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In 2008, a compulsory national basic teaching qualification was introduced for all university teachers in the Netherlands. At that time all eight University Medical Centres (UMCs) and the only Faculty of Veterinary Medicine had adopted or were setting up teacher development programmes. This study explores how these programmes relate to each other and to the basic teaching qualification. To gather information on teacher development programmes in the UMCs and the Veterinary Medicine Faculty an online survey was filled out by teacher development representatives from each of them. The programmes had main features in common (e.g. competency based and portfolio assessment), but differed somewhat in contents according to the local situation. Importantly, they had all been formally accepted as equivalent to the basic teaching qualification. We consider the freedom to tailor the qualifications to the medical context as well as to the local situation of the UMCs and the Veterinary Medicine Faculty one of the major success factors and the well-established collaboration between teacher development representatives of the UMCs and the Faculty of Veterinary Medicine as another. Challenges for the future include embedding the teacher development programmes in the institutional organizations and maintaining and further developing the programmes and the competencies of the qualified teachers, e.g. in a senior qualification.

Purpose: This study reevaluates the potential role of different tumour markers as prognostic indicators in untreated nephroblastoma., Methods: Expression of a broad panel of tumour markers was investigated by means of immunohistochemical analysis in 43 WT patients. Patients were treated by radical nephrectomy and had a mean follow-up of 11.9 years., Results: Generally, all the tumour markers studied were expressed in normal kidney tissue and at variable levels in the three cell types of WT (blastema, epithelium and stroma). Immunoreactive blastemal (Bcl-X, Bcl-2 and CD44s) and epithelial (Bcl-X, Bcl-2 and MIB-1) cells were present in the majority of tumours. No correlation was found between their expression and pathological stages. Univariate analysis showed that blastemal WT-1, TGF-α, VEGF, MIB-1 and p27 Kip1 were indicative for clinical progression. In a multivariate analysis, WT-1 protein expression by blastemal cells was an independent prognostic marker for clinical progression., Conclusions: The blastemal WT-1, TGF-α, VEGF, MIB-1 and p27Kip1 expression correlate with clinical progression in untreated nephroblastoma. Therefore, their expression may be of value in identifying patients with a high propensity to develop distant metastases.

Background: The quality of teachers in higher education is subject of increasing attention, as exemplified by the development and implementation of guidelines for teacher qualifications at Universities in The Netherlands., Aim: Because medical education takes a special position in higher education the Council of Deans of Medical Schools in The Netherlands installed a national task force to explore a method to weigh criteria for teacher qualifications of medical teachers., Methods: A framework was developed covering competencies of teachers throughout the medical education continuum and including medicine, dentistry and veterinary medicine., Results: The framework distinguishes 3 dimensions: (a) six domains of teaching (development - organization - execution - coaching - assessment - evaluation); (b) three levels in the organization at which teachers perform (micro, meso and macro level) and (c) competencies as integration of knowledge, skills and attitude and described as behaviour in specific context. The current framework is the result of several cycles of descriptions, feedback from the field and adaptations. It is meant as a guideline, leaving room for local detailing., Conclusion: The framework provides a common language that may be used not only by teachers and teacher trainers, but also by quality assurance committees, human resource managers and institutional boards.

To offer a more comprehensive curriculum in various dental topics, the dental school of the University of Groningen developed electives. This article gives an overview of the learning objectives of the different electives, the program and the way in which students are examined. Attention is also paid to some experiences of students and teachers with this kind of education. The electives seem to effectively prepare students for specific parts of dentistry, and they give an orientation on the scientific aspects of dentistry. Students and teachers are positive about the electives. The electives give good opportunities to the assessment of professional behavior.

Members of the Dutch working group on soft tissue tumours developed an up-to-standard evidence-based multidisciplinary clinical practice guideline for the diagnosis of soft tissue tumours and the treatment and follow-up of soft tissue sarcomas, in cooperation with the Dutch Association of Comprehensive Cancer Centres and the Dutch Institute for Healthcare Improvement. A soft tissue sarcoma is defined as every non-epithelial tumour that does not originate in haematopoietic or lymphatic system, central nervous system or bone. The guideline lists 'alarm signals' to raise awareness of malignancy and recommends consulting a multidisciplinary team. Non-invasive imaging has to be completed before proceeding to any invasive (diagnostic) procedure or assessment of dissemination. Aspiration cytology can be useful for differentiating between sarcoma and other malignancies. A definite diagnosis is obtained by means of image-guided needle biopsy. Tumours will be classified according to the World Health Organization and graded according to the Federation Nationale des Centres de Lutte Contre le Cancer. Surgical excision with a tumour free margin of 2 cm is the core of therapy, taking into account vital structures when necessary. In case of small superficial tumours (diameter < or = 3 cm) excision biopsy may be justified. Radiotherapy is almost always necessary and certainly indicated when wide margins are impossible even after re-resection. In the case of primary metastatic disease, an individual decision should be taken after multi-disciplinary consultation concerning the possibility of curative or palliative treatment. Neither neo-adjuvant nor adjuvant chemotherapy is standard. Chemotherapy may be useful in metastatic disease. The guideline advises referring patients who are eligible for chemotherapy to a centre and that they should be included in a study protocol.

The molecular biology underlying the development of highly malignant peripheral nerve sheath tumors (MPNSTs) remains mostly unknown. In the present study, the expression pattern of 10 selected cell cycle components is investigated in a series of 15 MPNSTs from patients with (n = 9) or without (n = 5) neurofibromatosis type 1 (NF1). Thirteen tumors did not express the cyclin-dependent kinase inhibitor, p16(INK4A), an observation that was related to homozygote gene deletions in three tumors, heterozygote deletions in five, and gross gene rearrangements in five. The absence of protein expression in the tumors with one seemingly intact allele was not caused by promoter hypermethylation of p16(INK4A) or p14(ARF). All tumor samples expressed normal sized RB1, cyclin D3, CDK2, CDK4, p21(CIP1), and p27(KlP1) proteins, and only a single tumor showed an aberrant protein band for one of these proteins, p21(CIP1). Cyclin D1 was absent in four tumors; all except one tumor showed expression of TP53 protein, and three of nine MPNSTs had expression of normal-sized MDM2. In conclusion, this study shows that the vast majority of MPNSTs had gross rearrangements of the p16(INK4A) gene, explaining the absence of the encoded protein in the same tumors. The level of expression was equally distributed between the familial (NF1) and sporadic cases, although it should be noted that the 2 cases with p16(INK4A) expression were sporadic. The data imply that the complete absence of p16(INK4A) is sufficient for activation of the cell cycle in most MPNSTs; thus, it is not necessary for tumor proliferation to further stimulate the cycle through alteration of other central components.

The assessment of the elective clerkship at the University of Groningen consists of a written case report, graded by one of four independent reviewers, and a rating of clinical performance by the students' supervisors. This study analyses the grades of 710 case reports and 189 ratings. The grades were found to be normally distributed, similar for the reviewers and consistent over the years, but inter- or intra-observer variation was not studied. The ratings of clinical performance were skewed towards 'excellent'. There was a low correlation between the two assessments (Spearman's r = 0.25; p = 0.001). This may be attributed among other things to the large number of supervisors and the face-to-face assessment of clinical performance versus the distant assessment of a written document. A more relevant explanation, however, is that the case reports measure primarily cognitive aspects, as compared with overall clinical performance.

