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Rudolf Virchow regarded medical education that did not include the history of medicine as barbarism. Despite this view, current education on medical history in medical faculties in the Netherlands is minimal in terms of the number of teaching staff and the hours spent on the subject. Important arguments for teaching medical history to medical students are academic development, a better understanding of the historic fundamentals of research, clinical practice and the medical profession and, more recently, a better understanding of the historical and social context of medicine. Modern education on the history of medicine provides a perfect opportunity for critical reflection on the complexity of modern-day medicine. On the basis of these arguments, history of medicine belongs within the framework for Undergraduate Medical Education as an independent domain with appropriate assessment.

Assessment of microvessel density by immunohistochemical staining is subject to a considerable inter-observer variation, and this has led to variability in correlation between microvessel density and clinical outcome in different studies. In order to improve the method of microvessel density measurement in tumour biopsies, we have developed a rapid, objective and quantitative method using flow cytometry on frozen tissues. Frozen tissue sections of archival tumour material were enzymatically digested. The single-cell suspension was stained for CD31 and CD34 for flow cytometry. The number of endothelial cells was quantified using light scatter- and fluorescence-characteristics. Tumour endothelial cells were detectable in a single cell suspension, and the percentage of endothelial cells detected in 32 colon carcinomas correlated highly (r=0.84, P

Outgrowth of solid tumors and metastases is dependent on the process of angiogenesis. Tumors escape from the formation of an effective infiltrate by downregulation of endothelial adhesion molecules. This downregulation of adhesion receptors is governed by the exposure to angiogenic factors. In recent years proof for this has been provided by demonstrating that freshly isolated tumor endothelial cells exhibit a decreased expression of ICAM-1 and -2 as compared to endothelial cells in normal tissue. In addition, adhesion molecules are downregulated on normal tissue endothelial cells when cultured with angiogenesis stimulators such as basic fibroblast growth factor and vascular endothelial cell growth factor, while under these conditions endothelial cells become less responsive to cytokines such as tumor necrosis factor-α with respect to the upregulation of endothelial adhesion molecules. Very recently it has been demonstrated that this harmful endothelial cell anergy can be counteracted by inhibitors of angiogenesis.

Patients with an unknown primary tumour (UPT) represent 5-10% of all new cancer patients. Data on survival and prognostic factors of UPTs are based on selected patient series from specialised institutions. Population-based data on incidence, histology and determinants of survival for patients with UPT are not available. All patients diagnosed with UPT between 1984 and 1992 and entered in the population-based Eindhoven Cancer Registry for Southeast Netherlands were included. Follow-up of vital status is complete up to 1999. 1285 patients were registered. In 1024 patients, the diagnosis was confirmed histopathologically: 479 (47%) had adenocarcinoma, 453 (44%) poorly differentiated carcinoma (PDC) or adenocarcinoma (PDA), 76 (7%) squamous cell carcinoma and 16 patients (2%) had an undifferentiated malignant neoplasm. In 26% of these patients with UPT, the tumour was already widely disseminated at presentation. The majority of patients (67%) received only supportive treatment. The median survival was 11 weeks and only 15% were still alive 1 year after diagnosis. Favourable subgroups comprised young patients and patients with metastases localised in lymph nodes. In 261 cases, the diagnosis was made clinically. These patients were evaluated separately. They were older than the biopsy-confirmed patients, received less cancer therapy and their prognosis was even worse (median survival of 7 weeks). In a comparison with data from a tertiary referral centre in the United States of America (USA), our patients were older, received less therapy and had a poorer prognosis. Demographics of our favourable subgroup resembled the patients from the American study. The differences were most likely caused by the differences in the patient populations. In conclusion, we have demonstrated in a population-based study that the prognosis for patients with UPT is more unfavourable than suggested in most clinical studies.

Unknown primary tumours (UPTs) are defined by the absence of a primary tumour in biopsy proved metastatic cancer. These tumours have a specific biology with clinical characteristics of rapid progression and random atypical metastases. Cytogenetic abnormalities have been demonstrated, particularly deletion of chromosome 1p. Diagnostic evaluation that includes pathology review, physical examination, chest radiography, computed tomography of the abdomen, and mammography is directed at the identification of treatable subsets. Based on clinicopathological criteria, therapy responsive subsets of patients with UPTs can be defined. These subsets have a better prognosis than the average median survival time of four months in patients with UPTs.

