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01 juli 2023, Contains fulltext : 294939.pdf (Publisher’s version ) (Open Access), PURPOSE: To evaluate guideline adherence and variation in the recommended use of neoadjuvant chemotherapy (NAC) and the effects of this variation on survival in patients with non-metastatic muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: In this nationwide, Netherlands Cancer Registry-based study, we identified 1025 patients newly diagnosed with non-metastatic MIBC between November 2017 and November 2019 who underwent radical cystectomy. Patients with ECOG performance status 0-1 and creatinine clearance ≥ 50 mL/min/1.73 m(2) were considered NAC-eligible. Interhospital variation was assessed using case-mix adjusted multilevel analysis. A Cox proportional hazards model was used to evaluate the association between hospital specific probability of using NAC and survival. All analyses were stratified by disease stage (cT2 versus cT3-4a). RESULTS: In total, of 809 NAC-eligible patients, only 34% (n = 277) received NAC. Guideline adherence for NAC in cT2 was 26% versus 55% in cT3-4a disease. Interhospital variation was 7-57% and 31-62%, respectively. A higher hospital specific probability of NAC might be associated with a better survival, but results were not statistically significant (HR(cT2) = 0.59, 95% CI 0.33-1.05 and HR(cT3-4a) = 0.71, 95% CI 0.25-2.04). CONCLUSION: Guideline adherence regarding NAC use is low and interhospital variation is large, especially for patients with cT2-disease. Although not significant, our data suggest that survival of patients diagnosed in hospitals more inclined to give NAC might be better. Further research is warranted to elucidate the underlying mechanism. As literature clearly shows the potential survival benefit of NAC in patients with cT3-4a disease, better guideline adherence might be pursued.

Item does not contain fulltext, Dit case report betreft een patiënt met hematurie ten gevolge van een kiemceltumor van de linker testis, welke doorgroeide in de blaaswand. Mannen met een niet-ingedaalde testis hebben een verhoogde kans op het ontwikkelen van een testiculaire kiemceltumor. Bij de 67-jarige patiënt in deze casus werd tijdens cystoscopie een tumor in de blaas gevonden. De patiënt onderging een diagnostische transurethrale resectie van de tumor, laboratoriumonderzoek en een CT-scan, op grond waarvan een stadium 2‑good-risk seminoom van de testis werd gediagnosticeerd. De patiënt werd behandeld met vier cycli van etoposide en cisplatine met nadien een open chirurgische resectie van de restlaesie. Het herstel verliep ongecompliceerd. Bij beeldvorming na zes maanden waren er geen tekenen van een recidief.

Item does not contain fulltext, PURPOSE: Testicular cancer (TC) treatment is clearly associated with cardiovascular morbidity and mortality. To enable development of preventive strategies for cardiovascular disease (CVD), we assessed cardiometabolic risk factors and quality of life (QoL) in TC survivors. METHODS: Incidence of coronary artery disease, myocardial infarction, and heart failure after TC treatment was assessed in a multicenter cohort comprising 4,748 patients treated at the age of 12-50 years between 1976 and 2007. Patients who had developed CVD and a random sample from the cohort (subcohort) received a questionnaire on cardiometabolic risk factors and QoL. A subgroup of responders in the subcohort additionally underwent clinical evaluation of cardiovascular risk factors. RESULTS: After a median follow-up of 16 years, 272 patients had developed CVD. Compared with orchidectomy only, cisplatin combination chemotherapy was associated with an increased CVD risk (hazard ratio [HR], 1.9; 95% CI, 1.1 to 3.1). Patients who were obese or a smoker at diagnosis (HR, 4.6; 95% CI, 2.0 to 10.0 and HR, 1.7; 95% CI, 1.1 to 2.4, respectively), developed Raynaud's phenomenon (HR, 1.9; 95% CI, 1.1 to 3.6) or dyslipidemia (HR, 2.8; 95% CI, 1.6 to 4.7) or had a positive family history for CVD (HR, 2.9; 95% CI, 1.7 to 4.9) had higher CVD risk. More TC survivors with CVD reported inferior QoL on physical domains than survivors who did not develop CVD. Of 304 TC survivors who underwent clinical evaluation for cardiovascular risk factors (median age at assessment: 51 years), 86% had dyslipidemia, 50% had hypertension, and 35% had metabolic syndrome, irrespective of treatment. CONCLUSION: Cardiovascular events in TC survivors impair QoL. Many TC survivors have undetected cardiovascular risk factors. We advocate early lifestyle adjustments and lifelong follow-up with low-threshold treatment of cardiovascular risk factors, especially in obese and smoking patients treated with platinum-based chemotherapy.

