PurposeTo describe recall of fertility-related consultations and cryopreservation and to examine reproductive goals and reproduction post-treatment in long-term survivors of adolescent and young... Show morePurposeTo describe recall of fertility-related consultations and cryopreservation and to examine reproductive goals and reproduction post-treatment in long-term survivors of adolescent and young adult (AYA) (age, 18-39 years) cancer.MethodsThis study included n = 1457 male and n = 2112 female long-term survivors (Mage = 43-45 years; 5-22 years from diagnosis) who provided self-report. Clinical data were supplied by the Netherlands Cancer Registry.ResultsMost male survivors (72.7%) recalled fertility-related consultations and 22.6% completed sperm cryopreservation. Younger age (OR = 2.8; 95%CI [2.2-3.6]), not having children (OR = 5.0; 95%CI [3.2-7.7]), testicular cancer or lymphoma/leukemia (OR = 2.8/2.5 relative to "others"), and more intense treatments (OR = 1.5; 95%CI [1.1-2.0]) were associated with higher cryopreservation rates. Time since diagnosis had no effect. Of men who cryopreserved, 12.1% utilized assisted reproductive technologies (ART). Most men (88.5%) felt their diagnosis did not affect their reproductive goals, but 7.6% wanted no (additional) children due to cancer. Half of female survivors (55.4%; n = 1171) recalled fertility-related consultations. Rates of cryopreservation were very low (3.6%), but increased after 2013 when oocyte cryopreservation became non-experimental. Of women who cryopreserved, 13.2% successfully utilized ART. Most women (74.8%) experienced no effects of cancer on reproductive goals, but 17.8% wanted no (additional) children due to cancer.ConclusionsCryopreservation in men varied by patient/clinical factors and was very low in women, but data of more recently treated females are needed. Utilizing cryopreserved material through ART was rare, which questions its cost-effectiveness, but it may enhance survivors' well-being.Implications for Cancer SurvivorsThe extent to which cryopreservation positively affects survivors' well-being remains to be tested. Moreover, effects of cancer on reproductive goals require further attention, especially in women who refrain from having children due to cancer. Show less
Although anti-cancer treatments have significantly advanced over the past decades, obstacles to accomplishing successful treatment still exist. The occurrence of treatment resistance is one of the... Show moreAlthough anti-cancer treatments have significantly advanced over the past decades, obstacles to accomplishing successful treatment still exist. The occurrence of treatment resistance is one of the major factors that limit the long-lasting efficacy of anti-cancer treatment. Additionally, substantial variability in pharmacokinetics (PK) / pharmacodynamics (PD) of anti-cancer drugs also challenges successful oncology treatment. Therefore, gaining knowledge of and ultimately better suppressing evolutionary resistance development during treatment, and applying personalized treatment are desired to improve anti-cancer treatment. In this thesis, we have applied quantitative modeling approaches to address these needs, aiming for improved treatment for oncology patients. Our work demonstrated that with the quantitative models, the evolutionary progression of tumors could be characterized and predicted, accounting for interactions among heterogeneous tumor cells and supported by mutant gene variants detected in circulating tumor DNA (ctDNA). In addition, we developed population PK /PD models which enabled quantitative description of the PK and PD of anti-cancer drugs and corresponding variabilities in real-world patients. The developed models have been further applied to support the identification of optimal treatment strategies and guide individualized treatment for oncology patients. Show less
Cancers accounts for approximately one-in-six deaths worldwide. Despite the advances in treatment options over the past couple decades surgery remains the cornerstone for almost all solid tumors.... Show moreCancers accounts for approximately one-in-six deaths worldwide. Despite the advances in treatment options over the past couple decades surgery remains the cornerstone for almost all solid tumors. Radical excision is crucial for curative treatment, however, intraoperative tumor identification is hampered by (1) fibrosis, inflammation and necrosis due to neoadjuvant therapy, and (2) an altered surgical field due to the adoption of laparoscopic and robotic procedures. In response, fluorescence guided surgery (FGS) has been introduced to the operating theater. FGS utilizes near-infrared light to visualize, an often intravenously administered, tumor-targeting tracer in real-time. In this thesis, uPAR was studied as target for FGS and uPAR-targeting FGS tracers were developed and compared in various cancer models. Show less