BACKGROUND Cancer incidence and mortality rates rarely are studied in people age > 85 years. Usually, patients ages 65 years, 75 years, and 85 years of age are combined into 1 group because of small numbers. The number of people age ≥ 85 years in the Netherlands increased from 99,000 in 1976 to 203,000 in 1995 (an increase of 105%). The growth of the total population in this period was only 13%. This study addressed cancer incidence and mortality rates among the very elderly in the Netherlands. METHODS Cancer mortality data (1976–1995) and population data were obtained from Statistics Netherlands, whereas cancer incidence data (1989–1995) were provided by the Netherlands Cancer Registry. Cancer incidence and mortality rates were calculated and trends in cancer mortality were studied. RESULTS Total cancer incidence rates were highest in the age group 85–94 years, in men and women (3466/100,000 person-years and 1604/100,000 person-years, respectively). Prostate carcinoma was the most frequent cancer in men ages 85–94 years, followed by colorectal carcinoma. In women ages 85–94 years, colorectal carcinoma was most frequent, closely followed by breast carcinoma. In the 95+ years age group squamous cell skin carcinoma was the most frequent cancer in both men and women, followed by prostate carcinoma in men and breast carcinoma in women. Cancer mortality rates increased with increasing age to nearly 3700/100,000 person-years in men age 95+ years and 2500/100,000 person-years in women age 95+ years. In men, lung carcinoma was the most frequent cancer-related cause of death in patients age ≤ 85 years, whereas in older men this applied to prostate carcinoma. In women, breast carcinoma was the most frequent cancer-related cause of death in all age groups > 55 years. Cancer as a cause of death became less prominent with increasing age. Over the period 1991–1995, 42% of deaths in men ages 55–64 years were attributed to cancer versus 52% of deaths in women (total population); these proportions in the 95+ years age group were 11% and 7%, respectively. CONCLUSIONS Peak incidence rates of major cancers were found in the very elderly population in the Netherlands. Different trends in age specific mortality rates of individual cancer sites were found, with stable rates in the middle age groups and increasing rates in the oldest age groups. This may reflect a real increase caused for instance by changes in mortality from other diseases and/or an artifactual increase caused by increased cancer detection rates in the (very) elderly. Cancer 2000;89:1121–33. © 2000 American Cancer Society.

Monocyte tissue factor expression is supposed to play an important role in the hypercoagulability of blood in cancer patients. The relation between coagulation parameters and the expression of monocyte membrane proteins involved in hemostasis or monocyte activation was studied in 21 patients with a disseminated malignancy and 21 age- and sex-matched healthy controls. In the cancer patient group no increase of monocyte tissue factor expression was found (8.4% vs. 7.8%; P = 0.83), but a significant increase of monocyte-bound activated protein C (APC) (28.8% vs. 13.4%; P = 0.009) and monocyte CD16 expression (34.5% vs. 27.0%; P = 0.007) was observed. There was also a significant increase of D-dimers (2.0 vs. 0.2 μg/ml; P = 0.001), a decrease of antithrombin (83.5% vs. 102.0%; P = 0.004), but no increase of TAT complexes (1.7 vs. 1.5 μg/l; P = 0.38) or factor VII(a) (68.5% vs. 75.0%; P = 0.52). The increase of D-dimers was significantly correlated with the monocyte APC (R = 0.60; P = 0.005), but not with monocyte tissue factor levels (R = -0.22; P = 0.35) or TAT complexes (R = 0.12; P = 0.60). These results reflect a local rather than systemic thrombin and fibrin formation. It is suggested that the APC formed locally enters the circulation and binds to peripheral blood monocytes. APC bound on monocytes is known to inhibit monocyte cytokine production and might therefore be involved in regulatory responses of monocytes in cancer patients. (C) 2000 Wiley-Liss, Inc.