Background: Chemotherapy sensitivity of soft-tissue sarcomas (STS) is limited, which may be due to multidrug resistance (MDR). MDR is associated with expression of P-glycoprotein (P-gp), Multidrug Resistance-associated Protein 1 (MRP1) and Lung Resistance-related Protein (LRP). It is unknown whether in STS metastasis is more resistant than the primary counterpart., Materials and Methods: In 35 chemonaive STS and their metastases (86% chemonaive), MDR proteins were immunohistochemically assessed. Eleven metastases presented synchronously, 24 metachronously. Expression was scored positive (>5% positive tumour cells) or negative., Results: P-gp was positive in 31/34 primaries (91%), versus 22/32 metastases (69%) (p=0.005). This difference was significant for metachronous metastases (p=0.008). MRP1 was positive in 18/32 primaries (56%) and 22/33 metastases (67%). MRP1 was more expressed in synchronous metastases than primaries (p=0.047), but for the overall group this significance disappeared. LRP expression did not differ: 27/34 primaries (80%), versus 28/34 metastases (82%)., Conclusion: P-gp, MRP1, LRP expression in the primary tumours was high. Metastatic progression did not coincide with MDR-protein up-regulation.

Purpose: Postradiation sarcoma, a sarcoma developing in a previously irradiated field, is a rare tumor. Surgery appears to be the only curative treatment option. In general the prognosis is poor, and new treatments options are needed. One study reported the expression of KIT receptor tyrosine kinase in two postradiation angiosarcomas. Success of inhibition of KIT in malignant gastrointestinal stromal tumors with imatinib mesylate seems mutation-dependent, with a favorable response in the presence of exon 11 mutations., Experimental Design: We performed a clinical, immunohistochemical, and genetic assessment of postradiation sarcomas, including angiosarcomas. Archival tumor tissue was available from 16 patients diagnosed with a postradiation sarcoma between 1978 and 2001. Data on the first and secondary tumor, treatment, and follow-up was documented. KIT expression was assessed by immunohistochemistry. For comparison, 23 spontaneous soft tissue sarcomas of similar histological types were analyzed. Exon 11 of the c-kit gene was analyzed by direct DNA sequencing., Results: Fifteen patients received initial irradiation for malignant disease and 1 patient for a benign condition. The median delivered dose was 50 Gy. The median latency period between irradiation and diagnosis of postradiation sarcomas was 222 months. Histological types included: angiosarcoma, fibrosarcoma, malignant fibrous histiocytoma, osteosarcoma, rhabdomyosarcoma, and unspecified sarcoma. In concordance with the literature, patients had a poor outcome. Only 3 of 16 patients were disease-free 43, 60, and 161 months after being diagnosed of postradiation sarcoma, all 3 having favorable tumor and treatment characteristics. Fourteen of 16 tumor samples were KIT-positive (88%). In 8 cases >80% of tumor cells stained positively. Five of 23 (22%) spontaneous soft tissue sarcomas of comparable histological types, including 2 angiosarcomas, were KIT-positive. Molecular genetic analysis of exon 11 of the c-kit gene was attainable for 13 of the 16 postradiation sarcomas. No mutations were found., Conclusions: Postradiation sarcomas are aggressive malignancies, seldom amenable to curative treatment. A majority of the analyzed tumors showed extensive expression of the KIT protein, but no mutations in exon 11 of the c-kit gene were found. Still, without the availability of effective therapies, treatment with the KIT inhibitor imatinib mesylate might be considered for patients with postradiation sarcomas.

The biological behaviour of different histological types and grades of soft tissue sarcomas (STS) varies. This might result in a differing sensitivity to cytotoxic drugs. Cross-resistance to functionally and structurally distinct natural-product drugs, known as multidrug resistance (MDR), is associated with the overexpression of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and lung resistance-related protein (LRP). The purpose of this study was to evaluate the expression of P-gp, MRP1 and LRP in STS according to their histological type and grade. In 141 chemotherapy-naive STS patients, the expression of the three MDR proteins was detected by immunohistochemistry. Nine histological types were documented. These were 19% grade 1, 34% grade 2 and 47% grade 3 tumours. Expression of P-gp and LRP was observed more frequently than the expression of MRP1 (P<0.0001). P-gp expression was most pronounced in malignant fibrous histiocytoma (MFH), but was low in leiomyosarcomas. MRP1 was expressed in most malignant peripheral nerve sheath tumours (MPNST). LRP was strongly expressed in MFH and unspecified sarcomas, but was low in liposarcomas. MRP1 and LRP expression was significantly more common in grades 2 and 3 compared with grade 1 tumours. P-gp expression was correlated with MRP1, especially in grade 3 STS. In conclusion, P-gp, MRP1 and LRP are expressed in the majority of STS, but this expression varies according to the histological type. MRP1 and LRP, but not P-gp expression, were found to be correlated to tumour grade. MDR might contribute to the observed differences in clinical behaviour within the heterogeneous group of STS.

Background: Pediatric rhabdomyosarcomas (RMS) have a more advantageous prognosis after multimodality treatment compared with adult RMS, which might be related to a decreased sensitivity to chemotherapy in adults. Resistance to chemotherapy might be conveyed by the multidrug resistance (MDR)-associated proteins P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and lung resistance-related protein (LRP). It was therefore suggested that these proteins were expressed differently in pediatric and adult patients., Methods: The expression of P-gp, MRP1, and LRP was assessed immunohistochemically in 45 specimens of untreated RMS: 29 were obtained from children younger than 16 years old and 16 were obtained from adults. All children had an embryonal or botryoid RMS. Among the adults, there were 10 embryonal, 3 alveolar, and 3 pleomorphic RMS. Samples were scored as negative or positive according to the percentage of immunoreactive tumor cells: 0.5 (1-5%), 1 (5-25%), 2 (26-50%), 3 (51-75%), or 4 (> 75%)., Results: Expression of LRP was more pronounced in embryonal and pleomorphic RMS in adults compared with RMS in children. In addition, LRP expression correlated with age at diagnosis. Alveolar RMS had remarkably low LRP expression. Expression of P-gp and MRP1 did not differ significantly between children and adults., Conclusions: In this series of embryonal and pleomorphic RMS, an increased LRP expression was observed in adults, which may explain their worse response to chemotherapy reported in other studies. In alveolar RMS, a low LRP expression was observed, suggesting that other mechanisms are responsible for the resistant phenotype in most of these tumors., (Copyright 2003 American Cancer Society.)

Rhabdomyosarcomas generally respond well to chemotherapy, and the residual lesions often are better differentiated than their primaries. This phenomenon may be explained by selective multidrug resistance (MDR) of differentiated tumor cell populations. We assess the role of MDR proteins in chemotherapy-induced differentiation in rhabdomyosarcomas in a clinical setting. Paraffin-embedded samples of 13 pairs of primary untreated rhabdomyosarcomas and their residual, recurrent, or metastatic lesions after chemotherapy were assessed for expression of MDR proteins, including P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP-1), and lung resistance-related protein (LRP). Expression was semiquantitatively scored based on the percentage of isolated immunoreactive tumor cells as follows: 0, negative; 0.5, <5%; 1, 5% to 25%; 2, 26% to 50%; 3, 51% to 75%, and 4, >75%. All specimens after chemotherapy, except the late recurrences, were better differentiated than their primary, untreated specimens. Pgp or MRP-1 expression did not change significantly, but LRP expression increased significantly after chemotherapy. In both untreated and treated samples, LRP was expressed primarily in differentiated cells. The findings indicate that the in vivo expression of LRP, but not of Pgp and MRP-1, is induced by chemotherapeutic treatment in rhabdomyosarcomas. The preferential expression of LRP in differentiated cells and the subsequent more extensive expression after chemotherapy suggests that LRP plays a role in therapy-induced differentiation., (Copyright 2003, Elsevier Science (USA). All rights reserved.)