Contains fulltext : 247667.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, BACKGROUND: Pazopanib and sunitinib are oral tyrosine kinase inhibitors (TKI) approved for the treatment of renal cell carcinoma. For both oncolytics, a clear target trough concentration level in plasma has been defined above which improved clinical efficacy can be expected. However, many factors can alter TKI exposure, including disease characteristics. CASE: A 79-year old male with metastatic papillary renal cell carcinoma and malignant ascites was treated with pazopanib. Initially, treatment with pazopanib at adequate trough concentrations resulted in regression of ascites. After a 6-month puncture-free interval, paracenteses were again required and the plasma trough concentration of pazopanib had decreased to 5 mg/L without any dose adjustments. Despite a dose increase, pazopanib levels remained subtherapeutic and could not prevent new paracenteses. Pazopanib concentrations in the drained ascites fluid were comparable to plasma concentrations and remained high also after treatment discontinuation. This observation suggests that the ascites compartment may act as a third space in which pazopanib accumulates. During subsequent treatment with sunitinib, a similar distribution over ascites fluid was observed. CONCLUSION: Presence of ascites or pleural effusion in patients treated with TKIs may lead to subtherapeutic plasma exposure, which may hamper treatment efficacy. Measuring TKIs plasma concentrations regularly during treatment is essential to identify patients with subtherapeutic exposure.

Contains fulltext : 252025.pdf (Publisher’s version ) (Open Access), OBJECTIVE: The shared decision-making (SDM) process for the treatment of pancreatic and oesophageal cancer primarily takes place with healthcare professionals (HCPs) in the hospital setting. This study aims to explore the perspectives of general practitioners (GPs) on their possible roles during this SDM process, their added value and their requirements for involvement in SDM. METHODS: Semi-structured interviews were conducted with 12 GPs about their views on SDM for patients with cancer. The interviews were analysed by two researchers using an inductive open coding approach. RESULTS: Five potential roles in SDM were described by the interviewed GPs, of which the role as 'coach' of the patient was mentioned by all. GPs see their main added value as their long-standing relationship with the patient. To be able to participate optimally in SDM, GPs indicated that they need to be kept up to date during the patient's care process and should receive enough medical information about treatment options and contextual information. CONCLUSION: GPs see different potential roles for themselves when involved in SDM. Hospital HCPs that want to facilitate GP involvement should take the initiative, provide the GPs with enough and timely information and must be easy to consult.

Contains fulltext : 231080.pdf (publisher's version ) (Open Access)

Contains fulltext : 232106.pdf (Publisher’s version ) (Open Access), AIM: Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Because of the large interpatient pharmacokinetic variability and established exposure-response and exposure-toxicity relationships in clinical trial patients, therapeutic drug monitoring (TDM) seems promising for optimizing sunitinib exposure. We aimed to investigate the relationship between sunitinib exposure and treatment outcome in a real-world patient cohort. METHODS: We performed a retrospective observational cohort study in 53 patients with metastatic RCC and 18 patients with metastatic GIST treated with sunitinib and receiving TDM-guided dosing. Time on treatment - as a surrogate for progression-free survival - in patients who achieved adequate sunitinib exposure was compared with patients who did not. Additionaly, the median sunitinib exposure was compared in patients with or without sunitinib-induced toxicity leading to dose reduction. RESULTS: The median time on treatment in patients with RCC who achieved adequate sunitinib exposure (n = 39) was 32 weeks, compared to 15 weeks in patients who did not achieve adequate sunitinib exposure (n = 12) (P = 0.244). In 29 patients (41%) with toxicity leading to dose reduction, sunitinib sum plasma trough concentration (C(trough) ) until dose reduction was significantly higher compared to patients without toxicity leading to dose reduction (median 60 ng/mL vs 44 ng/mL; P < 0.001) and reduced to comparable levels after dose reduction (44 ng/mL; P = 0.488). CONCLUSION: In our real-world patient cohort, patients with sunitinib-induced toxicity requiring dose reduction had significantly higher sunitinib exposure compared to patients without toxicity. The threshold for toxicity, however, was lower compared to that previously described in clinical trials.

