[Beyond happiness]. / Het geluk voorbij.

Cancer has a drastic effect on the day-by-day feeling of well-being of many people in our greying society. After a long history of melancholia and powerlessness unexpectedly many advances in the treatment of cancer have now been made. However, the happiness brought about by successful treatment is being dulled by the consequences of this often intensive treatment. Despite longer survival having been achieved, chronic severe fatigue and a high risk of developing cardiovascular disease or a second tumour now stand between the cancer survivor and happiness. The price that has to be paid for surviving cancer seems to be higher than was originally thought.

[Guideline "Cancer rehabilitation"]. / Richtlijn 'Oncologische revalidatie'.

Initiated by IKNL (Integraal Kankercentrum Nederland), a multidisciplinary guideline for cancer rehabilitation for adult oncology patients has been developed. The guideline describes the rehabilitation care of adult patients with cancer, during and after treatment. The guideline focuses on (a) prevalence of complaints either resulting from cancer or the treatment, (b) detection of these complaints and indicated referral, (c) the intake procedure before cancer rehabilitation, (d) intervention and evaluation within cancer rehabilitation and (e) the importance of patient empowerment. The guideline is directed at all professionals giving care to patients with cancer. It concerns those (such as medical specialists, general practitioners and nurses) who are responsible for detecting cancer-related complaints and for referral to cancer rehabilitation, as well as health care professionals involved in cancer rehabilitation care (such as consultants in rehabilitation medicine, physiotherapists and psychologists). The main goal of the guideline is that every cancer patient or ex-cancer patient with (residual) complaints resulting from cancer or its treatment receives timely and appropriate cancer rehabilitation.

[Thomas Schwencke and Wolfgang Amadeus Mozart]. / Doctor Thomas Schwencke en Wolfgang Amadeus Mozart.

Thomas Schwencke (1694-1767) was Professor of Anatomy and Surgery and Lecturer in Obstetrics at the Surgical School in The Hague, the Netherlands. In 1743 he published the very first textbook on haematology. Furthermore, he described his observations on the variolation of smallpox, and published the design of a new obstetric instrument. Schwencke was physician of the city of The Hague and also physician at the court of the princes van Nassau-Weilburg. In 1765 Princess Caroline of Nassau-Weilburg invited the young Wolfgang Amadeus Mozart to perform concerts. During his Dutch tour the young Mozart fell seriously ill, probably from typhoid fever. At the request of the court Mozart was seen for a second opinion and thereafter successfully treated by Schwencke. Mozart could continue his concert tour and Schwencke's reputation as Mozart's physician was established.

Quality assurance of medical education in the Netherlands: programme or systems accreditation?

Accreditation is an instrument that is used worldwide to monitor, maintain and improve the quality of medical education. International standards have been defined to be used in reviewing and evaluating the quality of education. The organization and the process of accreditation of medical education programmes in the Netherlands and in Flanders are described in some detail. Accreditation can be based on the results of a detailed assessment of an educational programme or on an evaluation of the educational system and the organization of the institution in question. The Flemish-Dutch accreditation organization (NAO) is moving from programme accreditation towards a combination of programme and systems accreditation. The pros and cons of these two approaches are discussed.

Molecular evidence for a clonal relationship between multiple lesions in patients with unknown primary adenocarcinoma.

Unknown primary adenocarcinoma (UPA) comprises a group of heterogeneous cancers of great clinical and biological interest. UPA presents as metastatic disease without a detectable primary site after medical workup. Here we investigated whether or not a clonal relationship exists between multiple tumors within individual UPA patients. A molecular resemblance would argue for an early clonal outgrowth of tumor cells from the primary lesion, a mutual feature observed within this group of neoplasms. In 14 patients with UPA multiple tumors, obtained at autopsy, were analyzed by molecular allelotyping and immunohistochemistry. In addition, tumors of 4 patients could be analyzed by comparative genomic hybridization (CGH). Similar genetic and phenotypic profiles were used as indicator for a clonal relationship, whereas different profiles implicate independent tumors. The molecular data indicated that the multiple lesions in the 14 UPA patients, including the primary tumors, are clonally related. In agreement with the theory of tumor progression, some metastatic lesions showed additional genetic alterations besides the characteristics that were shared with the primary tumor. Furthermore, 8 UPA patients had tumors with a high frequency of allelic loss and/or imbalance (FALI; 43-71%), while 6 patients demonstrated a lower FALI (14-29%), suggesting the occurrence of chromosomal instability in the former group. Our data provide molecular evidence for a clonal relationship between multiple metastases and the primary tumor within individual UPA patients, independent of the anatomical origin of the cancer. This finding is in agreement with the suggestion that tumor progression is rapid in UPA patients, limiting the chance of clonal divergence. The identification of 2 groups of UPAs with either a high or low FALI indicates that chromosomal instability is not the only driving force behind early tumor cell dissemination. Thus, other molecular mechanisms must underlie the common biology of these tumors.

Effects of radiotherapy and chemotherapy on angiogenesis and leukocyte infiltration in rectal cancer.