Identification of patients with a low grade glioma with a long-term recurrence-free survival is of clinical value as radiotherapy can be postponed until recurrence. The recurring glioma may increase in malignancy compared to the original tumor, which is possibly related to radiotherapy. We studied proliferation by counting mitotic figures and by MIB-1 labeling, apoptosis by TUNEL and expression of proteins related to cell cycle regulation by immunohistochemical analysis of p53, p21, bcl-2 and bax expression in 48 low grade gliomas. Astrocytomas (A, n = 14) and oligodendrogliomas (O, n = 4) with a recurrence-free survival of more than 9 years after surgery had a signficantly lower p53 index compared to A (n = 18) and O (n = 12) with a histopathologically documented recurrence. Additionally, the recurrence-free A had a higher p21 index. No significant differences were observed in MIB-LI, TUNEL-LI, bcl-2 and bax expression. Initially low grade gliomas and their corresponding recurrences were compared (n = 30). In the gliomas without radiotherapy (n = 15), no differences in mitotic rate, TUNEL-LI, p53, p21, bcl-2 and bax expression were found between primary tumors and their recurrences. Only MIB-LI was higher in the recurrent tumors. In the gliomas with radiotherapy (n = 15) no differences were detected in these parameters between the original tumor and the recurrent tumor except for a higher number of mitoses in the recurrent tumors. We conclude that low grade gliomas with a long-term recurrence-free survival were characterized by a low p53 protein expression and, in the case of A, a higher p21 index. We found no evidence that radiotherapy is involved in changes of proliferation, apoptosis or expression of proteins related to cell cycle regulation in recurring gliomas.

Most adult testicular germ cell tumors have a characteristic chromosomal abnormality that is an isochromosome 12p [i(12p)]. Furthermore, these tumors are characterized by a chromosome number in the triploid range and gains and losses of (parts of) specific chromosomes. Cytogenetic investigation of three cases of infantile testicular germ cell tumors, all diagnosed as yolk sac tumors, revealed highly abnormal karyotypes. We found one case to be diploid; the other two cases were in the hypertriploid/hypotetraploid range. Structural abnormalities of chromosomes 1, 3, and 6 were recurrent and no i(12p) was found. Our results, together with data from the literature, suggest that infantile and adult testicular germ cell tumors have a different origin and pathogenetic pathway. Aberrations of chromosomes 1, 3, and 6 may play an important role in the pathogenesis of infantile testicular yolk sac tumors.

Soft tissue sarcomas (STSs) are rare tumors, notorious for early hematogenous metastasizing. Metastatic disease is seldom amenable to curative treatment; therefore new treatment modalities are required. Treatment-related and tumor-related prognostic factors can be assessed to estimate the risk for subsequent metastases, as will be discussed. By this means, high-risk patients can be defined; they are the candidates for clinical trials mandatory for treatment development. The metastatic process as well as the reaction to chemotherapy depends on the biological make-up of the tumor. Current chemotherapy regimens do not improve the survival rates of patients with metastatic disease, due to resistance mechanisms of tumor cells. New drugs with direct access to the cell death machinery in tumor cells might contribute to more effective treatment of STS patients.

Purpose: Leiomyosarcomas (LMS) of deep and superficial tissues were examined to identify prognostic markers explaining their different biological behaviour and to define differences between cutaneous and subcutaneous LMS. LMS and leiomyomas (LM) of the skin were compared to and consistent differences that could aid in the (sometimes difficult) diagnosis., Patients: Material was obtained from 27 patients with a deep LMS, 14 with a superficial LMS, and 21 with a LM., Methods: Proliferation markers (mitotic and Ki-67 indices), DNA ploidy, size, grade, and the amount of apoptosis were studied. Statistical analysis was performed and survival curves were constructed by the Kaplan-Meier method and compared by the log-rank test., Results: Superficial LMS were smaller than deep LMS (p < 0.05), and the overall survival of patients with a superficial LMS was better than with a deep LMS (p < 0.05).Within the group of superficial LMS only entirely subcutaneous, and not cutaneous tumors metastasized.No differences were found in the other examined parameters. Proliferation and apoptotic indices were significantly higher in superficial LMS compared to superficial LM., Discussion: The difference in clinical outcome between patients with a superficial and deep LMS, seems to be related to site and size.The metastatic potential of subcutaneous LMS, however, seems to be related to location alone and not to size.The amount of apoptosis and proliferation can be used as additional criteria in the differentiation between superficial LMS and LM.

Background: Multidrug resistance (MDR) is associated with expression of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and lung resistance-related protein (LRP). Tumor necrosis factor (TNF-alpha) is able to modify the expression of these three proteins in different cell types. The effect of TNF-alpha in the clinical situation on patients with soft tissue sarcomas (STS) is indeterminate., Methods: Thirty-seven patients with a locally advanced extremity STS underwent hyperthermic isolated limb perfusion (HILP) with TNF-alpha and melphalan; 15 patients received additional interferon gamma. Clinical and histologic responses were documented and used to define the overall response. Samples before and after HILP were analyzed immunohistochemically for P-gp, MRP1, and LRP. Samples were scored as negative or positive (< or = 5% or > 5% positive tumor cells)., Results: Six patients had an overall complete response, 25 patients had a partial response, and 4 patients with STS revealed no change; in 2 patients, the response remained unclear. The percentage STS samples that were positive for all three proteins dropped from 92% before HILP to 85% after HILP. P-gp positive samples were encountered more often than MRP1 positive samples (P < 0.05). The percentage of samples that were negative for all three MDR proteins increased after HILP from 6% to 16%. MDR status had no significant correlation with tumor response., Conclusions: HILP with TNF-alpha and melphalan results in excellent overall tumor response in patients with locally advanced STS. STS more often are positive for P-gp than for MRP1. MDR status in patients with STS is not predictive for tumor response after HILP. Data from the current study suggest that the combination of TNF-alpha and melphalan does not induce MDR positive STS: a result with clinical importance when consecutive, adjuvant, doxorubicin-containing chemotherapy is considered., (Copyright 2001 American Cancer Society.)

Cardiac myxomas are significant causes of cardiovascular morbidity and mortality. Their genetic background is presently unknown. Recently, linkage analysis in cardiac myxomas of Carney complex patients has indicated that 2p16 and 17q2 might carry genes responsible for the development of hereditary cardiac myxomas. Less is known about sporadic cardiac myxomas. To date, cytogenetic analysis has been performed on 13 sporadic cases, and no specific rearrangement has been deduced. We studied 15 sporadic cardiac myxomas and reviewed the literature. Ten of the present cases revealed abnormal karyotypes with clonal and nonclonal rearrangements including dicentric chromosomes and telomeric associations. No cytogenetic evidence was found for a role of 2p16 in the development of sporadic cases. Region 17q2 was involved in structural rearrangements, but to a lesser extent than other regions. Structural rearrangements involving regions 12p1 and 17p1 are more frequently present and might therefore harbor genes important for the development of sporadic cardiac myxomas.