In this thesis, different preclinical strategies were explored aiming at the identification of putative novel therapies for prostate and bladder cancer. The first part of this thesis (Chapter 2 and... Show moreIn this thesis, different preclinical strategies were explored aiming at the identification of putative novel therapies for prostate and bladder cancer. The first part of this thesis (Chapter 2 and Chapter 3) describes the generationof preclinical, patient-derived model systems of prostate and bladder cancer. In Chapter 2, an overview is provided of the most commonly used patient-derived model systems for urological tumors, and a framework on how these patient derived tumor models can be employed to address preclinical and clinical unmet needs is presented. In Chapter 3, we developed and optimized the culture of ex vivo tumor tissue slices and employed this model to detect anti-tumor responses of chemotherapeutic agents Docetaxel and Gemicitabin. Subsequently in Chapters 4, 5 and 6, we describe the use of multiple preclinical translational models, including patient-derived tumor models. In Chapter 4 and 5 the translational potential of the approved antipsychotic drug penfluridol was determined in bladder and prostate cancer. In Chapter 6, the use of oncolytic reovirus jin-3 as putative novel therapeutic strategy for the treatment of prostate is investigated. Finally, in Chapter 7, we describe a novel preclinical screening strategy based on E-cadherin (re)induction and inhibition of invasion for the identification of a new class of small molecules for the treatment of aggressive epithelial cancers. Show less
PurposeThe present study aimed to determine the prevalence of self-reported oral problems and the oral health-related quality of life (OHRQoL) in childhood cancer survivors (CCS).MethodsPatient and... Show morePurposeThe present study aimed to determine the prevalence of self-reported oral problems and the oral health-related quality of life (OHRQoL) in childhood cancer survivors (CCS).MethodsPatient and treatment characteristics of CCS have been collected in a cross-sectional study, part of the multidisciplinary DCCSS-LATER 2 Study. To assess self-reported oral health problems and dental problems, CCS filled out the 'Toegepast-Natuurwetenschappelijk Onderzoek' (TNO) oral health questionnaire. OHRQoL was assessed by the Dutch version of the Oral Health Impact Profile-14 (OHIP-14). Prevalences were compared with two comparison groups from the literature. Univariable and multivariable analyses were performed.ResultsA total of 249 CCS participated in our study. The OHIP-14 total score had a mean value of 1.94 (sd 4.39), with a median score of 0 (range 0-29). The oral problems 'oral blisters/aphthae' (25.9%) and 'bad odor/halitosis' (23.3%) were significantly more often reported in CCS than in comparison groups (12% and 12%, respectively). The OHIP-14 score was significantly correlated with the number of self-reported oral health problems (r = .333, p<0.0005) and dental problems (r = .392, p <0.0005). In multivariable analysis, CCS with a shorter time since diagnosis (10-19 years vs. >= 30 years) had a 1.47-fold higher risk of >= 1 oral health problem.ConclusionThough the perceived oral health is relatively good, oral complications following childhood cancer treatment are prevalent in CCS. This underlines that attention to impaired oral health and awareness on this topic is mandatory and regular visits to the dentist should be a part of long-term follow-up care. Show less
Transcriptome signature reversion (TSR) has been extensively proposed and used to discover new indications for existing drugs (i.e. drug repositioning, drug repurposing) for various cancer types.... Show moreTranscriptome signature reversion (TSR) has been extensively proposed and used to discover new indications for existing drugs (i.e. drug repositioning, drug repurposing) for various cancer types. TSR relies on the assumption that a drug that can revert gene expression changes induced by a disease back to original, i.e. healthy, levels is likely to be therapeutically active in treating the disease. Here, we aimed to validate the concept of TSR using the PRISM repurposing data set, which is-as of writing-the largest pharmacogenomic data set. The predictive utility of the TSR approach as it has currently been used appears to be much lower than previously reported and is completely nullified after the drug gene expression signatures are adjusted for the general anti-proliferative downstream effects of drug-induced decreased cell viability. Therefore, TSR mainly relies on generic anti-proliferative drug effects rather than on targeting cancer pathways specifically upregulated in tumor types. Show less
