this network analysis was performed with the aim to explore the interconnectedness between HRQoL factors, in the analysis described as nodes, among long-term AYAs.MethodsThis population-based cohort study used cross-sectional survey data of long-term AYAs, who were identified by the Netherlands Cancer Registry (NCR). Participants completed a one-time survey (SURVAYA study), including the EORTC survivorship questionnaire (QLQ-SURV111) to assess their long-term HRQoL outcomes and sociodemographic characteristics. The NCR provided the clinical data. Descriptive statistics and a network analysis, including network clustering, were performed.ResultsIn total, 3596 AYAs (on average 12.4 years post diagnosis) were included in our network analysis. The network was proven stable and reliable and, in total, four clusters were identified, including a worriment, daily functioning, psychological, and sexual cluster. Negative health outlook, part of the worriment cluster, was the node with the highest strength and its partial correlation with health distress was significantly different from all other partial correlations.ConclusionThis study shows the results of a stable and reliable network analysis based on HRQoL data of long-term AYAs, and identified nodes, correlations, and clusters that could be intervened on to improve the HRQoL outcomes of AYAs. Show less
To generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims... Show moreTo generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims to contribute to the knowledge on SUMO regulated oncogenesis, understanding the consequences of abolishment of SUMO signaling and exploiting the potential of SUMO E1 inhibitors. To this end, we describe SUMO as a potential biomarker for cancer aggressiveness and increase our understanding on SUMO’s role in cell cycle progression. We exploited the potential of SUMO E1 inhibition by combining with hypomethylating compound 5-Aza-2’ deoxycytidine, leading to increased cytostatic efficacy. Furthermore, we repurposed the SUMO E1 inhibitor TAK981 and hypomethylating drug 5-Aza-2’ deoxycytidine to improve engineered TCR (eTCR) T cell therapy and broaden our understanding of its immunomodulatory potential. Show less
The aim of this thesis was to develop novel treatment strategies for different types of eye melanoma utilizing zebrafish models. We first establish orthotopic and ectopic xenograft models for uveal... Show moreThe aim of this thesis was to develop novel treatment strategies for different types of eye melanoma utilizing zebrafish models. We first establish orthotopic and ectopic xenograft models for uveal and conjunctival melanoma by engraftment of the immortalized cells derived from these tumors into zebrafish embryos. Next, we expanded these models with spheroids and zebrafish patient-derived xenografts for pre-clinical, personalized screening of anti-uveal melanoma drug responses. We demonstrated that these models can be harnessed to explore the in vivo interactions of the tumor cells with blood vessels and macrophages leading to angiogenic response. We finally apply the conjunctival melanoma model to clarify the inhibitory effects of ginsenosides and correlate their structures with potential antitumoral mechanisms. Show less
Background: Fear of cancer recurrence (FCR) is one of the greatest problems with which cancer survivors have to deal. High levels of FCR are characterized by intrusive thoughts about cancer-related... Show moreBackground: Fear of cancer recurrence (FCR) is one of the greatest problems with which cancer survivors have to deal. High levels of FCR are characterized by intrusive thoughts about cancer-related events and re-experiencing these events, avoidance of reminders of cancer, and hypervigilance, similar to post-traumatic stress disorder (PTSD). Eye movement desensitization and reprocessing (EMDR) therapy focuses on these images and memories. It is effective in reducing PTSD and may be effective in reducing high levels of FCR. Objective: The aim of the present study is to investigate the effectiveness of EMDR for severe FCR in breast and colorectal cancer survivors. Method: A multiple-baseline single-case experimental design (n = 8) was used. Daily repeated measurements for FCR were taken during the baseline phase and treatment phase, post-treatment, and at the 3 month follow-up. Participants answered the Cancer Worry Scale (CWS) and the Fear of Cancer Recurrence Inventory, Dutch version (FCRI-NL) five times, i.e. at the start and at the end of each phase (baseline, treatment, post-treatment, and follow-up). The study was prospectively registered at clinicaltrials.gov (NL8223). Results: Visual analysis and effect size calculation by Tau-U were executed for the daily questionnaire on FCR. The weighted average Tau-U score was .63 (p < .01) for baseline versus post-treatment, indicating large change, and .53 (p < .01) between baseline and follow-up, indicating moderate change. The scores on the CWS and FCRI-NL-SF decreased significantly from baseline to follow-up. Conclusion: The results seem promising for EMDR therapy as a potentially effective treatment for FCR. Further research is recommended. Show less