Purpose: Several studies have reported clinical behavior and chemotherapy resistance in leiomyosarcomas, but these studies did not differentiate between soft tissue leiomyosarcomas (LMS) and malignant gastrointestinal stromal tumors (GIST). Multidrug resistance (MDR) has been associated with the expression of P-glycoprotein (P-gp), multidrug resistance protein (MRP(1)), and lung resistance protein (LRP). The aim of the present study was to compare LMS and GIST with respect to clinical outcome and MDR parameters., Patients and Methods: Clinical outcome was evaluated in 29 patients with a primary deep-seated LMS and 26 patients with a primary malignant GIST. Paraffin-embedded material, available for 26 patients with LMS and 25 with GIST, was used for immunohistochemical detection of P-gp, MRP(1), LRP, and c-kit., Results: Mean overall survival (OS) was 72 months for LMS patients and 31 months for GIST patients (P: <.05). Metastases occurred in 16 (59%) of 27 assessable LMS patients and in 10 (56%) of 18 assessable GIST patients. LMS predominantly metastasized to the lungs (14 of 16 patients), whereas GIST tended to spread to the liver (five of 10 patients) and the abdominal cavity (three of 10 patients; P: <.001). P-gp and MRP(1) expression was more pronounced in GIST than in LMS (P: <.05): the mean percentage of P-gp expressing cells was 13.4% in patients with LMS and 38.4% in patients with GIST, and the mean percentage MRP(1) expressing cells was 13.3% in patients with LMS and 35.4% in patients with GIST. LRP expression did not differ between LMS and GIST. c-kit was expressed in 5% of the LMS patients and in 68% of the GIST patients., Conclusion: LMS patients have a better survival than GIST patients, and the metastatic pattern is different. Expression of MDR proteins in LMS is less pronounced than in GIST.

Background: In general, although biological behavior and prognosis of liposarcomas (LPS) are more favorable compared with most other soft tissue sarcomas (STS), prognosis can vary widely depending on tumor characteristics, especially histological subtype and tumor grade., Patients and Methods: All consecutive, completely resected stage I-III LPS (as determined by the American Joint Committee on Cancer staging guidelines), treated at the Groningen University Hospital from 1977-2000, were analyzed., Results: A total of 69 patients, 35 males and 34 females, median age 51 (range 11-80) years, were reviewed. After a median follow-up of 71 (range 5-231) months, the overall local recurrence and metastasis rate at five years after diagnosis were 27% and 16%, respectively. Retroperitoneal localization was a significant negative prognostic factor regarding local recurrence; dedifferentiation, grade II-III, and deep location regarding distant metastasis; and dedifferentiation, grade II-III, stage II-III, size >20 cm and non-radical resection regarding survival., Conclusions: LPS have a relatively mild biologic behavior, with the exception of very large, deeply located, dedifferentiated and/or grade II-III LPS. Radical resection is important for disease-specific survival. LPS have a relatively mild biologic behavior, with the exception of very large, deeply located, dedifferentiated and/or grade II-III LPS.

In hematoxylin-eosin-stained sections of 20 pediatric sarcomas the mitotic index was assessed by four experienced pathologists and four less-experienced observers without prior instructions. In adjacent sections immunolabeled for MIB-1, the proliferation index was assessed as the estimated percentage of labeled cells in the tumor cell population. ANOVA revealed that the variation between tumors explained 77% of the variation in mitotic indices in the group of experienced observers compared with 49% in the less experienced group. The variation between tumors explained 64% of the variation in proliferation indices in the experienced group and 71% in the less experienced group. The proliferation indices showed less variation between observers than the mitotic indices. No correlation was found between mitotic and proliferation indices. The results suggest that training is an important factor in the reliability of mitotic counting. The use of proliferation markers has a higher reproducibility, especially in less-experienced observers. However, for clinical use it has the disadvantage of being the more expensive, more time-consuming technique; moreover, the biological significance of proliferation has not been established and may differ from that of mitotic activity.

An 8-year-old girl presented with a cerebral tumor and 3 recurrences within 15 months. The primary tumor was a low-grade astrocytoma, but the recurrences showed progressively malignant phenotypes with increasing mitotic activity and MIB-1 labeling indices. Radiotherapy was given between the first and the second recurrences. Cytogenetic analysis of the first and the second recurrences showed abnormal karyotypes. There seemed to be 2 common breakpoints in these 2 recurrences. TP53 gene mutation screening, using comprehensive denaturing gradient gel electrophoresis, revealed among others a possibly causative mutation of exon 5 in 3 of 4 tumor samples. The meaning of TP53 mutations in low-grade astrocytomas is still unclear, but the highly abnormal karyotypes, which are unusual in these tumors, probably provide genetic evidence for the unexpected aggressive behavior of the tumor in this patient.

The radiolabeled amino acid L-3-[123I]-iodo-alpha-methyltyrosine (IMT) is a new tumor tracer that accumulates in many tumors and is suitable for single photon emission computed tomography (SPECT) imaging. Using IMT SPECT, we studied 32 patients with a soft-tissue tumor suspected to be a soft-tissue sarcoma to determine whether: (a) tumors can be visualized; (b) benign and malignant lesions can be distinguished; and (c) IMT uptake is related to tumor grade and proliferation. Whole-body imaging was performed 15 min after administration of 300 MBq IMT, biopsy, or resection 1-2 weeks later. IMT uptake was quantified using a region-of-interest method resulting in tumor:background (T:B) ratios. These were compared with tumor grade, mitotic index, tumor cellularity, vascularity, and the Ki-67 proliferation index. Eleven patients had a benign tumor, and 21 patients had a soft-tissue sarcoma. Six benign tumors demonstrated minor IMT uptake, and five lipomas had no uptake. All malignant tumors had high uptake and were clearly visualized. T:B ratios in malignant tumors (3.83 +/- 1.16) were higher (P < 0.001) than in benign tumors (1.52 +/- 0.60). Small (<5 mm) metastases in two patients were not detected. Taking the T:B ratio 2.0 as the cutoff level, the sensitivity for detection of malignancy was 100%, and specificity was 88%. IMT uptake correlated with histological grade (r = 0.82; P < 0.001), mitotic index (r = 0.75; P < 0.001), tumor cellularity (r = 0.73; P < 0.01), and with the Ki-67 proliferation index (r = 0.63; P < 0.01). In conclusion, IMT SPECT visualized all soft-tissue sarcomas. Uptake in sarcomas was clearly higher than in benign lesions, yielding 100% sensitivity for detection of malignancy at 88% specificity. Uptake increased with higher tumor grade and higher proliferation rate.

Background: Chromosome breakage could influence the expression of genes. This has been noticed in specific cases of acute myeloid leukaemia, where the 16p13 breakpoint affects the expression of the multidrug resistance related protein (MRP). Myxoid liposarcomas (LPS) are characterized by the t(12; 16)(q13; p11), which leads to the formation of a FUS-CHOP fusion transcript. This study investigates the relationship between the cytogenetically detected breakpoint 16p11 in myxoid LPS, the presence of the FUS-CHOP fusion transcript in nonmyxoid LPS and the expression of the lung resistance major vault protein (LRP) gene on 16p11.2., Materials and Methods: Of 16 cases with a diagnosis of a (possible) liposarcoma with an abnormal karyotype, fresh frozen tumour material was available for immunohistological detection of LRP. Cases without a cytogenetically detected t(12; 16)(q13; p11), were analyzed for the presence of a FUS-CHOP fusion transcript by RT-PCR., Results: In all 9 myxoid LPS a t(12; 16)(q13; p11) was found and LRP expression was absent or low. In none of the remaining 7 cases was a FUS-CHOP fusion transcript found, and four tumours were LRP positive (P = 0. 02). LRP expression in myxoid LPS (mean: 1.3%) was lower (P = 0.07) than in the nonmyxoid tumours (mean: 35.7%)., Conclusions: These observations indicate a relation between the t(12; 16)(q13; p11), leading to a FUS-CHOP fusion transcript in myxoid LPS, and the low or absent expression of the LRP-gene located on 16p11.2.