Contains fulltext : 236936.pdf (Publisher’s version ) (Closed access)

Background: Testicular cancer (TC) survivors have an increased risk of various second primary malignancies. A recent cohort study detected an increased risk of colorectal cancer (CRC) in TC survivors treated with platinum-based chemotherapy with a hazard ratio of 3.9. CRC risk increased with higher cisplatin-dose. We know that colonoscopy surveillance in high-risk populations results in reduced incidence and mortality of CRC. TC survivors treated with platinum-based chemotherapy can potentially benefit from colonoscopy surveillance; however, to which extent is unknown. Furthermore, the pathogenesis of these secondary CRCs is unknown, and better insights into the carcinogenesis may affect surveillance decisions. Methods: This prospective multicenter study will be performed in four Dutch hospitals. TC survivors are eligible if treated with ≥ 3 cycles of cisplatin before age 50. Colonoscopy will be performed ≥ 8 years after initial treatment (minimum and maximum ages at colonoscopy, 35 and 75 years, respectively). The primary aim of the study is the diagnostic yield of advanced neoplasia detected during colonoscopy. As secondary aim, we will evaluate the molecular profile of advanced colorectal neoplasia and will assess current platinum levels in blood and urine and correlate blood-platinum levels with prevalence of colorectal lesions. Furthermore, we will investigate effectiveness of fecal immunochemical testing (FIT) and burden of colonoscopy by two questionnaires. Demographic data, previous history, results of colonoscopy, hemoglobin level of FIT and results of molecular and platinum levels will be obtained. Yield of colonoscopy will be determined by detection rate of adenoma and serrated lesions, advanced adenoma detection rate and CRC detection rate. The MISCAN model will be used for cost-effectiveness analyses of CRC surveillance. With 234 participants undergoing colonoscopy, we can detect an absolute difference of 6% of advanced neoplasia with 80% power. Discuss

Contains fulltext : 229162.pdf (Publisher’s version ) (Closed access), OBJECTIVES: Radical cystectomies (RCs) are increasingly centralized, but bladder cancer can be diagnosed in every hospital The aim of this study is to assess the variation between hospitals of diagnosis in a patient's chance to undergo a RC before and after the volume criteria for RCs, to identify factors associated with this variation and to assess its effect on survival. METHODS AND MATERIALS: Patients diagnosed with muscle-invasive bladder cancer (cT2-4a,N0/X,M0/X) without nodal or distant metastases between 2008 and 2016 were identified through the Netherlands Cancer Registry. Multilevel logistic regression analysis was used to investigate the hospital specific probability of undergoing a cystectomy. Cox proportional hazard regression analysis was used to assess the case-mix adjusted effect of hospital-specific probabilities on survival. RESULTS: Of the 9,215 included patients, 4,513 (49%) underwent a RC. The percentage of RCs varied between 7% and 83% by hospital of diagnosis before the introduction of the first volume criteria (i.e., 2008-2009; minimum of 10 RCs). This variation decreased slightly to 17%-77% after establishment of the second volume criteria (i.e., 2015-2016; minimum of 20 RCs). Age, cT-stage and comorbidity were inversely and socioeconomic status was positively associated with RC. Both being diagnosed in a community hospital and/or being diagnosed in a hospital fulfilling the RC volume criteria were associated with increased use of RC compared to academic hospitals and hospitals not fulfilling the volume criteria. For each 10% increase in the percentage of RC in the hospital of diagnosis, 2-year case-mix adjusted survival increased 4% (hazard ratio 0.96, 95% confidence interval 0.94-0.98). CONCLUSION: Probability of RC varied between hospitals of diagnosis and affected 2-year overall survival. Undergoing a RC was associated with age, cT-stage, socioeconomic status, type of hospital, and whether the hospital of diagnosis fulfilled the RC volume

Contains fulltext : 218257.pdf (Publisher’s version ) (Open Access), BACKGROUND AND PURPOSE: The aim of this study was to assess the prevalence of cancer and its characteristics in patients with ischemic stroke and to compare this with cancer prevalence in the general population. METHODS: This was a multicenter cohort study with 2736 patients presenting with ischemic stroke or transient ischemic attack. The prevalence of cancer was assessed by interview and verified by reviewing all medical records. In stroke patients with a history of cancer, we studied the subtype of cancer and its treatment characteristics. We used the national database of The Netherlands Cancer Registry to calculate population-based age and sex cancer standardized prevalence ratios (SPRs) for patients with ischemic stroke. RESULTS: Cancer prevalence in ischemic stroke patients was 12%, corresponding to an SPR of 1.2 [95% confidence interval (CI), 1.0-1.3]. Increased SPRs were observed for cancer of the central nervous system (SPR, 18.2; 95% CI, 9.0-27.4), head and neck (SPR, 3.4; 95% CI, 2.3-4.6), lower respiratory tract (SPR, 2.4; 95% CI, 1.5-3.3) and urinary tract (SPR, 2.1; 95% CI, 1.4-2.9), but not for other cancer types. Cardiovascular risk factors, stroke etiology, treatment and outcome were not different between patients with or without a history of cancer. CONCLUSIONS: In stroke patients, the prevalence of cancer, most prominently cancer of the central nervous system, head and neck, lower respiratory and urinary tract, was higher than in the general population. Medical treatment for the prevention of stroke in cancer survivors deserves further study.