Anthracyclines and taxanes are very effective drugs in the treatment of advanced breast cancer. With G-CSF support, the dose-intensity of this combination can be increased by reducing the interval between chemotherapy cycles, the so-called ‘shortening of cycle time’. We treated 36 patients with advanced breast cancer in a multicentre phase I/II study. The treatment regimen consisted of epirubicin 75 mg m−2followed by paclitaxel 135 mg m−2(3 h) in combination with G-CSF. At least six patients were treated in each cohort and were evaluated over the first three cycles. Starting at an interval of 14 days, in subsequent cohorts of patients the interval could be shortened to 10 days. An 8-day interval was not feasible due mainly to incomplete neutrophil recovery at the day of the next scheduled cycle. In the 10-day interval cohort it was feasible to increase the paclitaxel dose to 175 mg m−2. The haematological and non-haematological toxicity was relatively mild. No cumulative myelosuppression was observed over at least three consecutive cycles. In combination with G-CSF, epirubicin 75 mg m−2and paclitaxel 175 mg m−2could be safely administered every 10 days over at least three cycles, enabling a dose intensity of 52 and 122 mg m−2per week, respectively. © 2000 Cancer Research Campaign

Up to 30% of patients with idiopathic thrombocytopenic purpura (ITP) are refractory to standard therapy with corticosteroids and splenectomy. The treatment of refractory ITP is barely effective, but promising results of interferon therapy were reported recently. In a prospective study 21 refractory ITP patients were treated with interferon alpha 2B at 3 million Units three times a week for a period of 4 weeks. Ten out of 21 patients had a response, of whom 2 had a complete response of 3.5 and 7 months duration, after which both relapsed. One other patient retreated after relapse has a complete response of 24+ months. The characteristics of the responding patients were not different from the non-responding patients. Adverse effects were minimal. Short treatment with interferon in refractory ITP patients may be justified and the results reported here challenge us to elucidate the mechanism of action of interferon.

The prognostic significance of steroid-receptor activity is still debatable. Discrepancies in results are probably attributable to few patients, heterogeneous patient populations, and short follow-up. We investigated the prognostic significance of estrogen- and progesterone-receptor (ER and PgR, respectively) activity as a continuous variable in a homogeneous patient population. The prognostic significance of steroid-receptor activity was examined in 329 node-negative and 320 node-positive unselected breast cancer patients. In node-negative patients, ER values of primary tumors between 100 and 400 fmol/mg protein appeared to be a significant predictor for low risk of recurrence, whereas high ER (> 400) revealed an unfavorable prognosis. The classic cutoff level of ER (< 10 fmol/mg proteins) had no prognostic significance, however. In patients receiving adjuvant chemotherapy--the node-positive breast cancer patients--the classic cutoff value of ER (10 fmol/mg protein) predicts significantly distant metastases-free survival and overall survival only in the first 4 years of follow-up after diagnosis. Progesterone receptor is a time-dependent prognosticator in node-negative breast cancer patients (cutoff point for PgR, 80 fmol/mg). In node-positive breast cancer patients treated with chemotherapy or a combination of chemo- and hormonal therapy, PgR values lower than 60 fmol/mg had a worse prognosis. The results show the poor performance of standard cutoff points for ER and PgR positivity in predicting prognosis. Better prognosis is related to higher receptor levels but this relation is predominantly time-dependent. Moreover, patients who have high ER levels have a prognosis that is worse when compared with intermediate ER levels. Standard cutoff points for steroid receptors should not be used to select patients for prognosis.

Unknown primary tumors (UPT) are characterized by early and widespread metastasis. There is a strong indication that angiogenesis measured as microvessel density (MVD) correlates with the incidence of metastases in several solid tumors. The objective of this study was to compare MVD in liver metastases of UPT with MVD in known primaries and in liver metastases of colon and breast tumors and to investigate the prognostic significance of MVD in UPT. The clinical data and the MVD in liver metastases of 39 consecutive patients with UPT adenocarcinomas were studied. For comparison, MVD in the primary tumor and in liver metastases from known primary adenocarcinomas of the colon (n = 24) and the breast (n = 6) were measured. Most of the pathological material was obtained by needle biopsy. MVD was determined on formalin-fixed, paraffin-embedded histological sections of liver metastases, using the CD34 and von Willebrand Factor (vWF) antibodies and immunocytochemistry. The association of MVD with age, gender, number of metastases and tumor differentiation was assessed in the UPT population. The prognostic value of clinical variables and of MVD on survival was estimated by univariate and multivariate regression analysis. There was no difference between the MVD in liver metastases of UPT and known primaries. The MVD counts in the primary tumors of colon and breast were, however, significantly higher than in the metastases. MVD counts correlated well between anti-CD34 and anti-vWF. Within the UPT population there was no association between MVD and age, gender, number of metastases and tumor differentiation. The MVD was the only prognostic factor for survival in univariate analysis. High MVD was correlated with short survival. In the multivariate analysis, the number of metastases, tumor differentiation, therapy and MVD were all prognostic indicators for survival.