This thesis aimed to find opportunities to improve proactivity and patient-centredness in palliative care, focussing on education and care outcomes. The 2009 national blueprint on medical education... Show moreThis thesis aimed to find opportunities to improve proactivity and patient-centredness in palliative care, focussing on education and care outcomes. The 2009 national blueprint on medical education and the Dutch medical curricula did not comprise all essential elements about end-of-life care. Factors associated with approaching death in patients with advanced cancer visiting the LUMC’s Emergency Department (ED) in the last three months of life were lung cancer, neurologic deterioration, dyspnoea, hypercalcemia and jaundice. Patients with haematological malignancies received more potentially inappropriate care than advanced cancer patients. They rarely had limitations on life-sustaining treatments, although they often died of disease progression or treatment toxicity. The surprise question (SQ) is a simple tool to identify patients with palliative care needs . Adding poor performance status to the SQ improved the predictive value for one-year mortality in advanced cancer patients visiting the LUMC’s ED. The Leiden Guide on Palliative Care (LGP) was developed by the Centre of Expertise in Palliative Care to assess symptom burden and information needs. Patients and family wanted information about current problems and about their worries. Patients, family and clinicians found the LGP helpful. Using their input, the LGP was improved for use by generalist palliative care clinicians. Show less
Court, J.R. de la; Bruns, A.H.W.; Roukens, A.H.E.; Bass, I.O.; Steeg, K. van; Toren-Wielema, M.L.; ... ; Heijmans, J. 2022
Introduction This guideline was written by a multidisciplinary committee with mandated members of the Dutch Society for Infectious Diseases, Dutch Society for Hematology, Dutch Society for Medical... Show moreIntroduction This guideline was written by a multidisciplinary committee with mandated members of the Dutch Society for Infectious Diseases, Dutch Society for Hematology, Dutch Society for Medical Oncology, Dutch Association of Hospital Pharmacists, Dutch Society for Medical Microbiology, and Dutch Society for Pediatrics. The guideline is written for adults and pediatric patients. Method The recommendations are based on the answers to nine questions formulated by the guideline committee. To provide evidence-based recommendations we used all relevant clinical guidelines published since 2010 as a source, supplemented with systematic searches and evaluation of the recent literature (2010-2020) and, where necessary, supplemented by expert-based advice. Results For adults the guideline distinguishes between high- and standard-risk neutropenia based on expected duration of neutropenia (> 7 days versus <= 7 days). Where possible a distinction has been made between pediatric and adult patients. Conclusion This guideline was written to aid diagnosis and management of patients with febrile neutropenia due to chemotherapy in the Netherlands. The guideline provides recommendation for children and adults. Adults patient are subdivided as having a standard- or high-risk neutropenic episode based on estimated duration of neutropenia. The most important recommendations are as follows. In adults with high-risk neutropenia (duration of neutropenia > 7 days) and in children with neutropenia, ceftazidime, cefepime, and piperacillin-tazobactam are all first-choice options for empirical antibiotic therapy in case of fever. In adults with standard-risk neutropenia (duration of neutropenia <= 7 days) the MASCC score can be used to assess the individual risk of infectious complications. For patients with a low risk of infectious complications (high MASCC score) oral antibiotic therapy in an outpatient setting is recommended. For patients with a high risk of infectious complications (low MASCC score) antibiotic therapy per protocol sepsis of unknown origin is recommended. Show less
In this thesis, we aimed to develop and validate a patient and a physician questionnaire to measure the shared decision making (SDM) process in oncology. We identified SDM measurement challenges:... Show moreIn this thesis, we aimed to develop and validate a patient and a physician questionnaire to measure the shared decision making (SDM) process in oncology. We identified SDM measurement challenges: there is limited evidence on measurement properties, patients’ role is not assessed while it is present in SDM models, patients and healthcare professionals have been involved only to a limited extent in the development of SDM measurement instruments, and a reflective measurement model is often assumed, while a formative might be more appropriate. The aim of this thesis was therefore to develop and validate questionnaires to assess the SDM process in oncology from both the patient and the physician viewpoints. We chose the oncology setting because it is a setting in which patients often face preference-sensitive decisions, and in which most patients prefer an active or collaborative role in treatment decision making. To inform the development and validation process of our questionnaires, we used the original Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist and we wrote two reviews: one on existing SDM measurement instruments and one on existing SDM models. The iSHARE questionnaires shows adequate measurement properties Show less