Contains fulltext : 208839.pdf (publisher's version ) (Closed access), Pazopanib is taken fasted in a fixed oral daily dose of 800 mg. We hypothesized that ingesting pazopanib with food may improve patients' comfort and reduce gastrointestinal (GI) adverse events. Therefore, we investigated the bioequivalent dose of pazopanib when taken with food compared with 800 mg pazopanib taken fasted. In addition, we investigated the differences in GI toxicity, patient satisfaction, and patient's preference for either intake. The intake of 600 mg pazopanib with food resulted in a bioequivalent exposure and was preferred over a standard pazopanib dose without food. No differences were seen in GI toxicities under both intake regimens. Patients seem to be more positive about their feelings about side effects and satisfaction with their therapy when pazopanib was taken with food. Forty-one of the patients (68%) preferred the intake with a continental breakfast.

Contains fulltext : 194749.pdf (publisher's version ) (Closed access)

In dit eindwerkstuk wordt de volgende vraag beantwoord: Hoe verhoudt de narratieve constructie van identiteit zich tot ‘ontplaatsing’ in de dichtbundel Habitus van Radna Fabias? Aan de hand van theorie wordt een beeld geschetst van de relatie tussen ontplaatsing, literatuur en identiteit. Hieruit volgt dat literatuur een middel is tot het omgaan met ontplaatsing en het vormen van een identiteit. Deze identiteit is in de context van ontplaatsing echter meerduidig. Deze meerduidigheid wordt gereproduceerd in poezië, waaruit een ambigue narratieve identiteit volgt. Uit de analyse van de bundel blijkt dat de identiteit van het lyrisch subject wordt opgebouwd door middel van verschillende maskers en rollen. Ieder masker draagt bij aan narratief van ontplaatsing en overstijgt tevens dit narratief.

Item does not contain fulltext, AIM: Fixed dose oral tyrosine kinase inhibitors imatinib, sunitinib and pazopanib show a high interpatient variability in plasma exposure. A relationship between plasma exposure and treatment outcome has been established, which supports the rationale for dose optimization of these drugs. The aim of this study was to monitor how many patients reached adequate trough levels after therapeutic drug monitoring-based dose optimization in daily practice. METHODS: A cohort study was performed in patients treated with imatinib, sunitinib or pazopanib of whom follow-up drug levels were measured between August 2012 and April 2016. Patients' characteristics were collected by reviewing electronic patient records. Drug levels were measured using high-performance liquid chromatography coupled with tandem mass spectrometry and trough levels were estimated using a predefined algorithm. Dose interventions were proposed based on trough levels. RESULTS: In total, 396 trough levels were determined in 109 patients. Median sample frequency per patient was 3. During the first measurement only 38% of patients showed trough levels within the predefined target ranges despite standard dosing; 52% of the patients showed drug levels below and 10% above the target range. In 35 out of 41 patients (85%) dose interventions led to adequate trough levels. Eventually, 64% of the total cohort reached adequate trough levels. CONCLUSIONS: Dose optimization proved an effective tool to reach adequate trough levels in patients treated with imatinib, sunitinib and pazopanib. The percentage of patients with adequate trough levels increased from 38 to 64%. Therapeutic drug monitoring may add to the improvement of efficacy and reduction of toxicity and costs of these treatments.

Item does not contain fulltext, Despite advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC), there is still an unmet need in the treatment of this disease. A phase 2 radioimmunotherapy (RIT) trial with lutetium 177 ((177)Lu)-girentuximab was initiated to evaluate the efficacy of this approach. In this nonrandomized single-arm trial, patients with progressive metastatic ccRCC who met the inclusion criteria received 2405 MBq/m(2) of (177)Lu-girentuximab intravenously. In the absence of persistent toxicity and progressive disease, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. A total of 14 patients were included. After the first therapeutic infusion, eight patients (57%) had stable disease (SD) and one (7%) had a partial regression. The treatment was generally well tolerated but resulted in grade 3-4 myelotoxicity in most patients. After the second cycle, continued SD was observed in five of six patients, but none were eligible for retreatment due to prolonged thrombocytopenia. In conclusion, RIT with (177)Lu-girentuximab resulted in disease stabilization in 9 of 14 patients with progressive metastatic ccRCC, but myelotoxicity prevented retreatment in some patients. PATIENT SUMMARY: We investigated the efficacy of lutetium 177-girentuximab radioimmunotherapy in patients with metastatic kidney cancer. The treatment resulted in disease stabilization in 9 of 14 patients. The main toxicity was prolonged low blood cell counts. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02002312 (https://clinicaltrials.gov/ct2/show/NCT02002312).