Effects of medroxyprogesterone acetate on appetite, weight, and quality of life in advanced-stage non-hormone-sensitive cancer: a placebo-controlled multicenter study.Simons JP, Aaronson NK, Vansteenkiste JF, ten Velde GP, Muller MJ, Drenth BM, Erdkamp FL, Cobben EG, Schoon EJ, Smeets JB, Schouten HC, Demedts M, Hillen HF, Blijham GH, Wouters EF.Department of Pulmonology, University Hospital, Maastricht, the Netherlands.PURPOSE: To investigate the effects of medroxyprogesterone acetate (MPA) on appetite, weight, and quality of life (QL) in patients with advanced-stage, incurable, non-hormone-sensitive cancer. PATIENTS AND METHODS: Two hundred six eligible patients were randomized between double-blind MPA 500 mg twice daily or placebo. Appetite (0 to 10 numerical rating scale), weight, and QL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-QLQ-C30]) were assessed before the start of treatment (t = 0), and 6 weeks (t = 6) and 12 weeks (t = 12) thereafter. RESULTS: One hundred thirty-four patients (68 MPA and 66 placebo) were assessable at t = 6 and 99 patients (53 MPA and 46 placebo) at t = 12. A beneficial effect of MPA on appetite was observed after both 6 weeks (P = .008) and 12 weeks (P = .01) of treatment. After 12 weeks, a mean weight gain of 0.6 +/- 4.4 kg was seen in the MPA, versus an ongoing mean weight loss of 1.4 +/- 4.6 kg in the placebo group. This difference of 2.0 kg was statistically significant (P = .04). During the study, several areas of QL deteriorated in the total group of patients. With the exception of an improvement in appetite and possible also a reduction in nausea and vomiting, no measurable beneficial effects of MPA on QL could be demonstrated. The side effects profile of MPA was favorable: only a trend toward an increase in (usually mild) peripheral edema was observed. CONCLUSION: In weight-losing, advanced-stage non-hormone-sensitive cancer patients, MPA exhibits a mild side effects profile, has a beneficial effect on appetite, and may prevent further weight loss. However, general QL in the present study was not measurably influenced by MPA treatment.Publication Types: Clinical Trial Multicenter Study Randomized Controlled Trial

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., GMS Zeitschrift für Medizinische Ausbildung; 27(2):Doc23; ISSN 1860-3572

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.

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.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.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).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.

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

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 ∼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.

Elevated levels of soluble uPAR (s-uPAR) and other fibrinolytic parameters functionally related to the urokinase-type plasminogen activator system might indicate the presence of cancer cells. In 25 breast cancer patients with metastases s-uPAR was significantly increased compared with 25 patients without metastases and with 25 healthy controls: 420 pg mL-1 vs. 145 pg mL-1 (P = 0.005) and 190 pg mL-1 (P = 0.003). Plasmin-alpha2-antiplasmin (PAP) complexes and d-dimers were significantly increased in breast cancer patients with metastases compared with patients without metastases and with healthy controls. The levels of plasminogen activator inhibitor (PAI)-1 activity, uPA antigen and factor (F)XIIa did not significantly differ between the patient groups and healthy controls. PAP complexes (529 microg L-1 vs. 420 microg L-1; P = 0.03), d-dimers (278.5 ng mL-1 vs. 79.0 ng mL-1; P = 0.005) and FXIIa (1.64 ng mL-1 vs. 1.19 ng mL-1; P = 0.01) were significantly higher in patients with metastases not surviving compared with patients with metastases surviving the 3-year follow-up period. Plasma s-uPAR levels in the patients with metastases did not discriminate between patients surviving and patients not surviving after 3-year follow-up. No significant differences in s-uPAR or any of the other parameters were found in the five patients developing metastases during follow-up. A single value of s-uPAR is of limited value in the follow-up of breast cancer patients with and without metastatic disease and does not predict survival or future metastases.