A rare case of a spinal papillary meningioma in a 19-year-old adolescent is described. Six months after radical resection the patient showed dissemination along the cerebrospinal pathway. Papillary meningiomas are rare tumours with a relatively high incidence in childhood. Most papillary meningiomas reported in the literature are considered as aggressive variants of meningioma with often local recurrence, dissemination in the CSF and metastases to remote sites. This case supports that, although the histogenesis remains unexplained, papillary meningiomas deserve recognition on the basis of their high morbidity and mortality.

The purpose of the study was to gain insight into epidemiological aspects of soft tissue sarcomas (STS), based on the population-based cancer registry of the Comprehensive Cancer Center North-Netherlands (CCCN), and to provide data for the development of future STS clinical trials. 456 primary STS (Kaposi, urogenital and gastro-intestinal STS excluded), registered from 1989 to 1995 by the cancer registration of the Comprehensive Cancer Center North-Netherlands (CCCN), were analysed. The annual, age-adjusted, STS incidence was 3.6 per 100,000. Incidence increased with age. Half of the patients were over the age of 65 years. Malignant fibrous histiocytomas and liposarcomas were most frequently encountered. At presentation, nodal involvement was rare (3-8%). Distant metastases were more frequently encountered (9-14%), and appeared to be related to tumour size and site. Above 70 years of age, 16% of patients received no treatment at all, especially for metastatic disease.

Cytogenetic studies in small groups of patients with malignant peripheral-nerve-sheath tumors (MPNST) revealed complex karyotypes with no consistent changes. A computer-assisted cytogenetic analysis using a cytogenetic database was performed to determine recurrent cytogenetic alterations in 51 MPNSTs (44 from the literature and 7 new cases) and to allow direct cytogenetic comparison between NF-1-associated and sporadic MPNSTs. Significant loss (p < 0.05) was observed in the chromosomal regions 9p2, 11p1, 11q2 and 18p1. Also, loss in 1p3, 9p1, 11q1, 12q2, 17p1, 18q1-q2, 19p1, 22q1, X and Y was detected. Gain of chromosomal material was found in chromosome 7, especially 7q1 (p < 0.05). Most involved breakpoints were: 1p13, 1q21, 7p22, 9p11, 17p11, 17q11, 22q11. Cytogenetic differences between NF-1-associated and sporadic MPNSTs included a relative loss of chromosomal material in NF-1-associated MPNSTs in 1p3, 4p1 and 21p1-q2 and a relative gain in 15p1-q1. Differences in breakpoints between the NF-1 associated and the sporadic MPNST group were observed in 1p21-22 (28% of NF-1 vs. 0% of sporadic MPNSTs), 1p32-34 (17% vs. 0%), 8p11-12 (7% vs. 27%) and 17q10-12 (24% vs. 7%). This approach, in which the cytogenetic results of various reports are combined, shows that losses in 9p2 and gains in 7q1 could be of oncogenetic importance in MPNSTs. Loss of 17q1, on which the NF-1 gene has been located (17q11.2), is not a common cytogenetic finding in NF-1-associated MPNSTs. The observed differences between NF-1-associated and sporadic MPNSTs might reflect different oncogenetic pathways., (Copyright 1999 Wiley-Liss, Inc.)

In a previous study, it was shown that rhabdomyosarcomas widely express "neural" markers, such as neural cell adhesion molecules (N-CAM) and neurofilament protein isoforms. In the current study, a series of Ewing's sarcomas of bone and soft tissue sarcomas other than rhabdomyosarcoma was probed for the same antigens. It was found that N-CAM was widely expressed in the various sarcoma types, except Ewing's sarcomas, though less than in rhabdomyosarcomas. Similar to rhabdomyosarcomas, neurofilament isoforms were found throughout all sarcoma types but were largely restricted to those expressed early in neurogenesis, that is, poorly phosphorylated medium-weight isoforms. Neurofilament expression was most extensive in Ewing's sarcomas. It was concluded that the expression of "neural" markers (N-CAM, neurofilaments) is widespread in sarcomas and does not signify a neural tumor. The absence of N-CAM expression in Ewing's sarcoma may be helpful in its distinction from other sarcomas.

The value of AgNOR staining as a tumor biological marker was tested in 26 children with pilocytic astrocytomas (20) and fibrillary astrocytomas (6). All patients were surgically treated and then followed up by periodic MRI or CT scans. Follow-up ranged from 8 to 84 months, with a mean of 44 months. AgNOR expression was determined by using semi-automated computer-assisted surface area measurements. AgNOR values ranged from 1.4 to 81.4 microm(2) per cell, with a mean of 26.6 and a median of 15.2. The median value was taken as a "cut-off" score separating two groups of patients with low and high AgNOR scores. Of the 13 patients in the low scoring group, 8 had total resections without recurrence, 3 had stable residual tumors, 1 had regressing residual tumor after irradiation and 1 had a recurrence 5 years after neuroradiologically complete resection of a fibrillary astrocytoma. In the group with high AgNOR scores only 2 patients had total resections without recurrence; 5 had stable residual tumors and 6 had residual tumors that showed progression, all within 1 year after surgery. Among the patients with classic juvenile pilocytic astrocytomas of the cerebellum 7 had residual tumor, which progressed in 2 patients, both of whom had high AgNOR scores. Among 7 patients with optic/hypothalamic tumors the 3 with rapidly progressing tumors all had very high AgNOR scores. The determination of AgNOR expression might be helpful in selection of patients with residual tumor after surgery, who may benefit from additional chemotherapy or (stereotactic) radiation therapy.

Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan (HILP-TM) with or without IFN-gamma is a promising local treatment in patients with locally advanced extremity soft tissue sarcomas (STSs), with response rates of up to 84%. The mechanisms of the treatment response are poorly understood. Here, we determined the HILP-TM-induced changes in mitotic activity, proliferation, and apoptosis in 37 STSs; the additional effect of IFN-gamma; and the association of HILP-TM with treatment response and clinical outcome. On archival material, obtained before and 6-8 weeks after HILP-TM with (n = 15) or without (n = 22) IFN-gamma, the number of mitoses was counted, and the proliferation fraction was determined by immunohistological staining for the proliferation associated Ki-67 antigen (MIB1). Apoptosis was visualized by enzymatic detection of DNA fragmentation (terminal deoxynucleotidyl transferase-mediated nick end labeling method). Clinical and histological response, follow-up status, and survival were recorded. The number of mitoses dropped 57% and proliferation rate decreased with 40% after HILP-TM, whereas the amount of apoptosis after HILP-TM more than doubled as before HILP-TM. The addition of IFN-gamma to HILP-TM did not influence the changes in tumor parameters and did not affect treatment response. A better clinical response to HILP-TM was correlated with high mitotic activity and low amount of apoptosis in tumor samples before HILP-TM. Patients with highly proliferative STS before and after HILP-TM had a relatively poor prognosis. Furthermore, patients who developed distant metastases after HILP-TM had a relatively high number of dividing cells in the tumor remnants after treatment.

In adults, the TP53 tumor suppressor gene is frequently mutated in astrocytic brain tumors which is supposed to represent an early event in their development. In juvenile pilocytic and low-grade astrocytomas, however, TP53 mutations have until now been reported as rare, which has led to the suggestion that these tumors may follow a different molecular pathogenesis with an involvement of genes other than TP53. Our analysis of 20 pilocytic and two low-grade astrocytomas of childhood, based on a comprehensive denaturing gradient gel electrophoresis (DGGE) mutation detection assay of the entire coding region, including all splice site junctions of TP53, showed mutations considered as causative in 7 of the 20 (35%) pilocytic astrocytomas and in one of the two low-grade astrocytomas. Our finding is significantly different from the mutation frequency of 1.3% (2/155) previously reported for these tumor types. This may be attributed to the mutation detection system used, which also detects mutations occurring outside the evolutionary conserved region of TP53. Our results suggest that, contrary to the present notion, TP53 mutations may well play a role in the development of juvenile astrocytomas. Furthermore, no mutations were found in tumors of patients with progression of residual tumor after postoperative follow-up. This suggests that TP53 mutations may be associated with less aggressive forms of juvenile astrocytomas, analogous to the situation in adult astrocytomas.