Objectives: We have developed two Dutch questionnaires to assess the shared decision-making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine:... Show moreObjectives: We have developed two Dutch questionnaires to assess the shared decision-making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine: scores, construct validity, test-retest agreement (iSHAREpatient), and inter-rater (iSHAREpatient-iSHAREphysician) agreement. Methods: Physicians from seven Dutch hospitals recruited cancer patients, and completed the iSHAREphysician and SDM-Questionnaire-physician version. Their patients completed the: iSHAREpatient, nine-item SDM-Questionnaire, Decisional Conflict Scale, Combined Outcome Measure for Risk communication And treatment Decision-making Effectiveness, and five-item Perceived Efficacy in Patient-Physician Interactions. We formulated, respectively, one (iSHAREphysician) and 10 (iSHAREpatient) a priori hypotheses regarding correlations between the iSHARE questionnaires and questionnaires assessing related constructs. To assess test-retest agreement patients completed the iSHAREpatient again 1-2 weeks later. Results: In total, 151 treatment decision-making processes with unique patients were rated. Dimension and total iSHARE scores were high both in patients and physicians. The hypothesis on the iSHAREphysician and 9/10 hypotheses on the iSHAREpatient were confirmed. Test-retest and inter-rater agreement were >.60 for most items. Conclusions: The iSHARE questionnaires show high scores, have good construct validity, substantial test-retest agreement, and moderate inter-rater agreement. Practice implications: Results from the iSHARE questionnaires can inform both physician- and patient-directed efforts to improve SDM in clinical practice. Show less
Purpose: Individuals with gray, blue, or green eyes have a higher chance of developing uveal melanoma (UM) than those with brown eyes. We wondered whether iris pigmentation might be related not... Show morePurpose: Individuals with gray, blue, or green eyes have a higher chance of developing uveal melanoma (UM) than those with brown eyes. We wondered whether iris pigmentation might be related not only to predisposition to UM but also to its behavior; therefore, we compared the clinical, histopathologic, and genetic characteristics of UM between eyes with different colors. Design: We determined iris color in a large cohort of patients enucleated for UM. Clinical and histopathologic tumor characteristics, chromosome status, and survival were compared among 3 groups on the basis of iris color. Participants: A total of 412 patients with choroidal/ciliary body UM, who had undergone primary enucleation at the Leiden University Medical Center, Leiden, The Netherlands, between 1993 and 2019, were divided into 3 groups based on iris color: gray/blue, green/hazel, and brown. The validation cohort included 934 patients with choroidal/ciliary body UM treated at Wills Eye Hospital (WEH). Methods: Comparison of clinical, histopathologic, and genetic characteristics of UM in patients with different iris colors. Main Outcome Measures: Melanoma-related survival in UM patients, divided over 3 iris color groups, in relation to the tumor's chromosome 3 and 8q status. Results: Moderate and heavy tumor pigmentations were especially seen in eyes with a brown iris (P < 0.001). Survival did not differ between patients with different iris colors (P = 0.27); however, in patients with a light iris, copy number changes in chromosome 3 and 8q had a greater influence on survival than in patients with a dark iris. Likewise, chromosome 3 and chromosome 8q status affected survival more among patients with lightly pigmented tumors than in patients with heavily pigmented tumors. The WEH cohort similarly showed a greater influence of chromosome aberrations in light-eyed individuals. Conclusions: Although iris color by itself did not relate to UM-related survival, chromosome 3 and 8q aberrations had a larger influence on survival in patients with a light iris than those with a brown iris. This suggests a synergistic effect of iris pigmentation and chromosome status in the regulation of oncogenic behavior of UM. Iris color should be taken into consideration when calculating a patient's risk for developing metastases. (C) 2021 by the American Academy of Ophthalmology. Show less
Purpose: Uveal melanoma (UM) is a rare disease and the most common primary intraocular malignancy in adults, with a high risk of metastases. Reliable prognostication systems are based on anatomic... Show morePurpose: Uveal melanoma (UM) is a rare disease and the most common primary intraocular malignancy in adults, with a high risk of metastases. Reliable prognostication systems are based on anatomic features, as in the tumor-node-metastasis staging of the American Joint Committee on Cancer (AJCC) system, or on genetic information, as in The Cancer Genome Atlas (TCGA) system. Prior evidence suggests that combining both systems may be beneficial. We evaluated the benefit of combining the TCGA and AJCC systems in a large cohort of patients.Design: Retrospective case series of patients with UM.Participants: Nine hundred seventy-nine patients with a choroidal or ciliary body melanoma treated at the Wills Eye Hospital between 1998 and 2020, 94% of whom received eye-sparing treatment.Methods: Tumors were classified into 4 TCGA groups based on chromosome copy number: A (disomy 3, normal 8q), B (disomy 3, any 8q gain), C (monosomy 3, 1 extra copy of 8q), and D (monosomy 