BackgroundCancer patients may experience a decrease in cognitive functioning before, during and after cancer treatment. So far, the Quality of Life Group of the European Organisation for Research... Show moreBackgroundCancer patients may experience a decrease in cognitive functioning before, during and after cancer treatment. So far, the Quality of Life Group of the European Organisation for Research and Treatment of Cancer (EORTC QLG) developed an item bank to assess self-reported memory and attention within a single, cognitive functioning scale (CF) using computerized adaptive testing (EORTC CAT Core CF item bank). However, the distinction between different cognitive functions might be important to assess the patients’ functional status appropriately and to determine treatment impact. To allow for such assessment, the aim of this study was to develop and psychometrically evaluate separate item banks for memory and attention based on the EORTC CAT Core CF item bank.MethodsIn a multistep process including an expert-based content analysis, we assigned 44 items from the EORTC CAT Core CF item bank to the memory or attention domain. Then, we conducted psychometric analyses based on a sample used within the development of the EORTC CAT Core CF item bank. The sample consisted of 1030 cancer patients from Denmark, France, Poland, and the United Kingdom. We evaluated measurement properties of the newly developed item banks using confirmatory factor analysis (CFA) and item response theory model calibration.ResultsItem assignment resulted in 31 memory and 13 attention items. Conducted CFAs suggested good fit to a 1-factor model for each domain and no violations of monotonicity or indications of differential item functioning. Evaluation of CATs for both memory and attention confirmed well-functioning item banks with increased power/reduced sample size requirements (for CATs ≥ 4 items and up to 40% reduction in sample size requirements in comparison to non-CAT format).ConclusionTwo well-functioning and psychometrically robust item banks for memory and attention were formed from the existing EORTC CAT Core CF item bank. These findings could support further research on self-reported cognitive functioning in cancer patients in clinical trials as well as for real-word-evidence. A more precise assessment of attention and memory deficits in cancer patients will strengthen the evidence on the effects of cancer treatment for different cancer entities, and therefore contribute to shared and informed clinical decision-making. Show less
Protein glycosylation has profound implications in a wide range of molecular and biological processes occurring in cancer, where specific changes in the glycan structures have shown to be... Show moreProtein glycosylation has profound implications in a wide range of molecular and biological processes occurring in cancer, where specific changes in the glycan structures have shown to be associated with the development and progression of the disease paving the way for the development of new clinical biomarkers as well as providing specific targets for therapeutic intervention, patient stratification and personalized medicine. Protein glycosylation is also critical for the development of biopharmaceuticals, as even minor shifts in manufacturing procedures can substantially impact the bioactivity, safety, and efficacy of therapeutic proteins. Although a variety of mass spectrometric and chromatographic methods are available for the identification and characterization of glycans from complex sample mixtures, the lack of standardized protocols across platforms often results in inconsistent results, making data integration and comparison challenging. Furthermore, most of the current technology for the study of intact glycans would not be suitable for the rapid analysis of large sample sets, mainly due to limitations in sample throughput. The scope of this thesis is to establish standardized, high-throughput glycomics technologies for the quantitative analysis of protein N- and O-glycosylation and improve current methodologies in order to facilitate the characterization of intact oligosaccharides from in vitro established model systems. Show less
Cells constitute the tissues of our body and are responsible for producing various changes in response to different situations. For instance, the repair of damaged DNA. DNA resides within the cell... Show moreCells constitute the tissues of our body and are responsible for producing various changes in response to different situations. For instance, the repair of damaged DNA. DNA resides within the cell nucleus and can be transcribed and translated into proteins, which play vital roles in numerous cellular processes. The cell relies on modifying existing proteins to carry out essential functions. These modifications can involve the conjugation of small molecules such as Ubiquitin (Ub) or Small Ubiquitin-like Modifiers (SUMOs), leading to protein degradation, conformational changes or intracellular relocation of critical proteins. The conjugation of these small molecules involves a well-orchestrated sequence of enzymatic activities performed by dedicated enzymes: E1 (activating), E2 (conjugating) and E3 (ligase). Among these, the E3 ligase enzymes hold significant importance as they confer substrate specificity.In this thesis, we have developed an advanced Mass-Spectrometry technology called TULIP2 (Targets for Ubiquitin Ligases Identified by Proteomics 2), which facilitates the identification of Ubiquitination targets for specific E3 ligases of interest. Using this technology, we have investigated the BRCA1-BARD1 E3 ligase and explore the in vivo role of the E2 UBE2D3. Furthermore, we have adapted the TULIP2 technology to create the SUMO Activated Target Traps (SATTs), enabling the identification of an E3-specific SUMO proteome. Show less