Background and Purpose: In the 1980s a combined modality therapy of intraarterial doxorubicin, neoadjuvant radiotherapy and surgery was initiated at the Groningen University Hospital as a limb-saving treatment for locally advanced, primarily irresectable high-grade soft tissue sarcomas (STS) of the extremities. This study presents the short- and long-term results., Patients and Methods: Between 1983 and 1987, 11 patients were treated with intraarterial doxorubicin, preoperative radiotherapy (10 x 3.5 Gy) and surgical resection. Non-radical resections received additional postoperative radiotherapy of 20-30 Gy., Results: The limb-salvage rate was 91%, without local recurrences during a median follow-up of 84 months. Six patients died (55%); five from metastatic disease (45%). There were five long-term survivors with a median follow-up of 10 years. Three patients (60%) suffered serious late complications, resulting in disabilitating limb function., Conclusion: Although this approach is feasible as a limb-saving treatment for these unfavorable STS, long-term morbidity is high.

Unlabelled: This study was undertaken to investigate the relationship of PET using fluorodeoxyglucose (FDG) or L-[1-11C]-tyrosine (TYR) with histopathologic findings in soft-tissue tumors, before and after therapy. Histopathologic parameters that were studied were tumor grade, mitotic rate, proliferation activity and amount of necrosis., Methods: PET with either FDG or TYR was performed in 55 patients with a lesion suspected to be a malignant soft-tissue tumor. In 28 patients, a second PET study was performed after therapy. Metabolic rate of glucose consumption (MRglc) and protein synthesis rate (PSR) were calculated. Histologic parameters were obtained from a biopsy specimen that was taken just after the first PET study and from the tumor remnant that was resected after therapy., Results: MRglc correlated with tumor grade (r = 0.71) and mitotic rate (r = 0.68) but not with proliferation or necrosis. After therapy, there was no longer a correlation with mitotic rate. PSR correlated with tumor grade (r = 0.53), mitotic rate (r = 0.73) and proliferation (r = 0.66). After therapy, correlation with mitosis and proliferation had improved, and a negative correlation was found between PSR and necrosis (r = -0.74)., Conclusion: These results validate the use of both FDG and TYR to give an in vivo indication of histologic tumor parameters. However, FDG gives a better indication of tumor grade, whereas TYR is more accurate in predicting mitotic rate and proliferation, especially after therapy. FDG may therefore not be the most suited tracer for monitoring therapy. TYR might be more appropriate for that purpose.

A case of a 2-year-old boy with a palpable mass in the left thigh is presented. Incisional biopsy was performed and subsequent histopathological examination revealed an infiltrative tumor composed of relatively large cells. The tumor cells were immunoreactive for vimentin and keratin, but not for desmin or smooth muscle actin. Cytogenetic analysis showed a 46,XY,t(11;22)(q24;q12) karyotype. The translocation (11;22)(q24;q12) is said to be characteristic for the family of Ewing's sarcoma and related tumors. As a result of the t(11;22)(q24;q12) the EWS gene on chromosome 22q12 joins the 3' part of FLI-1 gene on chromosome 11q24, which encodes a member of the ets family of transcriptional regulators. Using reverse transcription polymerase chain reaction (RT-PCR) a corresponding EWS-FLI-1 fusion product was detected. Additional immunohistological staining for p30/p32MIC2, which is suggestive, but not specific for Ewing's sarcoma, appeared to be weakly positive. In the current case a diagnosis of Ewing's sarcoma was considered unlikely, because of the location of the tumor and the immunohistological profile. Nevertheless it was decided to treat the patient according to a Ewing's sarcoma protocol based on the genotype of the tumor. The findings were compared with other extraosseous pediatric small cell tumors showing the t(11;22)(q24;q12) described in the literature.

Unlabelled: PET with L-[1-11C]-tyrosine (TYR) was investigated in patients undergoing hyperthermic isolated limb perfusion (HILP) with recombinant tumor necrosis factor alpha (rTNF-alpha) and melphalan for locally advanced soft-tissue sarcoma and skin cancer of the lower limb., Methods: Seventeen patients (5 women, 12 men; age range 24-75 y; mean age 52 y) were studied. TYR PET studies were performed before HILP and 2 and 8 wk afterwards. The protein synthesis rates (PSRs) in nanomoles per milliliter per minute were calculated. After final PET studies, tumors were resected and pathologically examined. Patients with pathologically complete responses (pCR) showed no viable tumors after treatment. Those with pathologically partial responses (pPR) showed various amounts of viable tumors in the resected tumor specimens., Results: Six patients (35%) showed a pCR and 11 patients (65%) showed a pPR. All tumors were depicted as hot spots on PET studies before HILP. The PSR in the pCR group at 2 and 8 wk after perfusion had decreased significantly (P < 0.05) in comparison to the PSR before HILP. A significant difference was found in PSR between the pCR and pPR groups at 2 and at 8 wk (P < 0.05). Median PSR in nonviable tumor tissue was 0.62 and ranged from 0.22 to 0.91. With a threshold PSR of 0.91, sensitivity and specificity of TYR PET were 82% and 100%, respectively. The predictive value of a PSR > 0.91 for having viable tumor after HILP was 100%, whereas the predictive value of a PSR < or = 0.91 for having nonviable tumor tissue after HILP was 75%. The 2 patients in the pPR groups with a PSR < 0.91 showed microscopic islets of tumor cells surrounded by extensive necrosis on pathological examination., Conclusion: Based on the calculated PSR after HILP, TYR PET gave a good indication of the pathological outcome. Inflammatory tissue after treatment did not interfere with viable tumor on the images, suggesting that it may be worthwhile to pursue TYR PET in other therapy evaluation settings.

With the introduction of new (immuno-)histochemical techniques it is now possible to assess rates of proliferation and apoptosis in brain gliomas using archival paraffin embedded material. As proliferation and apoptosis are related to tumour growth rate quantification of these processes has prognostic value and is related to tumour grading. In this study we assessed the proliferation rate by measuring the Ki-67 labelling index using the MIB-1 antibody (MIB-LI) and the apoptotic rate using the in situ labelling of DNA strand breaks with TUNEL (TUNEL-LI) in 315 supratentorial gliomas. MIB-LI and TUNEL-LI in astrocytomas (A) where significantly lower compared to anaplastic astrocytomas (AA), glioblastomas (GBM) and oligodendroglial tumours [oligodendrogliomas (O) and anaplastic oligodendrogliomas (AO)]. MIB-LI and TUNEL-LI were significantly lower in AA compared to GBM. In astrocytic tumours MIB-LI and TUNEL-LI appeared to be correlated. As the distinction between A and AA is of clinical value but can be difficult histomorphologically we analysed the prognostic value of MIB-LI and TUNEL-LI in gliomas with particular emphasis on A and AA. MIB-LI below 10% was of prognostic value in A and AA, O and AO but not in GBM on univariate survival analysis. TUNEL-LI was of no prognostic value. With multivariate survival analysis MIB-LI lost prognostic significance in O and AO. Astrocytomas with a gemistocytic component (AG) are similar to A with respect to survival and MIB-LI and TUNEL-LI. MIB-LI is of independent prognostic value in A and AA. Assessment of MIB-LI in A and AA can be used as an aid in distinguishing A and AA.