The unknown primary tumour (UPT) is an intriguing clinical phenomenon found in approximately 5% of all newly diagnosed patients with cancer. It is unclear whether UPT forms a distinct biological entity with specific genetic and phenotypic characteristics, or whether it is merely a clinical presentation of metastases in patients in whom the primary tumour cannot be detected and does not result in any visible clinical signs. Understanding the basic biology of UPT may shed light on this issue and, moreover, may have a direct impact on clinical care. A review of the literature revealed only a limited number of publications describing the genetic and phenotypic features of UPT, most of which focus only on the potential of these markers to predict prognosis. The question as to whether the biology of UPT is different from tumours of known primaries therefore remains unanswered. Further insight into the molecular mechanisms underlying the oncogenesis of UPT, e.g. by applying newly available DNA and gene profiling microarray techniques, will be necessary to understand its specific biology and to develop more effective treatments.

The MR and CT features of the pancreas are desct=ribed in an 18-year-old woman. Lipomatosis of the pancreas found on MR and CT and the clinical findings pancytopenia, short stature, and recurrent infections are typical for Shwachman syndrome

Background The aim was to gain insight into the diagnosis, treatment and prognosis of axillary recurrence after axillary clearance for invasive breast cancer in a large patient series. Methods Between 1984 and 1994, 4669 patients with invasive breast cancer underwent axillary clearance in eight community hospitals in the south-eastern part of the Netherlands. Using follow-up data in a population-based cancer registry, 59 patients with axillary recurrence were identified. Results The median interval between treatment of the primary tumour and the diagnosis of axillary recurrence was 2·6 (range 0·3–10·7) years. In 51 patients (86 per cent), axillary recurrence was found by palpation during routine follow-up. Surgery was part of the treatment of recurrence for 41 of 59 patients. Regional control (complete eradication of axillary recurrence) was achieved in 34 patients (58 per cent). The 5-year actuarial survival rate was 39 (95 per cent confidence interval 25–53) per cent. Patients with negative axillary lymph nodes at the time of diagnosis of the primary tumour and complete eradication of axillary recurrence had the best prognosis. Conclusion Patients with axillary recurrence had a poor prognosis, except when complete eradication was achieved and axillary lymph nodes were negative at the time of diagnosis of the primary tumour.

Leukocyte-endothelium interactions are diminished in tumors. It is reported here that, in a tumor-free in vivo model, angiogenic factors can down-regulate leukocyte adhesion to endothelium. Slow releasing pellets were loaded with either basic fibroblast growth factor (bFGF), vascular endothelial cell growth factor (VEGF) or vehicle alone and were placed in the scrotum of mice. After 3 days, a single intrascrotal injection of 1 microg/kg IL-1beta was given 4 h before vessels of the cremaster muscle were investigated for leukocyte rolling and adhesion by means of intravital microscopy. Exposure of normal tissue to either bFGF or VEGF resulted in markedly decreased levels of cytokine-induced leukocyte adhesion. Suppression of leukocyte rolling was not observed. Instead a moderate enhancement of rolling by VEGF was found. The observed differences could not be explained by differences in fluid dynamic parameters or systemic leukocyte counts. In conclusion, evidence is presented that, in vivo, angiogenic factors significantly reduce leukocyte adhesion, the final step preceding leukocyte infiltration. This observation may explain why tumors escape from immune surveillance.

We report the clinical efficacy of granulocyte colony-stimulating factor (G-CSF) in a 17-year-old woman with Shwachman's syndrome who was repeatedly admitted with severe infections and neutropenia. Bone marrow culture showed no increase in granulocyte colony-forming units upon stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF). The patient was treated with G-CSF 300 μg 3 times a week subcutaneously. A complete and sustained response of the neutropenia was obtained without side-effects during 21 months of treatment. No infectious episodes were encountered after starting G-CSF. This observation demonstrates the beneficial effect of G-CSF in treating the severe neutropenia in patients with Shwachman's syndrome.

‘Opleiden van medisch specialisten’ is vooral een praktisch boek voor iedereen die betrokken is bij de opleiding van medisch specialisten. De vier auteurs zijn erkende vernieuwers van het medisch onderwijs en pleitbezorgers voor een vernieuwing van de specialistenopleiding.