Contains fulltext : 170106.pdf (publisher's version ) (Open Access), Background Diarrhea is a frequently occurring adverse event during treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and is mostly accompanied by abdominal cramps, flatulence and pyrosis. These complaints impair quality of life and lead to dose reductions and treatment interruptions. It is hypothesized that the diarrhea might be due to ischemia in bowel mucosa or inflammation, but the exact underlying pathophysiological mechanism of the diarrhea is still unknown. We aimed at exploring the mechanism for diarrhea in these patients by thorough endoscopic and histological assessment. Materials and methods Endoscopies of the upper and lower gastrointestinal (GI) tract in 10 patients with metastatic renal cell carcinoma (mRCC) who developed diarrhea during treatment with VEGFR TKIs were performed. Results Ten patients were included. The results showed endoscopically normal mucosa in the lower GI tract in seven patients without signs of ischemic colitis or inflammation. Gastroduodenoscopy revealed gastro-esophageal reflux disease, bulbitis and/or duodenitis with ulcers in eight patients. In three selected patients with bulbitis/duodenitis additional video capsule endoscopy was performed but revealed no additional intestinal abnormalities. Conclusion We observed frequent mucosal abnormalities in the upper GI tract in VEGFR TKI-treated mRCC patients with diarrhea. Although these abnormalities provide insufficient explanation for the occurrence of diarrhea, we suggest to perform routine upper GI endoscopy in VEGFR TKI-treated patients with GI complaints.

Radboud Universiteit Nijmegen, 28 januari 2016, Promotores : Punt, C.J.A., Vissers, K.C.P. Co-promotor : Herpen, C.M.L. van, Contains fulltext : 150189.pdf (publisher's version ) (Open Access)

Contains fulltext : 153018.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 134069.pdf (publisher's version ) (Open Access), Prostate cancer (PCa) is the most common cancer in men and the second most common cause of cancer-related death in men. In recent years, novel therapeutic options for PCa have been developed and studied extensively in clinical trials. Sipuleucel-T is the first cell-based immunotherapeutic vaccine for treatment of cancer. This vaccine consists of autologous mononuclear cells stimulated and loaded with an immunostimulatory fusion protein containing the prostate tumor antigen prostate acid posphatase. The choice of antigen might be key for the efficiency of cell-based immunotherapy. Depending on the treatment strategy, target antigens should be immunogenic, abundantly expressed by tumor cells, and preferably functionally important for the tumor to prevent loss of antigen expression. Autoimmune responses have been reported against several antigens expressed in the prostate, indicating that PCa is a suitable target for immunotherapy. In this review, we will discuss PCa antigens that exhibit immunogenic features and/or have been targeted in immunotherapeutic settings with promising results, and we highlight the hurdles and opportunities for cancer immunotherapy.

Contains fulltext : 136260.pdf (publisher's version ) (Closed access), Malignant ascites and pleural effusion are challenging clinical problems, with a major impact on quality of life. We conducted a randomized phase II trial to assess the palliative value of cediranib, an oral vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). After a baseline paracentesis or thoracentesis (on day 0), patients with symptomatic malignant ascites and/or pleural effusion were randomized between immediate treatment with cediranib (Immediate Cediranib) or delayed treatment with cediranib (Delayed Cediranib) on day 29, or after a new puncture was needed. The primary objective of the study was the puncture-free survival, defined as the time from study start (day 1) to the first need for paracentesis or thoracentesis, or time to death, whichever event occurred first. Twelve patients were enrolled. The median puncture-free survival was 45 days (range 10-368) in the Immediate Cediranib patients and 7 days (range 4-13) in the Delayed Cediranib patients (P = 0.011). The change in puncture-free interval (the puncture-free survival after study start minus the puncture-free interval before study start) increased with a median of 31 days in the Immediate Cediranib patients and shortened with a median of 3 days in the Delayed Cediranib patients (P = 0.015). The most common adverse events were fatigue and anorexia. In conclusion, cediranib increased the puncture-free survival and puncture-free interval with an acceptable toxicity profile. This is the first study in which an oral VEGFR TKI showed beneficial palliative effects in patients with malignant effusions.

