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Biomedical subjects

Alexander M M Eggermont

Publications and source records attributed to Alexander M M Eggermont.

At least 19 recordsLinked to original sources

Years of life lost in patients with a false-negative diagnosis of primary melanoma. A prospective study of the German Central Malignant Melanoma Registry involving 9063 patients over 28 years.

A false-negative diagnosis of cancer can lead to a delay in effective treatment and a poorer prognosis. Here, we use the example of cutaneous melanoma to examine how many years of life are lost after a false-negative diagnosis compared to a primarily correct diagnosis. From 1996 to 2015, 9,063 patients are prospectively registered in the German Central Malignant Melanoma Registry and followed up until December 2023. A false-negative diagnosis is found in 206 (2.3%) patients. The median time to correct diagnosis is 24.0 months. The 10-year recurrence-free survival probabilities are 32.9% for false-negative diagnoses and 76.2% for correct diagnoses (p&#x2009;<&#x2009;0.001). The 10-year melanoma-specific survival probabilities are 62.1% versus 85.0% (p&#x2009;<&#x2009;0.001). On average, each person with an initial false-negative diagnosis loses 8.2 years of life compared to people with a correct diagnosis. This high number of years of life lost raises the question of whether similar results also apply to other types of cancer.

Humans↗

Differential effects of matrix and growth factors on endothelial and fibroblast motility: application of a modified cell migration assay.

Cell migration is crucial in virtually every biological process and strongly depends on the nature of the surrounding matrix. An assay that enables real-time studies on the effects of defined matrix components and growth factors on cell migration is not available. We have set up a novel, quantitative migration assay, which enables unharmed cells to migrate along a defined matrix. Here, we used this so-called barrier-assay to define the contribution of fibronectin (FN) and Collagen-I (Col-I) to vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and lysophosphatidic acid (LPA)-induced cell migration of endothelial cells (EC) and fibroblasts. In EC, both FN and Col-I stimulated migration, but FN-induced motility was random, while net movement was inhibited. Addition of bFGF and VEGF overcame the effect of FN, with VEGF causing directional movement. In contrast, in 3T3 fibroblasts, FN stimulated motility and this effect was enhanced by bFGF. This motility was more efficient and morphologically completely different compared to LPA stimulation. Strikingly, directional migration of EC was not paralleled by higher amounts of stable microtubules (MT) or an increased reorientation of the microtubule-organizing centre (MTOC). For EC, the FN effect appeared concentration dependent; high FN was able to induce migration, while for fibroblasts both low and high concentrations of FN induced motility. Besides showing distinct responses of the different cells to the same factors, these results address contradictive reports on FN and show that the interplay between matrix components and growth factors determines both pattern and regulation of cell migration. J. Cell. Biochem. 99: 1536-1552, 2006. (c) 2006 Wiley-Liss, Inc.

3T3 Cells↗

Giant solitary fibrous tumour of the liver.

BACKGROUND: Solitary fibrous tumour (SFT) is an uncommon mesenchymal neoplasm that most frequently affects the pleura, although it has been reported with increasing frequency in various other sites such as in the peritoneum, pericardium and in non-serosal sites such as lung parenchyma, upper respiratory tract, orbit, thyroid, parotid gland, or thymus. Liver parenchyma is rarely affected. Clinically, SFTs cause symptoms after having reached a certain size or when vital structures are involved. In recent years, SFTs are more often identified and distinguished from other tumours with a similar appearance due to the availability of characteristic immunohistochemical markers. CASE PRESENTATION: In this manuscript we report the case of a large tumour of the liver, which was histologically diagnosed as a SFT, and showed involvement of a single hepatic segment. Because of the patient's presentation and clinical course, it may represent a radiation-induced lesion. CONCLUSION: When a SFT has been diagnosed, surgery is the treatment of choice. The small number of patients with a SFT of the liver and its unknown natural behaviour creates the need to a careful registration and follow-up of all identified cases.

Journal Article↗

Synergistic antitumor effects of histamine plus melphalan in isolated hepatic perfusion for liver metastases.

