Pancreatic cancer is an aggressive cancer associated with a poor prognosis as a large proportion of these patients have locally advanced disease or metastases at the time of diagnosis. Currently... Show morePancreatic cancer is an aggressive cancer associated with a poor prognosis as a large proportion of these patients have locally advanced disease or metastases at the time of diagnosis. Currently onlypatients with localized pancreatic tumors can undergo surgery, which is the cornerstone in thetreatment of pancreatic cancer, whether or not preceded by neoadjuvant (chemo/radio)therapy. To establish the diagnosis, imaging techniques are used, tumor tissue must be obtained, and certain tumor markers can be determined in the blood. During surgery, the tumor must be removed in its entirety to prevent early recurrence. This thesis describes the potential role of tumor markers, which can be determined in the blood, and several experimental optical imaging techniques applied to pancreatic cancer. Show less
This thesis includes studies on how to measure and improve the quality of care for hip fracture patients in The Netherlands. Several determinants of quality of care such as treatment and outcomes... Show moreThis thesis includes studies on how to measure and improve the quality of care for hip fracture patients in The Netherlands. Several determinants of quality of care such as treatment and outcomes are studied, as well as the maturation of the Dutch Hip Fracture Audit (DHFA); a quality of care registry including all adult patients suffering a hip fracture in The Netherlands. Show less
The ageing of the world’s population requires new methods to prevent adverse outcomes such as delirium in older patients after surgery. Delirium is an expression of depleted reserves, which in turn... Show moreThe ageing of the world’s population requires new methods to prevent adverse outcomes such as delirium in older patients after surgery. Delirium is an expression of depleted reserves, which in turn decreases a patient’s resilience and makes a patient more frail. It may be triggered due to precipitating risk factors that shift the balance and overflow a patient’s resilience. A systematic review and meta-analysis demonstrated that delirium can be prevented by implementing multicomponent interventions. Therefore, a new multicomponent prehabilitation intervention was designed. The incidence of delirium was successfully reduced by implementing this prehabilitation program, however no effects were seen on all other short-term outcomes. On the long term, postoperative delirium increases the risk of 1-year mortality over 4 times and is associated with decreased functional outcomes after 6 and 12 months. Moreover, surgery and subsequent delirium affect the quality of life of patients and caregivers and may lead to depressive symptoms. Faster return to preoperative functioning may therefore be key to a faster return to preoperative quality of life. Future perioperative care pathways focusing on delirium prevention, optimisation and fast return to baseline functioning after surgery, should begin prior to hospital admission and end long after discharge. Show less
In the last two decades, treatment of rectal cancer has considerably improved in Europe. Although this applies to most solid malignancies, improvements in the diagnosis and treatment of rectal... Show moreIn the last two decades, treatment of rectal cancer has considerably improved in Europe. Although this applies to most solid malignancies, improvements in the diagnosis and treatment of rectal cancer surpass virtually all others. In the early 1990s, outcome after rectal cancer treatment was poor, with survival and recurrence rates of approximately 45%.1 Nowadays, survival after rectal cancer is sometimes even better than after colon cancer.2 While radiotherapy and chemoradiotherapy play an important role in the current, multidisciplinary treatment of rectal cancer, surgery remains the inevitable cornerstone for cure. For each and every improvement in surgical techniques, (neo)adjuvant treatment schedules, imaging and pathology, clinical trials and population-based audit registrations have played a crucial role. The aim of this thesis is to contribute to further improvements in rectal cancer treatment by investigating the multidisciplinary treatment forms, quality control and European collaboration. Show less