Contains fulltext : 134074.pdf (publisher's version ) (Open Access), Background: Impairment of cognitive functioning has been reported in several studies in patients treated with chemotherapy. So far, no studies have been published on the effects of the vascular endothelial growth factor receptor (VEGFR) inhibitors on cognitive functioning. We investigated the objective and subjective cognitive function of patients during treatment with VEGFR tyrosine kinase inhibitors (VEGFR TKI). Methods: Three groups of participants, matched on age, sex and education, were enrolled; 1. metastatic renal cell cancer (mRCC) or GIST patients treated with sunitinib or sorafenib (VEGFR TKI patients n = 30); 2. patients with mRCC not receiving systemic treatment (patient controls n = 20); 3. healthy controls (n = 30). Sixteen neuropsychological tests examining the main cognitive domains (intelligence, memory, attention and concentration, executive functions and abstract reasoning) were administered by a neuropsychologist. Four questionnaires were used to assess subjective cognitive complaints, mood, fatigue and psychological wellbeing. Results: No significant differences in mean age, sex distribution, education level or IQ were found between the three groups. Both patient groups performed significantly worse on the cognitive domains Learning & Memory and Executive Functions (Response Generation and Problem Solving) compared to healthy controls. However only the VEGFR TKI patients showed impairments on the Executive subdomain Response Generation. Effect sizes of cognitive dysfunction in patients using VEGFR TKI were larger on the domains Learning & Memory and Executive Functions, compared to patient controls. Both patients groups performed on the domain Attention & Concentration the same as the healthy controls. Longer duration of treatment on VEGFR TKI was associated with a worse score on Working Memory tasks. Conclusions: Our data suggest that treatment with VEGFR TKI has a negative impact on cognitive functioning, specifically on Learning & Memory, and

Contains fulltext : 133887pub.pdf (publisher's version ) (Closed access), Sunitinib is a multiple tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor pathway and inhibits angiogenesis, cell proliferation, and tumor cell invasion, and stimulates apoptosis. Treatment with sunitinib in first-line metastatic renal cell carcinoma improves progression-free survival and overall survival compared with interferon-alpha. Crohn's disease is characterized by chronic immune-mediated intestinal inflammation. Although the exact pathogenesis of Crohn's disease remains unknown, the involvement of angiogenesis is acknowledged. It is unknown whether sunitinib interferes with the natural course of Crohn's disease. We describe a patient with metastatic renal cell carcinoma and a history of Crohn's disease who was treated with sunitinib and developed a severe exacerbation of Crohn's disease. After rechallenge with sunitinib, a second exacerbation occurred. We therefore conclude that angiogenesis inhibitors should be administered with care in patients with a history of Crohn's disease.

Contains fulltext : 125443.pdf (publisher's version ) (Open Access), BACKGROUND: Bleomycin has become an integral part of chemotherapy in patients with germ-cell tumors. One of the most feared side effects is bleomycin-induced pneumonitis. In patients with mild or moderate BIP, radiological signs disappear almost completely within nine months after discontinuation of bleomycin treatment. CASE PRESENTATION: We present a patient with a history of non seminoma of the testis and bleomycin-induced pneumonitis. During follow-up, regression of the hypothesis of eosinophilic migration to the liver after regression of bleomycin-induced pneumonitis is highly suspicious based on transient eosinophilia and focal eosinophilic liver disease. CONCLUSION: As follow up may consist of CT scanning in germ-line tumor patients, transient eosinophilic liver lesions reported during regressive bleomycin-induced pneumonitis should not be presumed automatically as metastatic tumor relapse and require further sequential imaging and pathological examination.

Contains fulltext : 108175.pdf (publisher's version ) (Open Access), BACKGROUND: Chronic fatigue syndrome (CFS) is a clinical condition characterized by severe and disabling fatigue that is medically unexplained and lasts longer than 6 months. Although it is possible to effectively treat CFS, the nature of the underlying physiology remains unclear. Various studies have sought evidence for an underlying disturbance in immunity. The aim of this study was to compare the humoral and cellular immune responses upon influenza vaccination in CFS patients and healthy controls. RESULTS: Identical antibody titers were observed in CFS patients and healthy controls. Patients and controls demonstrated similar seroprotection rates against all three virus-strains of the influenza vaccine, both pre- and post-vaccination. Functional T cell reactivity was observed in both CFS patients and healthy controls. CFS patients showed a non-significant, numerically lower cellular proliferation at baseline compared to controls. Vaccination induced a significant increase in cellular proliferation in CFS patients, but not in healthy controls. Cytokine production and the number of regulatory T cells were comparable in patients and controls. CONCLUSIONS: The humoral and cellular immune responses upon influenza vaccination were comparable in CFS patients and healthy controls. Putative aberrations in immune responses in CFS patients were not evident for immunity towards influenza. Standard seasonal influenza vaccination is thus justified and, when indicated, should be recommended for patients suffering from CFS.

Contains fulltext : 109622.pdf (publisher's version ) (Open Access)

1 februari 2012, Item does not contain fulltext, Weight loss, cachexia and sarcopenia are profound problems in the frail oncologic patients. With the development and increasing use of angiogenesis inhibitors in metastatic cancer patients, the question arises as to their influence on body weight and composition. Angiogenesis is not only important for the growth, development and metastatic potential of tumors but also for physiological processes in adipogenesis. A less known approach of angiogenesis inhibitors is their experimental use in obese models. This review focuses on the effects on the body weight and composition of angiogenesis inhibitors, especially of those targeting the vascular endothelial growth factor pathway.