BACKGROUND: We and others have shown that angiogenesis and leukocyte infiltration are important prognostic factors in rectal cancer. However, little is known about its possible changes in response to radiotherapy (RTX), which is frequently given to rectal tumors as a neoadjuvant treatment to improve the prognosis. We therefore investigated the biologic effects of RTX on these parameters using fresh-frozen biopsy samples of tumor and normal mucosa tissue before and after RTX. METHODS: Biopsy samples were taken from a total of 34 patients before and after either a short course or long course of RTX combined with chemotherapy. The following parameters were analyzed by immunohistochemistry, flow cytometry, or quantitative real-time polymerase chain reaction: Microvessel density, leukocyte infiltration, proliferating epithelial and tumor cells, proliferating endothelial cells, adhesion molecule expression on endothelial cells, and the angiogenic mRNA profile. RESULTS: The tumor biopsy samples taken after RTX treatment demonstrated a significant decrease in microvessel density and the number of proliferating tumor cells and proliferating endothelial cells (p < 0.001). In contrast, the leukocyte infiltration, the levels of basic fibroblast growth factor in carcinoma tissue, and the adhesion molecule expression on endothelial cells in normal as well as carcinoma tissue increased significantly (p < 0.05). CONCLUSION: Our data show that together with an overall decrease in tumor cell and endothelial cell proliferation, RTX results in an increase in the expression of adhesion molecules that stimulate leukocyte infiltration. This suggests the possibility that, in addition to its direct cytotoxic effect, radiation may also stimulate an immunologic tumor response that could contribute to the documented improvement in local tumor control and distal failure rate of rectal cancers.

Proliferating endothelial cells and leukocyte infiltration as prognostic markers in colorectal cancer.

BACKGROUND & AIMS: Leukocyte infiltration in tumors is dependent on angiogenic potential. In this study we aimed to retrospectively investigate the angiogenic potential in archival colorectal cancer (CRC) tissues and its relationship to amount and composition of the inflammatory infiltrate. METHODS: In tumor tissues of 117 CRC patients with a 12-year follow-up, microvessel density (MVD) and proliferating endothelial cells (ECs) were assessed by CD31/CD34 double staining with the proliferation marker Ki-67. Leukocyte infiltration was determined by using CD45, CD3, CD8, CD16, CD20, and CD68 antibodies in peritumoral, tumor stroma, and intratumoral areas. RESULTS: Proliferating ECs, but not MVD, are correlated to Dukes' stage and survival in CRC (P < .05). This parameter correlated significantly with the expression of vascular endothelial growth factor (r = 0.82; P < .012). The number of inflammatory cells in the tumor stroma and cells infiltrated into the tumor cell nests, but not of peritumoral leukocytes, predicted patient survival. This was most obvious for T lymphocytes (CD3; P < .05) and polymorphonuclear cells (CD16; P < .04). We found a significant relationship between angiogenesis parameters and infiltrated leukocytes (r = -0.70; P < .02). Combination of high numbers of infiltrated leukocytes and low amounts of proliferating ECs demonstrated to be an improved prognostic value compared with either parameter alone (P < .006). CONCLUSIONS: We found a correlation between the intrinsic tumor parameters of ongoing angiogenesis and leukocyte infiltration with prognosis and survival in CRC. These findings have a potential impact on therapeutic applications for both antiangiogenesis as well as immunotherapy.

Angiogenic profile of breast carcinoma determines leukocyte infiltration.

To study the relationship between the angiogenic profile and leukocyte infiltration of tumors, single cell suspensions of archival frozen medullary and ductal breast cancer tissues were analyzed by flow cytometry. The amount of leukocytes and endothelial cells was measured, as well as the expression of intercellular adhesion molecule-1 (ICAM-1) on the endothelial cell fraction. A significantly higher number (3.2-fold) of infiltrating leukocytes was observed in medullary carcinoma. The composition of this infiltrate was similar to that seen in ductal carcinomas. The more intense infiltrate was explained by the approximately 3-fold enhanced endothelial ICAM-1 expression in medullary carcinoma. The angiogenic profile of all tumors was assessed by quantitative real-time reverse transcription-PCR analysis. Vascular endothelial growth factor (VEGF)-C and VEGF-D, but not VEGF-A, basic fibroblast growth factor, placental growth factor, and angiopoietins 1, 2, and 3 showed a relatively higher level of expression in ductal carcinoma than in medullary carcinoma. In vitro, both VEGF-C and VEGF-D were found to decrease endothelial ICAM-1 expression in the presence of basic fibroblast growth factor. These data suggest that in vivo angiogenic stimuli prevent the formation of an effective leukocyte infiltrate in tumors by suppressing endothelial ICAM-1 expression.

Clinical and immunohistochemical analysis of patients with unknown primary tumour. A search for prognostic factors in UPT.

BACKGROUND: The unknown primary tumour (UPT) is an intriguing clinical finding in approximately 5% of all newly diagnosed patients with cancer. To evaluate a correlation between the specific immunohistochemical alterations in UPT cells and the unique clinical features of UPT patients, to define the natural history of UPT and to verify prognostic factors, we undertook a detailed clinical and immunohistochemical analysis of patients with the diagnosis of adenocarcinoma of UPT. RESULTS: Patients with UPT present with a short history and have a poor prognosis. Univariate analysis was performed with clinical, biological and immunohistochemical variables. Patients with a higher age (>60 years), a poor performance score (2-3), liver metastases or more than two organ sites involved, or patients with elevated LDH-levels, were found to have worse prognosis. We confirm that the prognostic model published by Culine is a valuable model for the prediction of prognosis in patients with UPT. Immunohistochemical detection of proliferation (MIB-1), p53, vascular endothelial growth factor-A, CD34, CD44v6 and Her2neu indicated that these factors were of no prognostic value. CONCLUSION: In conclusion, patients with UPT have a very poor median prognosis of 12 weeks. Prognostically favourable factors are young age, good performance status, no liver metastases and normal LDH level. We found no relationship with immunohistochemical factors.