In the first part an update of a guideline for the physiotherapy treatment of patients with hip and knee OA is described. Then a set of quality indicators for the physiotherapy management is... Show moreIn the first part an update of a guideline for the physiotherapy treatment of patients with hip and knee OA is described. Then a set of quality indicators for the physiotherapy management is developed to be used as an instrument to measure guideline adherence. Subsequently the effect of educational strategies to enhance their uptake by physiotherapists in daily clinical practice is investigated. An interactive approach with patient colaboration and following a proces of clinical reasoning has shown to be the most effective strategy. The second part describes the extent of the provision of physiotherapy before and after joint replacement surgery from the physiotherapists__ and patients__ perspective. Results showed a large variation in provided interventions before and after surgery, although evidence for physiotherapy before joint replacement surgery is lacking. This indicates that more research is necessary focussing on effectiveness for specific groups of patients. In addition it was concluded that the presence of severe back pain in THA and dizziness in THA and TKA, should maybe ascertained before surgery and if present be treated if possible in order to decrease the chance of unfavourable outcome, although the predictive value of dizziness should be confirmed in a study with a prospective design. Show less
Data from clinical audits such as the Dutch Surgical Colorectal Audit, can be used for valid and meaningful feedback information, which may support improvement of quality of care. First, we showed... Show moreData from clinical audits such as the Dutch Surgical Colorectal Audit, can be used for valid and meaningful feedback information, which may support improvement of quality of care. First, we showed that the continuous feedback cycle of clinical auditing has an autonomous, positive effect on the quality of surgical care. Second, we describe how data from clinical audits can be used to monitor and improve national practice and performance in colorectal cancer care, especially for high-risk patients. Third, we describe how clinical auditing can be used for the evaluation and monitoring of the implementation of new techniques, such as laparoscopic surgery, on a national level. We demonstrate that, although there is a large hospital variation in the use of laparoscopic surgery, this does not explain the variation in outcome. Last, we investigate how data can be used to evaluate quality of care and give transparency to all stakeholders. As the various aspects of quality of care can be strongly interrelated, quality of care may best be represented using composite-measures. These composite measures can be used by all stakeholders to evaluate quality of care as a whole. The methodologies described in this thesis may be used in many other clinical audits. Show less
This thesis focus on preclinical validation of novel fluorescent contrast agents for solid tumor imaging (Part I), the clinical introduction of NIR fluorescence sentinel lymph node imaging in... Show moreThis thesis focus on preclinical validation of novel fluorescent contrast agents for solid tumor imaging (Part I), the clinical introduction of NIR fluorescence sentinel lymph node imaging in several cancer types using indocyanine green (Part II) and the clinical translation of NIR fluorescence imaging using clinically available fluorescent contrast agents for solid tumor imaging (Part III) Show less
Colorectal cancer is one of the most common cancers worldwide. Although there have been several improvements in screening, staging, and treatment in the past decades, survival differences remain.... Show moreColorectal cancer is one of the most common cancers worldwide. Although there have been several improvements in screening, staging, and treatment in the past decades, survival differences remain. For example among certain subgroups of patients, such as elderly patients and patients with comorbidities. Besides, inequalities in the quality of care between European countries remain. Quality control on surgery, radiotherapy, and pathology have been introduced in trials, followed by incorporation in the general care. Another option to incorporate improved quality of care is via an audit structure in which hospitals and clinicians can improve their results by learning from their own outcome statistics and those from colleagues treating a similar patient group. Although all these audit structures have achieved excellent results within countries, differences in outcome between European countries remain. A next step will b e to combine these national audits. The combined audit structure will provide a network in which __best practices__ can be compared and identified, including for certain subgroups, which has been initiated as European Registration of Cancer Care (EURECCA). To achieve optimal care for all patients, multidisciplinary care is the only way. By comparing multidisciplinary audit structures across countries, optimal treatment strategies within subgroups can be identified Show less
Quality of care- and of surgical oncology in particular- is gaining momentum. In this thesis the scientific bases of minimal volume standards and quality indicators are evaluated. Also the impact... Show moreQuality of care- and of surgical oncology in particular- is gaining momentum. In this thesis the scientific bases of minimal volume standards and quality indicators are evaluated. Also the impact of centralization of pancreatic surgery is investigated as is the influence of comorbidity on patient outcomes after colorectal surgery Show less