3, multiple 8q gain). The eighth edition of the AJCC staging manual was used for AJCC staging. Cox regression and the log-rank test were used for survival analysis.Main Outcome Measure: Metastasis-free survival.Results: Combining information of the 2 systems improved prognostication in intermediate groups: in TCGA group C, we saw an increased rate of metastasis in AJCC stage III (28%) compared with stage 11 (8.9%); the same was seen in AJCC stage II, going from TCGA group C (8.9%) to group D (46%), and in AJCC stage III, going from group C (28%) to group D (49%). In patients with AJCC stage II or III disease, loss of chromosome 3 and gain of 8q (TCGA groups C and D) significantly worsened the prognosis, with multiple 8q gain (TCGA group D) having a greater impact.Conclusions: Combining information from AJCC stages and TCGA groups yields a better predictive power even in this set of relatively small tumors. We propose that physicians take both systems into account whenever possible, especially in moderate-risk groups. (C) 2021 by the American Academy of Ophthalmology. Show less
Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis have been remarkably successful in inducing tumor remissions in... Show moreImmune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis have been remarkably successful in inducing tumor remissions in several human cancers, yet a substantial number of patients do not respond to treatment. Because this may be partially due to the mechanisms giving rise to high PD-L1 expression within a patient, it is highly relevant to fully understand these mechanisms. In this study, we conduct a bioinformatic analysis to quantify the relative importance of transcription factor (TF) activity, microRNAs (miRNAs) and mutations in determining PD-L1 (CD274) expression at mRNA level based on data from the Cancer Genome Atlas. To predict individual CD274 levels based on TF activity, we developed multiple linear regression models by taking the expression of target genes of the TFs known to directly target PD-L1 as independent variables. This analysis showed that IRF1, STAT1, NFKB and BRD4 are the most important regulators of CD274 expression, explaining its mRNA levels in 90-98% of the patients. Because the remaining patients had high CD274 levels independent of these TFs, we next investigated whether mutations associated with increased CD274 mRNA levels, and low levels of miRNAs associated with negative regulation of CD274 expression could cause high CD274 levels in these patients. We found that mutations or miRNAs offered an explanation for high CD274 levels in 81-100% of the underpredicted patients. Thus, CD274 expression is largely explained by TF activity, and the remaining unexplained cases can largely be explained by mutations or low miRNA abundance. Show less
Although clinical aspects of melanoma have been extensively studied, the literature largely concerns relatively healthy 20-70 years old patients. Special populations, such as the elderly, children,... Show moreAlthough clinical aspects of melanoma have been extensively studied, the literature largely concerns relatively healthy 20-70 years old patients. Special populations, such as the elderly, children, patients with multiple primary melanoma and those with familial melanoma, are frequently excluded from clinical studies. The studies presented in this thesis were aimed to assess prognostic factors and management of patients with clinically localized melanoma, in particular among the aforementioned special populations. Show less
Background Anti-cancer drugs commonly adversely affect fertility and sexual function. Despite this, patients report a lack of counselling of these potential adverse effects. The aim was to... Show moreBackground Anti-cancer drugs commonly adversely affect fertility and sexual function. Despite this, patients report a lack of counselling of these potential adverse effects. The aim was to determine Dutch oncologists' knowledge about the adverse effects of various cancer drugs on fertility and sexual function. Methods A cross-sectional survey was sent to members of the Dutch Society for Medical Oncology (n = 433). The survey questions included various cancer drugs' adverse effects on fertility, ovulation, spermatogenesis, and sexual function. Results One hundred and five of 392 oncologists responded (26.8%). Oncologists were more aware of the adverse effects on fertility compared to sexual function. Drugs that were mostly believed to negatively affect fertility were cisplatin (n = 81, 80.2%), epirubicin (n = 78, 78.0%) and cyclophosphamide (n = 80, 77.7%). Regarding sexual function, most mentioned drugs were tamoxifen (n = 67, 65.7%), GnRH-agonists (n = 64, 63.4%) and cisplatin (n = 58, 57.4%). Oncologists with expertise in urology possessed more awareness regarding sexuality-related adverse effects (cisplatin p = 0.038, etoposide p = 0.025, ifosfamide p = 0.06, vinblastine p = 0.000). Conclusion Results revealed that oncologists have different beliefs about possible sexual and fertility-related adverse effects concerning medication resources and literature. Based on our results, oncologists do not possess sufficient knowledge to inform patients about sexual and fertility-related adverse effects. Show less