Nonhuman primate adenoviruses have formed a valuable alternative for the use of human adenoviruses in vaccine development and gene therapy strategies by virtue of the low seroprevalence of... Show moreNonhuman primate adenoviruses have formed a valuable alternative for the use of human adenoviruses in vaccine development and gene therapy strategies by virtue of the low seroprevalence of neutralizing immunity in the human population. The more recent use of several human adenoviruses as oncolytic agents has exhibited excellent safety profiles and firm evidence of clinical efficacy. This raises the question whether nonhuman primate adenoviruses could also be employed for viral oncolysis in human patients. The research in this thesis provides a rational and data-supported decision on the use of nonhuman primate adenoviruses as a base for the development of new oncolytic derivatives with limited neutralizing immunity in the human population. Moreover, the development of a potent new gorilla-derived oncolytic adenovirus named GoraVir shows the feasibility of the approach. Hopefully, this research provides some reassurance regarding the future use of replication-competent nonhuman primate adenovirus vectors as therapeutic agents. Show less
This thesis aims to improve patient outcomes after major oncological gastrointestinal surgery, by identifying targets for optimizing perioperative care. On the one hand, identifying (adjustable)... Show moreThis thesis aims to improve patient outcomes after major oncological gastrointestinal surgery, by identifying targets for optimizing perioperative care. On the one hand, identifying (adjustable) prognostic factors for postoperative complications and then using them in prediction models, and gaining insight into the quality of life after surgery. Improving preoperative risk assessment and subsequent personalization of postoperative care can reduce the rate of postoperative complications and mortality. In addition, risk prediction can support clinical knowledge in making treatment decisions. Modifiable prognostic factors are particularly important to identify as they may be optimized prior to surgery. Modifiable prognostic factors can then be used in prehabilitation programs to improve a patient's physical condition and thus improve patient outcomes. In addition, information about treatment consequences and treatment-related health problems is important for treatment decision-making for patients and healthcare professionals. Especially, if several treatment options are available, knowledge about (long-term) consequences of the treatment options is important for shared decision-making. This knowledge can also contribute to optimizing postoperative care and rehabilitation programs. In conclusion, the leads described in this thesis for improving postoperative care can be used to improve short- and long-term patient outcomes after complex oncological gastrointestinal surgery. Show less
The use of existing medications for diseases they were not originally developed for is called drug repositioning. A popular drug repositioning method to find new drugs against specific cancer types... Show moreThe use of existing medications for diseases they were not originally developed for is called drug repositioning. A popular drug repositioning method to find new drugs against specific cancer types is to search for drugs which are expected to bring back the gene expression activity of cancer cells to that of healthy cells (‘normalization’). One of the main research goals of this thesis was to investigate of this method could also be used on the gene expression profiles of individual tumors, enabling personalization of drug repositioning candidates for each patient. We initially had some success with this approach but this eventually lead to a systematic validation of the underlying principle using almost 10,000 tumor samples across 18 different tumor types. Unfortunately, the predictive power of the method was found to be much lower than previously reported and the part that remained could be nullified by correcting the gene expression profiles of the drugs for the downstream effects of reduced cell division. These results indicate that the current use of the method does not result in drug repositioning candidates specific for a tumor type but is only able to select generally cell-toxic drugs. Show less
Abate, Y.; Solomon, K.; Azmera, Y.M.; Fouw, M. de; Kaba, M. 2023