Pati_nten met een degeneratieve ruptuur van de rotatorcuff vormen een uitdagend probleem voor de behandeld specialist in de besluitvorming met betrekking tot in de behandelstrategie. De opzet van... Show morePati_nten met een degeneratieve ruptuur van de rotatorcuff vormen een uitdagend probleem voor de behandeld specialist in de besluitvorming met betrekking tot in de behandelstrategie. De opzet van dit proefschrift was om beter inzicht te cre_ren in de evaluatie, klinische uitkomst en chirurgische behandeling van degeneratieve rotatorcuffrupturen. In Hoofdstuk 3 wordt de overeenstemming in de beoordeling van de Geometrische Classificatie van cuffrupturen door ervaren beoordelaars onderzocht met behulp van MR beeldvorming met artrografie. In Hoofdstuk 4 wordt een nieuwe methode ge_ntroduceerd om pati_nten met een symptomatische cuffruptuur te onderscheiden van mensen met een asymptomatisch ruptuur middels de kwalificatie van de adductor co-activatie tijdens schouderabductie. In Hoofdstuk 5 werd de associatie onderzocht van de ernst van de ziekte activiteit van reumatoide arthritis en kraakbeenschade, rotatorcuffrupturen en opwaartse migratie van de schouderkop. In Hoofdstuk 6 werd een gerandomiseerde studie uitgevoerd naar de klinische resultaten van een volledig artroscopische versus mini-open behandeling van rotatorcuffrupturen bij 100 pati_nten. In Hoofdstuk 7 werden de klinische uitkomsten en structurele integriteit op postoperatieve MRI onderzocht van volledig artroscopische behandeling van subscapularispeesr upturen. Het doel van Hoofdstuk 8 was de introductie en evaluatie van een nieuwe artroscopische techniek voor de behandeling van massieve cuffrupturen. In Hoofdstuk 9 werd de grootste serie uit de orthopaedische literatuur beschreven van teres major peestransposities. Show less
Surgery always concerns the balance of risk and benefit. Both risk and benefit can vary immensely among patients. Outcome and prognosis are determined by several patient, tumour and treatment... Show moreSurgery always concerns the balance of risk and benefit. Both risk and benefit can vary immensely among patients. Outcome and prognosis are determined by several patient, tumour and treatment characteristics. In order to achieve the best possible outcomes for colorectal cancer patients, detailed and objective information on risk profiles is indispensible. For the individual patient it should guide clinical judgment and the administration of tailored care. On a hospital or population level knowledge of risk factors can lead to adjusted (better tailored) treatment protocols and better information on case mix influences adding to an improved care for colorectal cancer patients. Show less
The aim of this thesis is to evaluate the effect of doxycycline on the proteolytic and inflammatory processes in abdominal aneurysms. This data is essential for the development of pharmaceutical... Show moreThe aim of this thesis is to evaluate the effect of doxycycline on the proteolytic and inflammatory processes in abdominal aneurysms. This data is essential for the development of pharmaceutical strategies for the stabilization of an AAA. Such an approach could reduce the need for elective surgery and endovascular repair. It has repeatedly been shown that AAA progression and rupture is related to the failure of collagen in the aortic wall. Yet the exact mechanism underlying this failure remains unknown. Furthermore, the precise mechanism of activation of collagenases and their inflammatory mediators that are responsible for the collagen turnover of AAA are unknown. In this thesis we attempt to determine how collagen metabolism is balanced in aneurysmal diseases and contribute to the knowledge which collagenases and inflammatory mediators are involved in the destruction of the collagen network in AAA disease. Moreover, we evaluate some of the effects of doxycycline on the proteases and inflammatory mediators in AAA. Analyses showed that doxycycline inhibits specific MMPs and inflammatory pathways that are involved in the collagen balance and aneurysm growth. Together, these observations provide a rationale for a randomized clinical trial studying the effect of doxycycline on aneurysm growth. Show less
This thesis consists of two parts. In part I, we have demonstrated that preoperatively administrated systemic (neoadjuvant) therapy is a feasible treatment strategy in early stage breast cancer to... Show moreThis thesis consists of two parts. In part I, we have demonstrated that preoperatively administrated systemic (neoadjuvant) therapy is a feasible treatment strategy in early stage breast cancer to achieve improved surgical options and to assess tumor response. We also demonstrated that overexpression of the breast cancer stem cell marker aldehyde dehydrogenase-1 in early stage breast cancer patients is inversely associated with age and is of prognostic importance. In part II, we have demonstrated proof-of-principle of intraoperative tumor detection and image-guided tumor resection by using the novel technique of near-infrared fluorescence imaging. We have performed two clinical trials to optimize the use of indocyanine green as a near-infrared fluorescence lymphatic tracer for the sentinel lymph node procedure in breast cancer patients. Show less