Part I - Hepatic perfusion for the treatment of unresectable liver metastasesBecause the majority of metastasized uveal melanoma (UM) patients have unresectable liver only metastases, locoregional... Show morePart I - Hepatic perfusion for the treatment of unresectable liver metastasesBecause the majority of metastasized uveal melanoma (UM) patients have unresectable liver only metastases, locoregional therapy was developed. In this thesis percutaneous hepatic perfusion (PHP) is described as a treatment for these patients. During this procedure, the chemotherapeutic agent is infused in the hepatic artery and thereby delivered to the liver and metastases directly. Via a veno-venous filtration system, the chemotherapeutic agent is filtered before it reaches the systemic circulation. In this thesis a clinical study was described treating 20 UM patients with metastases confined to the liver with PHP. It was concluded that the results PHP outbalanced the (minimal) toxicity for patients with uveal melanoma metastases.Part II - Tailored care for patients with pancreatic cancerThe poor prognosis of pancreatic cancer did not change much over the last decades, despite the improvements in treatment modalities. Previous studies have reported variations in incidence and mortality in pancreatic cancer between countries worldwide and European countries. A collaboration was initiated across Europe to compare patterns of care and identify best practices for pancreatic cancer care. A core dataset was identified to identificate differences in age, gender, incidence, tumour stage and differences in treatment strategies. To identify any differences in treatment and/or survival of elderly patients with pancreatic cancer, a comparison was performed of data on geriatric pancreatic cancer care and survival with data from the Netherlands and a special ‘Senior Adult Oncology Program’. Show less
Sztankay, M.; Wintner, L.M.; Roggendorf, S.; Nordhausen, T.; Dirven, L.; Taphoorn, M.J.B.; ... ; EORTC Quality Life Grp 2021
Purpose Implementation of patient-reported outcome measures (PROMs) in clinical routine requires knowledge and competences regarding their use. In order to facilitate implementation, an e-learning... Show morePurpose Implementation of patient-reported outcome measures (PROMs) in clinical routine requires knowledge and competences regarding their use. In order to facilitate implementation, an e-learning course for health care professionals (HCPs) on the utilisation of European Organisation for Research and Treatment of Cancer (EORTC) PROMs in oncological clinical practice is being developed. This study aimed to explore future users' educational needs regarding content and learning methods. Methods The sequential mixed methods approach was applied. A scoping literature review informed the guideline for qualitative interviews with HCPs with diverse professional backgrounds in oncology and cancer advocates recruited using a purposive sampling strategy. An international online survey was conducted to validate the qualitative findings. Results Between December 2019 and May 2020, 73 interviews were conducted in 9 countries resulting in 8 topic areas (Basic information on PROs in clinical routine, Benefits of PRO assessments in clinical practice, Implementation of PRO assessments in clinical routine, Setup of PRO assessments for clinical application, Interpretation of PRO data, Integration of PROs into the communication with patients, Use of PROs in clinical practice, Self-management recommendations for patients based on PROs) subsequently presented in the online survey. The online survey (open between 3 June and 19 July 2020) was completed by 233 HCPs from 33 countries. The highest preference was indicated for content on interpretation of PRO data (97%), clinical benefits of assessing PRO data (95.3%) and implementation of routine PRO data assessment (94.8%). Regarding learning methods, participants indicated a high preference for practical examples that use a mixed approach of presentation (written, audio, video and interactive). Conclusion Educational needs for an integration of PROs in communication in clinical care and coherent implementation strategies became evident. These results inform the development of an e-learning course to support HCPs in the clinical use of EORTC PRO measures. Show less