BACKGROUND: Nonresectable primary and metastatic liver tumors remain an important clinical problem. Melphalan-based isolated hepatic perfusion (M-IHP) leads to more than 70% objective responses in selective groups of patients with nonresectable metastases confined to the liver. Complete responses are rare and progression-free survival is limited. Tumor necrosis factor (TNF), a very active agent in isolated limb perfusion, is linked to serious hepatotoxicity, restricting its use in IHP. Because of its vasoactive properties, histamine (Hi) is an alternative to TNF. In this article we evaluate its potential synergistic effect in M-IHP, improving response rates. METHODS: Our experimental rat IHP model is used for the treatment of soft tissue sarcoma liver metastases. Blood samples are collected for monitoring liver enzymes. Livers are excised 72 h and 7 days after treatment for histologic evaluation. RESULTS: After sham-IHP and Hi-IHP, tumor progression was observed in 100% of treated animals, while after M-IHP this number fell to 62% and after Hi + M-IHP it fell to only 22% (P = 0.006). Overall response rates were of 55% for Hi + M-IHP vs. 25% for M-IHP, and, more importantly, complete responses (CR) were observed only after Hi + M-IHP (22%) (P = 0.009). Hepatotoxicity peaked within 24 h after IHP, independent of the treatment administered, recovered in 48 h, and was related mainly to the elevation of transaminases (grade 3 ASAT and grade 1 ALAT for control group and grades 3 and 4, respectively, for all other treatments). No serious systemic toxicity was observed. Histology of the liver showed no serious damage. CONCLUSION: Hi + M-IHP has synergistic antitumor effects without any increase in regional or systemic toxicity.

Animals↗

Intratumoural expression of TNF-R1 and EMAP-II in relation to response of patients treated with TNF-based isolated limb perfusion.

Tumour necrosis factor-alpha (TNF) has been used in the clinic for more than 10 years in an isolated limb perfusion (ILP). However, intra-tumoural expression of TNF receptor-1 (TNF-R1) and TNF-R1 upregulating factors are unknown. We determined the expression of TNF-R1, proEMAP and endothelial monocyte-activating polypeptide-II (EMAP-II) before and after ILP and evaluated this against clinical response. Tumour biopsies were taken before and after ILP of patients (n = 27) with advanced sarcoma or metastatic melanoma. Biopsies were randomly analysed by western blotting for proEMAP/EMAP-II and TNF-R1 expression. Appropriate melanoma biopsies were stained for EMAP-II, TNF-R1, CD31 and CD68. For melanomas we found that an up-regulation of EMAP-II, in contrast to proEMAP or TNF-R1, directly after ILP significantly correlated with a complete tumour response. No correlation was found for sarcoma patients. In a comparative analysis we found that the overall proEMAP and EMAP-II expression was higher in melanoma as compared to sarcoma cases and measurements in cell lines revealed high proEMAP expression by melanoma cells. We report high EMAP-II expression by endothelial cells and association with macrophages. In addition, macrophages are recruited to vessel-remnants after ILP. An upregulation of EMAP-II directly after ILP of melanoma patients correlates with and might predict a complete response to TNF-based ILP. The association of macrophages with EMAP-II expression and vascular damage suggests a role for EMAP-II in regulating the TNF-based anti-tumour effects observed with an ILP. Analysis of EMAP-II expression in melanoma biopsies should be implemented in the ILP procedure.

Adult↗

Endothelial monocyte-activating polypeptide-II and its functions in (patho)physiological processes.

Endothelial monocyte-activating polypeptide-II (EMAP-II) is a pro-inflammatory cytokine with anti-angiogenic properties. Its precursor, proEMAP, is identical to the p43 auxiliary component of the tRNA multisynthetase complex and therefore involved in protein translation. Although most of the activities have been ascribed to the active form EMAP-II, also p43 has reported cytokine properties. ProEMAP/p43 and EMAP-II act on many levels and on many cell types including endothelial cells, immune cells and fibroblasts. In this review we summarize all available data on isolation, expression and functions of EMAP-II both in physiological processes as well as in pathological settings, like cancer. We also discuss the different reported mechanisms for processing of proEMAP/p43 into EMAP-II. Finally, we speculate on the possible applications of this cytokine for (cancer) therapy.

Amino Acid Sequence↗

Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion.

Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting.

Animals↗

Isolated limb perfusion for an irresectable melanoma recurrence in a Jehovah's witness.

Isolated limb perfusion (ILP) is a treatment option for irresectable melanoma lesions, because with ILP 20-fold higher concentrations of chemotherapy can be achieved locally than is systemically possible and high response rates are subsequently achieved. Jehovah's witnesses do not accept any form of blood transfusion, either autologous or homologous blood or only blood products. The use of an extracorporeal circuit, without the use of any blood products is acceptable for Jehovah's witnesses. The case of a 59-year-old Jehovah's witness with an irresectable melanoma recurrence for which an ILP. Because of adequate blood flow through the perfused limb, the limb did not become acidotic, even though there was a significant drop in the Hb concentration in the limb during the ILP. Isolated limb perfusions without the use of any blood transfusion products are technically possible, but an adequate preoperative hemoglobin concentration is a prerequisite.