This thesis evaluates, using various methods, two important surgical procedures currently used in heart failure patients: surgical ventricular restoration and restrictive mitral annuloplasty. The... Show moreThis thesis evaluates, using various methods, two important surgical procedures currently used in heart failure patients: surgical ventricular restoration and restrictive mitral annuloplasty. The conductance catheter was used to analyze the hemodynamic effects of heart failure surgery invasively. It demonstrated improvement in systolic function of the left ventricle for both procedures at long term follow-up. Diastolic function demonstrated signs of impairment, although the functional effect remained limited, regarding limited or no increase in left ventricular end-diastolic pressure for SVR and RMA, respectively. Furthermore, assessment of left ventricular volumes demonstrated persistent reverse remodeling at follow-up. Clinical performance demonstrated significant improvement for both surgical procedures. The hemodynamic results together with the positive clinical outcome for both surgical procedures supports the use of these procedures in end-stage heart failure patients. Regarding the fact that using the conductance catheter is time consuming and can be burdensome for patients, a demand for less invasive methods was generated. Evaluation of alternative methods demonstrated that heart failure surgery can also be evaluated by single-beat analysis, a simplified method of the conventional conductance catheter method avoiding load interventions by temporary vena cava occlusions. Furthermore, echocardiography and to a certain extent, serum biomarker analysis can also be used. Show less
This thesis focuses on quality assurance of rectal cancer treatment, in particular of the surgical treatment. Both oncological short-term and long-term outcome parameters are studied, but also... Show moreThis thesis focuses on quality assurance of rectal cancer treatment, in particular of the surgical treatment. Both oncological short-term and long-term outcome parameters are studied, but also other end-points which are important for quality assurance are investigated, such as anastomotic leakage and stoma reversal. The introduction of total mesorectal excision (TME) surgery resulted in an improved survival of patients with rectal cancer. However, survival of the elderly patients and patients treated with an abdominoperineal resection improved less. For frail elderly patients, postoperative mortality is an important competitive risk factor and other treatment schedules might be more appropriate. The abdominoperineal resection itself was associated with a nonradical resection, decreased local control and decreased survival compared to patients treated with a low anterior resection. To improve these results, in selected cases preoperative treatment should consist of chemoradiotherapy and/or a widened resection. Anastomotic leakage is a feared complication after colorectal surgery. After surviving this complication, the overall survival rate in the long-term is still reduced. However, oncological outcome was not significantly affected. The presence of a stoma resulted in a lower symptomatic leakage rate. 20% of stomas was never reversed. Standardised postoperative surveillance resulted in an earlier confirmation of the diagnosis anastomotic leakage. Show less
The frequently diagnosed lumbar disc herniation can disappear by natural course, but still leads to high low back surgery rates. The optimal period of conservative care, before surgery is executed,... Show moreThe frequently diagnosed lumbar disc herniation can disappear by natural course, but still leads to high low back surgery rates. The optimal period of conservative care, before surgery is executed, was unknown. It is surprising that scientific evidence was lacking which justified “early” surgery. Surgery, after 6-12 weeks of sciatica, was compared to prolonged conservative care in 283 patients in a randomized study. Primary outcomes were perceived recovery, leg pain intensity and functioning. Early surgery resulted in a 2 times faster recovery rate, compared to prolonged conservative care. From the latter group 39 percent of patients could not evade surgery. Within one year, however, both groups presented similar recovery rates and outcome. The impossibility to sit, because of sciatica, seemed to be a good argument to decide for early surgery. Intense pain and disability were predictors for delayed surgery. Compared to men, females exhibited a 3 times higher odds to develop chronic pain. The higher medical costs of early surgery were fully compensated by quick resumption of working capacity. From a medical point of view one may favor a prolonged wait-and-see strategy but our western society urges patients to decide for early surgery to resume daily activities. Show less