Item does not contain fulltext, BACKGROUND: A noticeable proportion of colorectal cancer (CRC) patients are diagnosed with synchronous CRC. Large population-based studies on the incidence, risk factors and prognosis of synchronous CRC are, however, scarce, and are needed for better determination of risks of synchronous CRC in patients diagnosed with colonic neoplasia. METHODS: All newly diagnosed CRC between 1995 and 2006 were obtained from the Rotterdam Cancer Registry in The Netherlands, and studied for synchronous CRC. RESULTS: Of the 13,683 patients diagnosed with CRC, 534 patients (3.9%) were diagnosed with synchronous CRC. The risk of having synchronous CRC was significantly higher in men (OR 1.54, 95% CI 1.29-1.84) and in patients aged >70 years (OR 1.83, 95% CI 1.39-2.40). Synchronous CRC patients had a significantly higher risk of distant metastases (OR 1.69, 95% CI 1.27-2.26). In 34% (184/534) the two tumours were located in different surgical segments. Five-year relative survival of synchronous CRC was similar to patients with solitary CRC after multivariate adjustment for the presence of distant metastases. CONCLUSION: One out of 25 patients diagnosed with CRC presents with synchronous CRC. In the multivariate analysis, survival of patients with synchronous CRC was similar to patients with solitary CRC, when corrected for the presence of distant metastases at first presentation. One third of the synchronous CRC were located in different surgical segments, which stresses the importance of performing total colon examination preferably prior to surgery.

Contains fulltext : 95697.pdf (publisher's version ) (Closed access), PURPOSE: The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. Patients and Methods: Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. RESULTS: Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-gamma/IL-2 production and increased IL-10 compared with healthy controls. CONCLUSION: We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.

Samenvatting: Om de effecten van de sociale vaardigheidstraining ‘Opkomen voor jezelf (g)een kunst’ te onderzoeken is onder 43 deelnemers aan de training een evaluatiestudie uitgevoerd. De training richt zich op kinderen van 9 tot 19 jaar en combineert principes van sociale leertheorie (Bandura, 1977), Rational Emotive Therapy (RET) (Ellis, 1962), ontspanningstechnieken en psycho-educatie. De invloed van de training op de mate van gepest worden (KRV-J), sociale angst (SAS-K), competentiebeleving (CBSA) en sociale- en emotionele problemen (CBCL) werd onderzocht aan de hand van vragenlijsten welke door de deelnemers en hun ouders werden ingevuld. Door pre- en post-test scores te vergelijken is onderzocht of de training verandering teweeg heeft gebracht op de onderzochte variabelen. Alleen op het gebied van sociale angst werden effecten waargenomen: de mate van sociale angst leek licht toe te nemen (t(15)=-1.79, p=.09). In situaties waarin fysieke vaardigheden in het geding zijn (SAS-K), was een duidelijke toename te zien (t(15) = -2.28, p=.038). Op de overige uitkomstvariabelen was geen verandering zichtbaar. Verdere analyses correleerden beginscores met verschilscores (voormeting-nameting) op de uitkomst variabelen. De opvallendste uitkomsten hiervan zijn de sterke correlatie tussen de beginscore op de schaal ‘gepest worden’ en de verandering op het gebied van sociale angst in situaties waar fysieke vaardigheden in het geding zijn (r=.632, p<0.01). Kinderen die volgens hun ouders bij aanvang veel teruggetrokken gedrag vertoonden, lieten een sterke daling zien op het gebied van sociale angst voor uitzonderingsposities (r=0.641, p<0.01). En tot slot lieten deelnemers die bij aanvang meer vrienden hadden een grotere toename zien in hun competentiebeleving op de gebieden ‘onderhouden van vriendschappen’ (r=-0.698, p<0.01) en sociale acceptatie (r=-0.638, p<0.01). ‘Opkomen voor jezelf (g)een kunst’ heeft in dit onderzoek geen positieve effecten laten zien. Dit