Summary Patients with a monoclonal gammopathy without evidence of lymphoproliferative or plasma cell malignancy within a year are still at risk for malignant transformation to multiple myeloma, Waldenstrom's macro-globulinaemia or non-Hodgkin's lymphoma. In a prospective study performed at the Mayo Clinic, the cumulative incidence of malignant transformation was 29% in 14 years. We conducted a retrospective study to determine the frequency of malignant transformation among 334 un-selected out-patients with monoclonal gammopathy of undetermined significance (MGUS) from a community hospital in Southeastern Netherlands. The cumulative incidence of malignant transformation was 11% in 14 years (95% confidence interval 6–17%). The long-term survival of patients with MGUS was slightly lower than that of the average regional population. In a nested case-control study, presence of a kappa light chain was found to be a risk factor for malignant transformation (70% of patients who developed malignant transformation compared to 30% of the control group, P < 001). Likewise, an initial high gamma globulin level was also found to be a risk factor (18–7g/1 v 13–7g/l in the control group, P

9681 Background: To determine whether treatment with carboplatin, etoposide and paclitaxel (CEP) improves survival, response and toxicity profile in patients with AdenoCarcinoma of Unknown Primary ...

Anorexia and cachexia are well known sequelae of advanced cancer, having a negative influence on quality of life and survival. In the present randomized double-blind placebo (PLA) controlled multicenter study in 206 incurable advanced stage non-hormone-sensitive cancer patients with a weight loss of 8.6 ± 7.9% of pre-illness weight, we studied the effects of the synthetic progestagen MPA (Farlutal® 500 mg b.i. d. for 12 weeks) on AP (0–10 pt numerical rating scale), WT and QL (EORTC QLQ-C30 questionnaire). An efficacy evaluable analysis (repeated measures ANOVA, two-sided) after 12 weeks of treatment could be performed in 99 patients (53 MPA, 46 PLA). Compared with the PLA group, a significant beneficial effect of MPA on AP and WT was found: mean difference in AP and WT change respectively 1.4 (P = 0.010) and 2.0 kg (P = 0.040). QL assessment revealed a significant worsening of physical-, role- and cognitive functioning, dyspnea and constipation in the total group of patients. There were, however, no significant differences in changes of QL between the MPA and PLA treated patients. No significant side effects of MPA were observed. We conclude that in weight-losing cancer patients MPA induces a significant improvement of AP and WT We did not find a measurable effect on general QL.

In binnen- en buitenland staat professioneel gedrag van studenten en artsen in toenemende mate in de belangstelling. Een van de redenen hiervoor is dat studenten en arts-assistenten soms vastlopen op een laat tijdstip in de opleiding, wat het bieden van begeleiding bemoeilijkt of zelfs onmogelijk maakt. Daarnaast is er een toenemend aantal klachten tegen medische beroepsbeoefenaars, met name op het communicatieve vlak. De indruk bestaat dat de afgelopen jaren binnen medische curricula en opleidingen mogelijk te veel nadruk gelegd is op het meten van alleen kennis en vaardigheden. Hierdoor blijven enkele andere belangrijke facetten van de beroepsuitoefening, met name aspecten van professioneel gedrag, onderbelicht. Dit artikel gaat in op de betekenis en de inhoud van professioneel gedrag. Ook aandachtspunten bij de beoordeling van professioneel gedrag komen uitvoerig aan bod. Er wordt een pleidooi gehouden voor expliciete aandacht voor professioneel gedrag in het opleidingstraject van student naar professional.

Mit dem Impulscytophotometer (ICP-11) wurden DNS-Histogramme von Knochenmarkzellen bei akuten myeloischen und akuten lymphatischen Leukamien angefertigt. Die DNS-Histogramme der Leukamiezellen vor und nach cytostatischer Therapie wurden verglichen mit denen von normalen Knochenmarkzellen.

Twenty patients (15 male, 5 female) with nonresectable gastric adenocarcinoma were treated with FAP (5-fluorouracil 300 mg/m2 IV on days 1-5, adriamycin 50 mg/m2 IV on day 1, cisplatin 20 mg/m2 IV on days 1-5). Each course was repeated every 21 days. Eighteen patients were evaluable for response. The median age was 51 years, the range extending from 34 to 68. None had undergone chemotherapy. The median Karnofsky performance score was 80%. Nine (50%) partial responses (PR) and eight (44%) cases of stable disease (SD) were observed. One patient showed progression of the disease and died after 6 months. The median duration of response was 6+ months for PR and 6 months for SD. The median survival was 12 months. FAP toxicity was moderate, with the median WBC nadir 3.2 X 10(9)/l (range 0.7-4.2). One patient in PR died of septicemia. Nausea and vomiting were not dose-limiting. Neuropathy was mild in four and moderate in two patients. This FAP combination appears to be as effective with respect to response rate and duration as reported for 5-fluorouracil, adriamycin and mitomycin C (FAM).