In a series of rhabdomyosarcomas, the expression of neural cell adhesion molecules (NCAM) and neurofilament isoforms was probed in frozen sections. It was found that NCAM was widely expressed in rhabdomyosarcomas without relation to subtype or differentiation level. Neurofilament isoforms were found throughout all subtypes but were largely restricted to those neurofilament isoforms that are expressed early in neurogenesis, that is, poorly phosphorylated low- and medium-weight isoforms. It was concluded that the expression of these "neural" markers is widespread and does not signify a neural tumor.

Background: Adjuvant chemotherapy and endoprosthetic replacement for bone sarcomas of the lower extremity is well established. The specific long-term consequences of these endoprosthetic reconstructions for the patient's affected limb are unknown., Method: The oncologic results and the survival of the endoprostheses were reviewed in 32 patients with primary bone sarcoma of the femur or proximal tibia. There were 26 high-grade sarcomas, and 6 low-grade sarcomas. A proximal femoral endoprosthesis was used for reconstruction in 4 patients, a total or push-through femoral endoprosthesis in 11 patients, a distal femoral endoprosthesis in 15 patients, and a proximal tibial endoprosthesis in two patients., Results: Median survival was 10 years (range, 1.1 to 18.9 years) for patients with high-grade sarcoma, and 8.1 years (range, 7.1 to 10 years) for patients with low-grade sarcomas. Distant metastases developed in seven patients (22%), all with stage IIB sarcoma, with concomitant local recurrence in 3 patients (9%). Five-year overall and disease-free survival rates for high-grade sarcomas were 81% and 73%, respectively. The overall endoprosthetic survival rate was 87% at 5 years, 80% at 10 years, and 56% at 15 years. Median follow-up of the original endoprostheses was 8.3 years (range, 0.6 to 18.7 years). Endoprosthesis-related complications occurred in 13 patients (41%); most complications were mechanical failures. The highest complication rate was found in distal femoral replacements (60%); amputation was necessary in both patients treated with a proximal tibial endoprosthesis. Five endoprostheses (16%) were revised. An amputation of the involved limb was performed in four patients (13%): in two patients because of local recurrence and in the other two patients because of infection. For patients alive at follow-up, the median functional Enneking evaluation score was 22 points (range, 12 to 28 points), with the highest functional scores in patients with a distal femoral endoprosthesis, and the lowest functional scores in patients with total or push-through femoral replacements., Conclusion: Endoprosthetic reconstructions gave satisfying functional results in most patients after long-term survival. However, the proximal tibial and distal femoral endoprosthesis are particularly at risk for long-term endoprosthetic complications requiring additional surgical procedures.

In a 48-year-old man who suffered from progressive loss of vision in his left eye and metamorphopsia, pseudoxanthoma elasticum was diagnosed. Angioid streaks were observed in both eyes and the skin showed small yellow papules in a linear pattern. The right retina was twice treated by laser coagulation which resulted in temporary regression of neovascularization. Pseudoxanthoma elasticum is a genetic disorder with variable penetrance. There is no treatment. Patients should be told to refrain from contact sports and to avoid using aspirin.

Background: Mature teratoma is often found in resected retroperitoneal residual tumor masses (RRTM) after chemotherapy for disseminated nonseminomatous testicular germ cell tumors (NSTGCT). The aim of this report is to describe the clinical course of patients after resection of residual teratoma, with particular emphasis on relapse with either growing mature teratoma or secondary non-germ cell malignancy., Methods: During the period 1979-1995, 113 patients underwent a laparotomy for resection of RRTM after chemotherapy for NSTGCT. Only patients with mature teratoma in the RRTM were included in the current study, and data on the patients who experienced relapse were studied in detail., Results: Mature teratoma was found in 51 patients (45.1%) with RRTM resected after chemotherapy. Nine of these 51 patients (17.6%) relapsed; the relapses resulted from growing mature teratoma in 5 patients (9.8%), secondary non-germ cell malignancy in 3 patients (5.9%), and recurrent germ cell malignancy in 1 patient (2.0%). The primary treatment for all relapsing patients was surgical excision. All five patients with growing mature teratoma are alive without evidence of disease, as is the patient with recurrent germ cell malignancy. One of the three patients with non-germ cell malignancy died of disease, and the remaining two are alive with disease., Conclusions: Long term follow-up after resection of postchemotherapy residual teratoma is indicated because a proportion of patients develop growing mature teratoma or a secondary non-germ cell malignancy. The treatment for these recurrences should be complete surgical excision.

The proliferative potential of 39 pilocytic and 5 low grade astrocytomas was studied in relation to the Ki-67 activity as measured by the MIB-1 Labelings Index. The results were correlated to the biological behaviour of the tumor as measured by clinical and neuro-radiological (CT- or MRI-scans) follow-up of the patient. This study was undertaken to answer the question whether MIB-1 expression reflects differences in biological behaviour of these tumors, such as rapid progression of residual tumor or stable remaining tumor. MIB-1 LI values ranged from 0 to 19% in the group of pilocytic astrocytomas (mean 4.2%) and from 0 to 15% in the 5 low grade astrocytomas (mean 4,2%). All patients were operated and 23 of them had incomplete tumor resection as proven on postoperative neuro-imaging studies. Those 23 patients could be subdivided into two groups; one without progression of residual tumor during follow-up (n=12) and the other with tumor progression (n=11). mean MIB-1 LI in the group with 'quiescent' tumor tended to be lower than in the group with progressive tumor: 3,3% vs. 6,6%. Residual tumors which were negative for MIB-1 staining showed fewer progressions of residual tumor compared to those being positive for MIB-1 staining, however this difference was not significant (p=0, 15, Fisher exact test). Tumor samples of a second operation of the same patient had lower MIB-1 LI values than those of the samples taken at first operation. The proliferating potential seemed to be decreased after part of the tumor was resected. Pilocytic astrocytomas with a negative MIB-1 LI are unlikely to show progression of residual tumor after partial resection. MIB-1 staining might be an additional tool in determining the frequency and duration of follow-up and in making decisions regarding further treatment of a patient operated for a pilocytic astrocytoma with residual tumor.

Purpose: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic antitumor effect in locally advanced extremity soft-tissue sarcomas (STS). The aim of this study was to demonstrate the feasibility and efficacy of adjuvant radiotherapy after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed surgical resection., Methods and Materials: Between 1991 and 1995, 34 patients--16 males and 18 females, median age 50 (range 18-80) years--underwent HILP for locally advanced extremity STS. Resection of the residual tumor mass was performed in most patients after 6-8 weeks. Fifteen patients with histopathological viable tumor after resection received adjuvant 60-70 Gy external beam radiotherapy (EBRT) (44%, HILP + EBRT group). Nineteen patients received HILP without adjuvant EBRT (56%, HILP-only group). Five patients in the HILP-only group had also distant metastases (15%) and received HILP as a palliative treatment. Treatment morbidity, local recurrences, and regional and distant metastases were scored., Results: During a median follow-up of 34 months (range 8-54), limb salvage was achieved in 29 patients (85%): 14 patients after HILP + EBRT and 15 patients after HILP only. None of the patients from the HILP + EBRT group developed local recurrences; however, five patients from the HILP-only did (26%) (p < 0.05). Regional metastases were observed in one patient from the HILP + EBRT group (7%) and in two patients from the HILP-only group who were treated with curative intent (14%). Distant metastases occurred in four patients after HILP + EBRT (27%) and in four patients after HILP only with curative intent (29%). The mean morbidity (subjective, objective, medical management, and analytical evaluation) score in both groups was, respectively, 0.33 for skin and subcutaneous tissue and for muscle and soft tissue, 0.34 (HILP + EBRT group) and 0.33 (HILP-only group)., Conclusion: Adjuvant EBRT after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed tumor resection of locally advanced extremity STS is feasible and may increase local tumor control without increasing treatment morbidity.