1 april 2010, Contains fulltext : 88612.pdf (publisher's version ) (Closed access), OBJECTIVES: To assess the prior exposure to colorectal examinations between colorectal cancer (CRC) patients and matched control participants to estimate the effect of these examinations on the development of CRC and to obtain insight into the background incidence of colorectal examinations. METHODS: A population-based case-control study was conducted within the Dutch Integrated Primary Care Information database over the period 1996-2005. All incident CRC cases were matched with up to 18 controls (n=7,790) for age, sex, index date (date of CRC diagnosis) and follow-up before diagnosis. All colorectal examinations performed in symptomatic participants in the period 0.5-5 years before index date were considered in the analyses. RESULTS: Within the source population of 457 024 persons, we identified 594 incident cases of CRC. In the period 0.5-5 years before index date 2.9% (17 of 594) of the CRC cases had undergone colorectal examinations, compared with 4.4% (346 of 7790) in the control population [odds ratio (ORadj): 0.56, 95% confidence interval (CI): 0.33-0.94]. For left-sided CRC, significantly more controls than cases had undergone a colorectal examination (4.7 vs. 2.0%, respectively, ORadj: 0.36, 95% CI: 0.17-0.76), which was not seen for right-sided CRCs (3.3 vs. 3.9%, respectively, ORadj: 0.98, 95% CI: 0.42-2.25). CONCLUSION: Patients diagnosed with CRC were less likely than controls to have had a colorectal examination in previous years, being more pronounced in patients diagnosed with left-sided CRCs. If diagnostic examinations have a similar protective effect as screening examinations, this finding supports the concept that colorectal examination can have a major impact on the reduction of CRC risk.

Contains fulltext : 81207.pdf (publisher's version ) (Closed access)

Contains fulltext : 81935.pdf (publisher's version ) (Closed access), PURPOSE: Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen. PATIENTS AND METHODS: Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures. RESULTS: One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM. CONCLUSION: Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.

Contains fulltext : 80319.pdf (publisher's version ) (Closed access), Residents report that they received inadequate teaching in palliative care and low levels of comfort and skills when taking care of dying patients. This study describes the effects of a problem-based palliative care course on perceived competence and knowledge in a representative Dutch cohort of residents in internal medicine. Before and after the course, we carried out a questionnaire survey and knowledge test in 91 residents. The results show that many residents felt they had limited competence or were incompetent when taking care of patients in the palliative care phase. This was particularly true with respect to communication concerning euthanasia and physician-assisted suicide or hastened death (86% and 85% respectively reported limited competence or incompetence). Participants reported that they received inadequate training in palliative care and believed that specific education would make them feel more competent. The number of times that residents were engaged in palliative care situations and the years of clinical experience had a positive influence on perceived competence. Participating in the course improved perceived competence and knowledge in palliative care. No correlation was found between perceived competence and knowledge of palliative care.

Item does not contain fulltext, BACKGROUND: Endoscopic follow-up (FU) in patients treated for colorectal adenomas or cancer (CRC) is intended to reduce the incidence of CRC. In the Dutch postpolypectomy guidelines, the FU interval is solely determined by the number of previous adenomas, whereas in other countries size and histology are also taken into account. Whether this difference in policy is also reflected in clinical practice is unknown. Furthermore, FU guidelines after CRC are not standardized in The Netherlands, even though national recommendations are available. GOAL: To assess the adherence to the current Dutch postpolypectomy guidelines and to evaluate the FU policy after CRC resection. STUDY: A survey was sent to all Gastrointestinal Departments in The Netherlands. The survey consisted of questions on logistic organization of FU, postpolypectomy FU intervals, and FU after CRC. RESULTS: The response rate was 85%. In contrast to the national guidelines, size and histology of the adenomas were often taken into account, leading to shortening of the FU interval. With respect to the CRC cases, 52% of the respondents advised shorter FU intervals than advised by the national recommendations. CONCLUSIONS: Despite recent Dutch postpolypectomy guidelines, clinicians incorporate histology and size into their clinical strategy. Either further education on the guidelines is needed, or the guidelines need to be reconsidered. Furthermore, evidence-based guidelines for FU after CRC should be formulated.

Item does not contain fulltext, With the emergence of novel angiogenesis inhibitors, we are moving to a new era for patients with metastasized renal cell carcinoma. Since the results achieved reflect more a modification of the natural course of the disease than a cure, past achievements should not be neglected. Low-risk patients with clear cell histology, especially those with pulmonary metastasis only, should still be offered cytokine therapy. For intermediate-risk patients sunitinib is the treatment of choice. For high-risk patients, temsirolimus has to date provided the most convincing data, its availability is however limited. Data with sorafenib and sunitinib in the high-risk group are still anecdotal. The toxicity profiles of these 2 drugs are different and might particularly relate to patients with known cardiovascular co-morbidity. No sufficient data are available regarding sequential use. After cytokine failure, sorafinib is the treatment of choice. Patients should preferably be treated within clinical trials to answer unaddressed questions. It is well known that the strict entry criteria used within the clinical studies were applied very flexibly when drugs have been approved. These aspects require a careful follow-up to ascertain optimal use and to prevent misuse. Finally, the costs of prolonged treatment will be enormous, and only meaningful survival advantages will convince the health authorities to make these new treatments available for all patients.