Background Annually 57 million people across the globe require palliative care, 76% are from low- and-middle income countries. Continuity of palliative care contributes to a decline in emergency... Show moreBackground Annually 57 million people across the globe require palliative care, 76% are from low- and-middle income countries. Continuity of palliative care contributes to a decline in emergency room visits., decreased hospital deaths, improved patient satisfaction, better utilization of services, and cost savings. Despite efforts made to develop the palliative care guideline in Ethiopia, the service is not yet organized and linked to primary health care. This study aimed to explore barriers to the continuum of palliative care from facility to household for cancer patients in Addis Ababa. Methods Qualitative exploratory study was conducted with face-to-face interviews with a total of 25 participants. The study population was adult cancer patients, primary caregivers, healthcare providers, volunteers, and nationwide advocates. Data were audio recorded, transcribed verbatim and finally imported to Open code version 4.02 software for coding and analysis. Thematic analysis was guided by Tanahashi’s framework. Results The key barriers to continuity of palliative care included opioid scarcity and turnover and shortage of healthcare workers. A shortfall of diagnostic materials, cost of medications, lack of government backing, and homebased center’s enrollment capacity hampered accessibility. Care providers were instruments of cultural barriers in delivering appropriate end-of-life care, on the other hand, patients’ preference for conventional medicine hindered acceptability. Lack of community volunteers, failure of health extension workers to link patients, and spatial limits fraught utilization. The lack of defined roles and services at several levels and the workload on healthcare professionals affected the effectiveness of the nexus. Conclusion The continuum of palliative care service from health facility to household in Ethiopia is yet in its infancy compromised by factors related to availability, accessibility, acceptability, utilization, and effectiveness. Further research is required to delineate the roles of various actors; th Show less
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising approach for anti-cancer immunotherapy by bridging innate and adaptive immunity. Recent evidence... Show moreThe cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising approach for anti-cancer immunotherapy by bridging innate and adaptive immunity. Recent evidence suggests that chemotherapy-induced DNA damage can directly induce dendritic cell (DC) maturation and recruitment, which synergizes with STING activation to enhance anti-tumor effects. As an immunogenic cell death (ICD) inducer, oxaliplatin generates massive double-stranded DNA (dsDNA) crosslinks, release of tumor-associated antigens and promoting the "eat me" signal. STING activation improves antigen immunogenicity, which can promote T cell activation and infiltration. In this study, we developed liposomes encapsulating oxaliplatin and combine this formulation with a STING agonist (ADU-S100) for treating colorectal cancer. The liposomes efficiently inhibited the proliferation of tumor cells while induced ICD in CT26 colorectal cancer cells, which enhanced dendritic cell maturation and phagocytosis in vitro. The liposome-based immunochemotherapy exhibited the strongest efficacy, resulting in complete remission upon tumor inoculation. Mechanistic studies showed this potent anti-cancer effect was related to the significant recruitment of infiltrating CD8 and CD4 T cells, reduction of suppressive Treg cells, and a shift in the phenotype of tumor-associated suppressive macrophages that promote cancer to immune stimulating macrophages. Thus, our study demonstrated the potential of combining oxaliplatin-loaded liposomes with a STING agonist to reduce tumor growth by regulating the immunosuppressive state in the tumor. Show less
Deursen, L. van; Vaart, R. van der; Alblas, E.E.; Struijs, J.N.; Chavannes, N.H.; Aardoom, J.J. 2023
Purpose: This study aims to identify improvement opportunities within the colorectal cancer (CRC) care pathway using e-health and to examine how these opportunities would contribute to the... Show morePurpose: This study aims to identify improvement opportunities within the colorectal cancer (CRC) care pathway using e-health and to examine how these opportunities would contribute to the Quadruple Aim. Methods: In total, 17 semi-structured interviews were held (i.e., nine healthcare providers and eight managers involved in Dutch CRC care). The Quadruple Aim was used as a conceptual framework to gather and systematically structure the data. A directed content analysis approach was employed to code and analyze the data. Results: Interviewees believe the available e-health technology could be better exploited in CRC care. Twelve different improvement opportunities were identified to enhance the CRC care pathway. Some opportunities could be applied in one specific phase of the pathway (e.g., digital applications to support patients in the prehabilitation program to enhance the program's effects). Others could be deployed in multiple phases or extended outside the hospital care setting (e.g., digital consultation hours to increase care accessibility). Some opportunities could be easily implemented (e.g., digital communication to facilitate treatment preparation), whereas others require structural, systemic changes (e.g., increasing efficiency in patient data exchanges among healthcare professionals). Conclusion: This study provides insights into how e-health could add value to CRC care and contribute to the Quadruple Aim. It shows that e-health has the potential to contribute to the challenges in cancer care. To take the next step forward, the perspectives of other stakeholders must be examined, the identified opportunities should be prioritized, and the requirements for successful implementation should be mapped out. Show less
Deursen, L. van; Vaart, R. van der; Alblas, E.E.; Struijs, J.N.; Chavannes, N.H.; Aardoom, J.J. 2023