Background: The combination treatment regimen of thermal ablation (TA) and transarterial chemoembolization (TACE) has gained a place in treatment of hepatocellular carcinoma (HCC) lesions > 3 cm... Show moreBackground: The combination treatment regimen of thermal ablation (TA) and transarterial chemoembolization (TACE) has gained a place in treatment of hepatocellular carcinoma (HCC) lesions > 3 cm unsuitable for surgery. Despite a high heterogeneity in the currently used treatment protocols, the pooled results of combined treatments seem to outperform those of TA or TACE alone. TACE preceding TA has been studied extensively, while results of the reverse treatment sequence are lacking. In this retrospective cohort study we compared the two treatment sequences. Patients and methods: 38 patients (median age: 68.5 yrs (range 40-84), male: 34, liver cirrhosis: 33, early stage HCC: 21, intermediate stage HCC: 17) were included in two tertiary referral centers, of whom 27 were treated with TA and adjuvant TACE (TA + TACE). The other 11 patients received TA with neoadjuvant TACE (TACE + TA). Overall survival (OS), time to progression (TTP) and local tumor progression (LTP) free survival were determined for the entire cohort and compared between the two treatment sequences. Results: The median OS of all patients was 52.7 months and the median time to LTP was 11.5 months (censored for liver transplantation). No differences were found with respect to OS between the two treatment sequences. Median time to LTP for TACE + TA was 23.6 months and 8.1 months for TA + TACE (p = 0.19). Discussion: No statistical differences were found for OS, TTP and time to LTP between patients treated with TA combined with neoadjuvant or adjuvant TACE. Show less
In this thesis, mathematical modeling and simulation was applied as a tool to inform quantitative decision making in oncology drug discovery and development. Modeling based approaches were shown to... Show moreIn this thesis, mathematical modeling and simulation was applied as a tool to inform quantitative decision making in oncology drug discovery and development. Modeling based approaches were shown to be useful to understand the mechanism of action and deconvolve the complexities of novel biotherapeutic modalities being used to treat cancer, including monospecific and bispecific monoclonal antibodies and antibody drug conjugates. Several key observations and learnings were made. For example, modeling was shown to be a useful method to reduce animal experimentation, by enabling in vitro to in vivo correlations or use of simulation to replace experimental methodologies. Mechanism based modeling and simulation was found to be a useful means to translate from preclinical studies to the clinic to ensure progression of the best drug to clinical trials. These models could then be used to optimize design of clinical studies from selection of starting doses to recommended efficacious doses for pivotal trials. Modeling was shown to be beneficial to understand variability in the clinic and to identify factors impacting drug response in individual patients, paving the way for precision medicine strategies, informing clinical diagnostics, biomarkers, and doses for different oncology indications. Show less
Zaks, O.; Gaber, D.; Ben-Yaakov, K.; Sharvit-Bader, M.; Goz, A.; Rotfogel, Z.; ... ; Aharoni-Simon, M. 2021
Uveal melanoma (UM) and conjunctival melanoma (CM) are ocular malignancies that give rise to life-threatening metastases. Although local disease can often be treated successfully, it is often... Show moreUveal melanoma (UM) and conjunctival melanoma (CM) are ocular malignancies that give rise to life-threatening metastases. Although local disease can often be treated successfully, it is often associated with significant vision impairment and treatments are often not effective against metastatic disease. Novel treatment modalities that preserve vision may enable elimination of small tumors and may prevent subsequent metastatic spread.Very few mouse models of metastatic CM and UM are available for research and for development of novel therapies. One of the challenges is to follow tumor growth in-vivo and to determine the right size for treatment, mainly of the posterior, choroidal melanoma. Hence, the purpose of this study was to establish a simple, noninvasive imaging tool that will simplify visualization and tumor follow-up in mouse models of CM and UM.Tumors were induced by inoculation of murine B16LS9 cells into the sub-conjunctival or the choroidal space of a C57BL/6 mouse eye under a surgical microscope. Five to ten days following injection, tumor size was assessed by Phoenix MicronIVTM image-guided Optical Coherence Tomography (OCT) imaging, which included a realtime camera view and OCT scan of the conjunctiva and the retina. In addition, tumor size was evaluated by ultrasound and histopathological examination of eye sections.Tumor growth was observed 5-9 days following sub-conjunctival or sub-retinal injection of seven-thousand or seventy-thousand cells, respectively. A clear tumor mass was detected at these regions using the MicronIVTM imaging system camera and OCT scans. Histology of eye sections confirmed the presence of tumor tissue. OCT allowed an accurate measurement of tumor size in the UM model and a qualitative assessment of tumor size in the CM model. Moreover, OCT enabled assessing the success rate of the choroidal tumor induction and importantly, predicted final tumor size already on the day of cell inoculation.In conclusion, by using a simple, non-invasive imaging tool, we were able to follow intraocular tumor growth of both CM and UM, and to define, already at the time of cell inoculation, a grading scale to evaluate tumor size. This tool may be utilized for evaluation of new mouse models for CM and UM, as well as for testing new therapies for these diseases. Show less