The management of locally advanced soft-tissue sarcomas (STS) of the extremities in patients who present with regional and/or distant metastases at the time of diagnosis remains an unsolved problem. The recently introduced hyperthermic isolated limb perfusion (HILP) with tumour necrosis factor (TNF)-alpha and melphalan has been shown to be an effective limb-saving treatment modality, but is it feasible to use this approach with palliative intent? Nine patients, five men and four women, mean age 41 (range 21-75) years with locally advanced extremity STS and regional (n = 3) or distant (n = 6) metastases at the time of diagnosis, underwent a palliative HILP with TNF-alpha and melphalan. Resection of the residual tumour mass was performed, if possible, 6-8 weeks after HILP. Treatment-related morbidity, local recurrences and the limb salvage rate were scored during follow-up. The median follow-up period was 9 (range 3-39) months (seven deaths, but six were due to metastatic disease). Treatment-related morbidity was seen after 3 of the 10 perfusions performed (30%) and consisted of superficial wound infections (n = 2), blow out of the external iliac artery followed by an iliac thrombosis (n = 1). Two patients showed local recurrences after HILP followed by resection of the residual tumour mass, and one patient showed local progression after two perfusions without resection. Limb salvage was achieved in 8 patients (89%). Therefore, HILP with TNF-alpha and melphalan for locally advanced extremity STS in patients with disseminated disease is feasible. The local management of locally advanced extremity STS should be the same whether the intent is curative or palliative, as the local control improves the quality of life.

Colloid cysts of the third ventricle have been investigated by chemical characterization of the cyst contents using ELISA with monoclonal antibodies for certain carbohydrate epitopes as well as a polyclonal antiserum against peptide domains, and immunohistochemistry on the cyst wall using the same antibodies. Furthermore, the carbohydrate composition of one sample has been determined after gel filtration. The cyst contents reacted strongly with the monoclonal antibody for the sulfo-Lewis epitope, and with the antimucin polyclonal antiserum. In one case the cyst fluid exhibited a blood group A antigen. A sample of cyst wall obtained by biopsy showed strong immunoreactivity against sulfo-Lewis antigen, and the sialo-Lewis antigen. The presence of the S atom with its high atomic number relative to that of C, H, and O atoms, may contribute to the high density appearance of colloid cysts on CT-scans. The sulfo-Lewis and sialo-Lewis carbohydrate epitopes are known as ligands for selectins, involved in inflammatory processes, and may well account for the aseptic meningeal reaction that may follow spilling of cyst contents during operative evacuation. The carbohydrate epitopes exhibited by colloid cysts and their contents, have also been reported for the mucins of salivary glands, uterine cervix, gall bladder and colon, and therefore, are not inconsistent with the assumption of an endodermal origin of colloid cysts.

Pelvic girdle chondrosarcomas in children and adolescents are extremely rare. These high grade malignant chondrosarcomas with a locally aggressive growth pattern have a high tendency for thrombus formations in the afferent tumour vessels, associated with an increased risk of inferior vena cava thrombosis, pulmonary embolism and metastatic spread to the lungs. This tumour location is generally non-resectable for cure and, since adjuvant chemotherapy is ineffective, patients die from the tumour thrombus formation causing tumour emboli and metastatic disease to the lungs. Effective local tumour control can be achieved with high-dose hyperfractionated radiation therapy.

In patients with disseminated nonseminomatous testicular germ cell tumors (NSTGCT), a retroperitoneal residual tumor mass (RRTM) and/or a pulmonary residual tumor mass (PRTM) are often present after successful treatment with cisplatin-based polychemotherapy. Results and complications of postchemotherapy resection of PRTM were studied and survival was calculated. In the period 1979 to 1996, 31 patients with a median age of 28 years (range, 17 to 44 years) underwent 32 thoracotomies for the resection of a PRTM. A solitary lesion was encountered nine times (28.1%) and multiple lesions were encountered 23 times (71.9%). The median size was 15 mm (range, 2 to 60 mm). There were only three major postoperative complications (9.6%): prolonged ventilation, pneumothorax, and pneumonia. In 16 patients (51.6%), the resected PRTM showed mature teratoma, while in four patients (12.9%) it showed viable cancer. In 11 patients only necrosis and/or fibrosis were found (35.5%). Resection of an RRTM had been performed prior to thoracotomy in 20 patients. There was dissimilarity between the histologic features of the resected RRTM and PRTM in 10 of the 20 patients (50%). During a median follow-up of 80 months (range, 2.5 to 203 months), five patients died from metastatic disease (16.1%). The 5-year survival rate was 86.8% and the 10-year survival rate was 82.2%. Owing to the dissimilarity between the histologic features of the postchemotherapy resected RRTM and PRTM in 50% of the patients, all sites of pulmonary residual disease must be resected in patients with disseminated NSTGCT, irrespective of the histologic features of previously resected retroperitoneal residual disease. This approach offers minimal morbidity and a high 10-year survival rate.

Purpose: We determined sexual functioning after chemotherapy for disseminated nonseminomatous testicular germ cell tumor, and evaluated the impact of resection of post-chemotherapy residual retroperitoneal tumor., Materials and Methods: A total of 155 consecutive patients treated with chemotherapy for disseminated nonseminomatous testicular germ cell tumor (between 1980 and 1994) was questioned about their sexual functioning. The patients were divided in 2 subgroups: patients treated with or without resection of post-chemotherapy residual retroperitoneal tumor. Volume and location (divided into left para-aortal or right paracaval/interaortacaval) of the resected tumor were related to absence of ejaculation as well as decreased semen amount. In addition, libido, arousal, erection and orgasm were related to ejaculatory dysfunction., Results: A total of 43 patients (27.7%) was treated with chemotherapy only and 112 (72.3%) had additional resection of post-chemotherapy residual retroperitoneal tumor mass. Overall, 22.4% reported loss of libido, 14.1% decreased arousal, 16% erectile dysfunction, 23.1% decreased orgasmic intensity, 17.4% decreased semen amount and 18.7% complete absence of antegrade ejaculation. With exception of absence of ejaculation, sexual dysfunctions were reported in similar frequencies in both treatment subgroups. In the resection of post-chemotherapy residual retroperitoneal tumor subgroup, 25.9% of the patients had complete absence of ejaculation. The other sexual dysfunctions were related neither to decreased semen amount nor to complete absence of ejaculation. The mean volume of resected tumor was higher (95 cm.3) in patients with absence of ejaculation than in those without (40 cm.3), and patients with right paracaval/interaortacaval tumor (20 of 58, 34.5%) reported more often absence of ejaculation than those with left para-aortal tumor (9 of 54, 16.7%)., Conclusions: In patients treated for disseminated nonseminomatous testicular germ cell tumor, post-chemotherapy sexual morbidity cannot be neglected. Except for loss of antegrade ejaculation, sexual dysfunctions are not related to resection of post-chemotherapy residual retroperitoneal mass. A high volume of tumor and a right paracaval/interaortacaval location predispose to loss of antegrade ejaculation.