Ondanks moderne wondbehandeling en antibiotica, bestaan er nog steeds pati_nten met chronische wonden. Het ontstaan van antibioticaresistente bacteri_n, zoals MRSA (Metilcilline-resistente... Show moreOndanks moderne wondbehandeling en antibiotica, bestaan er nog steeds pati_nten met chronische wonden. Het ontstaan van antibioticaresistente bacteri_n, zoals MRSA (Metilcilline-resistente Staphylococcus Aureus), heeft in de laatste 10 tot 20 jaar tot een ware opkomst van behandelingen met maden geleid. Ronald Sherman heeft in 1989 madentherapie als het ware opnieuw ontdekt. Behandeling met steriele maden (Engels: Maggot Debridement Therapy) krijgt een steeds grotere vlucht, ook in Nederland. Het feit dat er, in de laatste tien jaar alleen al, meer dan 100 artikelen over maden zijn verschenen, laat zien dat madentherapie een sterke comeback heeft gemaakt in de geneeskunde. In januari 2004 heeft de Amerikaanse FDA (U.S. Food and Drug Administration), regel 510(k)#33391 uitgegeven, waardoor de productie en verkoop van maden als een medisch apparaat is toegestaan. De International Biotherapy Society heeft haar zevende internationale congres in 2007. Er zijn nu ongeveer 300 centra in Amerika en meer dan 1000 in Europa die madentherapie toepassen. Bewijs in de vorm van multi-center gerandomiseerd onderzoek van behandeling met maden is niet voorhanden. Er zijn drie gerandomiseerde studies naar madentherapie in de literatuur gepubliceerd, de pati_ntenaantallen van de studies waren klein, en de kwaliteit van de studies kon in twee gevallen niet gecontroleerd worden. De studie waarvan de kwaliteit wel gecontroleerd kon worden, ging maar over een totaal van twaalf pati_nten. Madentherapie heeft, na de introductie in het LUMC in 1999, ook een grote vlucht in Nederland genomen. In 2002 werd in het Rijnland Ziekenhuis een speciale wondenpolikliniek opgericht. Naast vele andere behandelmethoden is daar in 2007 de 150ste pati_nt met maden behandeld. Bij de start van de madentherapie bleken er nog vele basale klinische vragen onbeantwoord. Die vragen vormden de basis voor dit proefschrift. Show less
In this thesis, we evaluated the acute and chronic hemodynamic effects of non-pharmacological heart failure therapies. In particular, the effects of surgical treatment and biventricular pacing... Show moreIn this thesis, we evaluated the acute and chronic hemodynamic effects of non-pharmacological heart failure therapies. In particular, the effects of surgical treatment and biventricular pacing therapy were investigated by left ventricular pressure-volume loop analyses. We demonstrated that restrictive mitral annuloplasty effectively restored mitral leaflet coaptation without inducing significant acute changes in ventricular function. This indicates that this procedure can be safely applied in patients with heart failure. Surgical ventricular restoration was shown to achieve acute normalisation of left ventricular volumes, improved systolic function, and decreased left ventricular wall stress and mechanical dyssynchrony. At the expense of a higher diastolic pressure resulting from altered diastolic properties, stroke work and cardiac output were not importantly altered, but mechanical efficiency was significantly improved. Chronically, surgical therapy resulted in improved clinical status evidenced by improved NYHA class, quality of life score, and 6-min walking distance. Left ventricular function and dyssynchrony remained significantly improved at 6 months follow-up. In addition, we observed a decrease in pulmonary artery pressure, right ventricular reverse remodeling and reduced tricuspid regurgitation. Acute and chronic hemodynamic effects of cardiac resynchronization therapy (biventricular pacing) were demonstrated by pressure-volume loop analysis. Hemodynamic improvements, previously only shown in acute studies, were shown to be maintained at 6 months follow-up. In addition, ventricular-arterial coupling, mechanical efficiency, and chronotropic responses were improved. In conclusion, the acute and chronic hemodynamic effects of these non-pharmacological heart failure therapies were demonstrated by ventricular pressure-volume analysis. These findings provide insight in the underlying mechanisms and help to explain improved functional status achieved with these therapies. Show less
Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) in patients following cardiac surgery that can lead to major organ injury and postoperative morbidity.... Show moreCardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) in patients following cardiac surgery that can lead to major organ injury and postoperative morbidity. Initiation of CPB sets in motion an extremely complex and multifaceted response involving complement activation along with activation of platelets, neutrophils, monocytes, and macrophages. This in turn initiates the coagulation, fibrinolytic, and kallikrein cascades, increasing blood concentrations of various endotoxins and cytokines and increasing endothelial cell permeability. The basic physiological insults caused by CPB have been associated with major postoperative morbidity, including neurological, pulmonary adrenal dysfunction, and/or haematological abnormalities. Additional clinical manifestations associated with the SIRS include increased metabolism (fever), fluid retention, myocardial oedema, and detrimental haemodynamic alterations. The use of steroids to minimize or prevent the consequences of SIRS in the postoperative period has been extensively investigated in adults. Clinical investigations in the paediatric population are scarce. Our aim was to investigate how dexamethasone could influence the associated side effects of CPB in two organs, the small intestine and the heart. To that effect we chose two surrogate markers, gut permeability and cardiac troponin T production. Intestinal mucosal ischaemia, although transient, can occur in infants and children during and after CPB. Gut permeability had not been previously investigated in children undergoing cardiac surgery. In chapter two we describe, in an observational study, the natural course of gut permeability in patients undergoing cardiac surgery with and without CPB. Gut permeability has been investigated in healthy children and neonates not undergoing surgical or medical interventions during the study period. Patients with congenital cardiac diseases have preoperative gut permeability values up to seven times what we could expect in healthy children of similar age. In patients operated without CPB gut permeability was reduced in the postoperative period returning to near normal values 24 hours after surgery. On the other hand, in patients undergoing surgery with CPB gut permeability deteriorated even further in the postoperative period. 98 In chapter three we report the results of a study designed to test the hypothesis that dexamethasone has beneficial effects on intestinal permeability during the postoperative period. Dexamethasone given before CPB starts reduced intestinal permeability within 24 h after surgery. The differences are highly significant when compared to control patients not given dexamethasone. In the investigation reported in chapter four we studied the changes in intestinal permeability in patients undergoing stage I of the Norwood procedure. Neonates with hypoplastic left heart syndrome (HLHS) undergo surgical repair in three stages. These patients suffer from an imbalanced circulation potentially exposing the intestine to chronic ischaemia. The surgical repair requires a period of circulatory arrest. It comes as no surprise, therefore, that HLHS patients are at high risk of developing necrotizing enterocolitis in the postoperative period, with devastating consequences. We found that HLHS patients have abnormal intestinal permeability before and after surgery. Rhamnose is one of the four sugars used to test intestinal permeability. For the last thirty years it has been assumed that rhamnose is an inert sugar not metabolized by the human body. We have found this not to be the case, and the results are presented in chapter five. The type of anaesthetic agent used during adult coronary bypass surgery may influence considerably the postoperative production of cardiac troponin T (cTnT), a protein that reflects the extent of myocardial damage after a period of hypoxia. In particular halogenated ethers may exert its effect through a process called anaesthetic preconditioning, a phenomenon similar to ischaemic preconditioning. Anaesthetic preconditioning has not been investigated in paediatric cardiac surgery to the same extent as in adult cardiac surgery. In chapter six we present a study of the effects of three different anaesthetic agents, propofol, midazolam and sevoflurane, on the postoperative production of cTnT in paediatric cardiac surgical patients. Contrary to what happens in adult patients we could not find significant differences in the postoperative production of cTnT when midazolam, propofol or sevoflurane were used as anaesthetic agents. In chapter seven, we report on a study designed to test the hypothesis that dexamethasone given before CPB starts may have myocardial protective effects as assessed by the postoperative production of cTnT. Subgroup analysis in cyanotic and neonatal patients was also evaluated for the same hypothesis. 99 We found that dexamethasone did reduce postoperative cTnT concentrations. However, the reduction was short lived and was not accompanied by improvements in any of the other clinical parameters measured. Show less