PurposeThis study aims to identify improvement opportunities within the colorectal cancer (CRC) care pathway using e-health and to examine how these opportunities would contribute to the Quadruple... Show morePurposeThis study aims to identify improvement opportunities within the colorectal cancer (CRC) care pathway using e-health and to examine how these opportunities would contribute to the Quadruple Aim.MethodsIn total, 17 semi-structured interviews were held (i.e., nine healthcare providers and eight managers involved in Dutch CRC care). The Quadruple Aim was used as a conceptual framework to gather and systematically structure the data. A directed content analysis approach was employed to code and analyze the data.ResultsInterviewees believe the available e-health technology could be better exploited in CRC care. Twelve different improvement opportunities were identified to enhance the CRC care pathway. Some opportunities could be applied in one specific phase of the pathway (e.g., digital applications to support patients in the prehabilitation program to enhance the program’s effects). Others could be deployed in multiple phases or extended outside the hospital care setting (e.g., digital consultation hours to increase care accessibility). Some opportunities could be easily implemented (e.g., digital communication to facilitate treatment preparation), whereas others require structural, systemic changes (e.g., increasing efficiency in patient data exchanges among healthcare professionals).ConclusionThis study provides insights into how e-health could add value to CRC care and contribute to the Quadruple Aim. It shows that e-health has the potential to contribute to the challenges in cancer care. To take the next step forward, the perspectives of other stakeholders must be examined, the identified opportunities should be prioritized, and the requirements for successful implementation should be mapped out. Show less
Metastases remain the leading cause of cancer-related death worldwide. Therefore, improving the treatment efficacy against such tumors is essential to enhance patient survival. AU-011 (belzupacap... Show moreMetastases remain the leading cause of cancer-related death worldwide. Therefore, improving the treatment efficacy against such tumors is essential to enhance patient survival. AU-011 (belzupacap sarotalocan) is a new virus-like drug conjugate which is currently in clinical development for the treatment of small choroidal melanoma and high-risk indeterminate lesions in the eye. Upon light activation, AU-011 induces rapid necrotic cell death which is pro-inflammatory and pro-immunogenic, resulting in an anti-tumor immune response. As AU-011 is known to induce systemic anti-tumor immune responses, we investigated whether this combination therapy would also be effective against distant, untreated tumors, as a model for treating local and distant tumors by abscopal immune effects. We compared the efficacy of combining AU-011 with several different checkpoint blockade antibodies to identify optimal treatment regimens in an in vivo tumor model. We show that AU-011 induces immunogenic cell death through the release and exposure of damage-associated molecular patterns (DAMPs), resulting in the maturation of dendritic cells in vitro. Furthermore, we show that AU-011 accumulates in MC38 tumors over time and that ICI enhances the efficacy of AU-011 against established tumors in mice, resulting in complete responses for specific combinations in all treated animals bearing a single MC38 tumor. Finally, we show that AU-011 and anti-PD-L1/anti-LAG-3 antibody treatment was an optimal combination in an abscopal model, inducing complete responses in approximately 75% of animals. Our data show the feasibility of combining AU-011 with PD-L1 and LAG-3 antibodies for the treatment of primary and distant tumors. Show less
Type I interferons (IFN-I) are pleiotropic cytokines that were originally identified for their antiviral properties and are now recognized for playing key roles in the defense against a range of... Show moreType I interferons (IFN-I) are pleiotropic cytokines that were originally identified for their antiviral properties and are now recognized for playing key roles in the defense against a range of other microorganisms as well as cancer. Their production should be well-controlled to be of benefit to the host, as excessive or chronic IFN-I expression leads to adverse effects such as immunosuppression or the induction of severe immunopathology.The studies presented in this thesis are aimed at uncovering mechanisms that regulate the production of IFN-I. The obtained knowledge on the involved molecular processes, may aid the development of targeted therapies that enhance or intercept IFN-I responses for maximum host protection while minimizing damage. Show less
Hollander, L.S. den; Béquignon, O.J.M.; Wang, X.; Wezel, K. van; Broekhuis, J.; Gorostiola González, M.; ... ; Heitman, L.H. 2022
CC chemokine receptor 2 (CCR2), a G protein-coupled receptor, plays a role in many cancer-related processes such as metastasis formation and immunosuppression. Since ∼ 20 % of human cancers contain... Show moreCC chemokine receptor 2 (CCR2), a G protein-coupled receptor, plays a role in many cancer-related processes such as metastasis formation and immunosuppression. Since ∼ 20 % of human cancers contain mutations in G protein-coupled receptors, ten cancer-associated CCR2 mutants obtained from the Genome Data Commons were investigated for their effect on receptor functionality and antagonist binding. Mutations were selected based on either their vicinity to CCR2's orthosteric or allosteric binding sites or their presence in conserved amino acid motifs. One of the mutant receptors, namely S101P2.63 with a mutation near the orthosteric binding site, did not express on the cell surface. All other studied mutants showed a decrease in or a lack of G protein activation in response to the main endogenous CCR2 ligand CCL2, but no change in potency was observed. Furthermore, INCB3344 and LUF7482 were chosen as representative orthosteric and allosteric antagonists, respectively. No change in potency was observed in a functional assay, but mutations located at F1163.28 impacted orthosteric antagonist binding significantly, while allosteric antagonist binding was abolished for L134Q3.46 and D137N3.49 mutants. As CC chemokine receptor 2 is an attractive drug target in cancer, the negative effect of these mutations on receptor functionality and drugability should be considered in the drug discovery process. Show less
Purpose Recent data have shown a decreasing overall mortality in acromegaly over the last decades. However, cancer incidence and cancer-related mortality still appear to be increased. Our aim was... Show morePurpose Recent data have shown a decreasing overall mortality in acromegaly over the last decades. However, cancer incidence and cancer-related mortality still appear to be increased. Our aim was to obtain updated epidemiological data from Norway in a clinically well-defined cohort with complete register-based follow-up.Methods Patients diagnosed with acromegaly from South-Eastern Norway between 1999-2019 (n = 262) and age and sex matched population controls (1:100) were included (n = 26,200). Mortality and cancer data were obtained from the Norwegian Cause of Death and Cancer Registry. Mortality and cancer incidence were compared by Kaplan-Meier analyses and Cox regression; we report hazard ratios (HRs) with 95% confidence intervals (95% CI).Results Median age at diagnosis was 48.0 years (interquartile range (IQR): 37.6-58.0). Mean annual acromegaly incidence rate was 4.7 (95% CI 4.2-5.3) cases/10(6) person-years, and the point prevalence (2019) was 83 (95% CI 72.6-93.5) cases/10(6) persons. Overall mortality was not increased in acromegaly, HR 0.8 (95% CI 0.5-1.4), cancer-specific and cardiovascular-specific mortality was also not increased (HR: 0.7 (95% CI 0.3-1.8) and 0.8 (95% CI: 0.3-2.5) respectively). The HR for all cancers was 1.45 (1.0-2.1; p = 0.052).Conclusion In this large cohort study, covering the period 1999-2019, patients were treated with individualized multimodal management. Mortality was not increased compared to the general population and comparable with recent registry studies from the Nordic countries and Europe. Overall cancer risk was slightly, but not significantly increased in the patients. Show less
Background: Timely initiation of advance care planning (ACP) in general practice is challenging, especially in patients with non-malignant conditions. Our aim was to investigate how perceived... Show moreBackground: Timely initiation of advance care planning (ACP) in general practice is challenging, especially in patients with non-malignant conditions. Our aim was to investigate how perceived optimal timing of ACP initiation and its triggers relate to recorded actual timing in patients with cancer, organ failure, or multimorbidity. Methods: In this mixed-methods study in the Netherlands, we analysed health records selected from a database with primary care routine data and with a recorded ACP conversation in the last two years before death of patients who died with cancer, organ failure, or multimorbidity. We compared actual timing of ACP initiation as recorded in health records of 51 patients with the perceived optimal timing as determined by 83 independent GPs who studied these records. Further, to identify and compare triggers for GPs to initiate ACP, we analysed the health record documentation around the moments of the recorded actual timing of ACP initiation and the perceived optimal timing of ACP initiation. We combined quantitative descriptive statistics with qualitative content analysis. Results: The recorded actual timing of ACP initiation was significantly closer to death than the perceived optimal timing in patients with cancer (median 88 vs. 111 days before death (p = 0.049)), organ failure (227 vs. 306 days before death (p = 0.02)) and multimorbidity (113 vs. 338 days before death (p = 0.006)). Triggers for recorded actual versus perceived optimal timing were similar across the three groups, the most frequent being 'expressions of patients' reflections or wishes' (14% and 14% respectively) and 'appropriate setting' (10% and 13% respectively). Conclusion: ACP in general practice was initiated and recorded later in the illness trajectory than considered optimal, especially in patients with organ failure or multimorbidity. As triggers were similar for recorded actual and perceived optimal timing, we recommend that GPs initiate ACP shortly after a trigger is noticed the first time, rather than wait for additional or more evident triggers when the illness is in an advanced stage. Show less