Blood Transfusion↗

Outcome and prognostic factor analysis of 217 consecutive isolated limb perfusions with tumor necrosis factor-alpha and melphalan for limb-threatening soft tissue sarcoma.

BACKGROUND: Extensive and mutilating surgery is often required for locally advanced soft tissue sarcoma (STS) of the limb. As it has become apparent that amputation for STS does not improve survival rates, the interest in limb-preserving approaches has increased. Isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF) and melphalan is successful in providing local tumor control and enables limb-preserving surgery in a majority of cases. A mature, large, single-institution experience with 217 consecutive ILPs for STS of the extremity is reported. METHODS: At a prospectively maintained database at a tertiary referral center, 217 ILPs were performed from July 1991 to July 2003 in 197 patients with locally advanced STS of the extremity. ILPs were performed at mild hyperthermic conditions with 1-4 mg of TNF and 10-13 mg/L limb-volume melphalan (M) for leg and arm perfusions, respectively. RESULTS: The overall response rate was 75%. Limb salvage was achieved in 87% of the perfused limbs. Median survival post-ILP was 57 months and prognostic factors for survival were Trojani grade of the tumor and ILP for single versus multiple STS. The procedure could be performed safely, with a perioperative mortality of 0.5% in all patients with no age limit (median age, 54 yrs; range, 12-91). Systemic and locoregional toxicity were modest and easily manageable. CONCLUSION: TNF+M-based ILP can provide limb salvage in a significant percentage of patients with locally advanced STS and has therefore gained a permanent place in the multimodality treatment of STS.

Adolescent↗

Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study.

BACKGROUND: Completion lymph node dissection (CLND) is considered the standard of care in melanoma patients found to have sentinel lymph node (SLN) metastasis. However, the therapeutic utility of CLND is not known. The natural history of patients with positive SLNs who do not undergo CLND is undefined. This multi-institutional study was undertaken to characterize patterns of failure and survival rates in these patients and to compare results with those of positive-SLN patients who underwent CLND. METHODS: Surgeons from 16 centers contributed data on 134 positive-SLN patients who did not undergo CLND. SLN biopsy was performed by using each institution's established protocols. Patients were followed up for recurrence and survival. RESULTS: In this study population, the median age was 59 years, and 62% were male. The median tumor thickness was 2.6 mm, 77% of tumors had invasion to Clark level IV/V, and 33% of lesions were ulcerated. The primary melanoma was located on the extremities, trunk, and head/neck in 45%, 43%, and 12%, respectively. The median follow-up was 20 months. The median time to recurrence was 11 months. Nodal recurrence was a component of the first site of recurrence in 20 patients (15%). Nodal recurrence-free survival was statistically insignificantly worse than that seen in a contemporary cohort of patients who underwent CLND. Disease-specific survival for positive-SLN patients who did not undergo CLND was 80% at 36 months, which was not significantly different from that of patients who underwent CLND. CONCLUSIONS: This study underscores the importance of ongoing prospective randomized trials in determining the therapeutic value of CLND after positive SLN biopsy in melanoma patients.

Cohort Studies↗

Gene expression profiling of primary cutaneous melanoma and clinical outcome.

BACKGROUND: Gene expression profiling data for human primary cutaneous melanomas are scarce because of the lack of retrospective collections of frozen tumors. To identify differentially expressed genes that may be involved in melanoma progression and prognosis, we investigated the relationship between gene expression profiles and clinical outcome in a cohort of patients with primary melanoma. METHODS: Labeled complementary RNA (cRNA) from each tissue sample was hybridized to a pangenomic 44K 60-mer oligonucleotide microarray. Class comparison and class prediction analyses were performed to identify genes whose expression in primary melanomas was associated with 4-year distant metastasis-free survival among 58 patients with at least 4 years of follow-up, distant metastasis, or death. Results were validated immunohistochemically at the protein level in 176 independent primary melanomas from patients with a median clinical follow-up of 8.5 years. Survival was analyzed with a Cox multivariable model and stratified log-rank test. All statistical tests were two-sided. RESULTS: We identified 254 genes that were associated with distant metastasis-free survival of patients with primary melanoma. These 254 genes include genes involved in activating DNA replication origins, such as minichromosome maintenance genes and geminin. Twenty-three of these genes were studied at the protein level; expression of five (MCM4, P = .002; MCM3, P = .030; MCM6, P = .004; KPNA2, P = .021; and geminin, P = .004) was statistically significantly associated with overall survival in the validation set. In a multivariable Cox model adjusted for tumor thickness, ulceration, age, and sex, expression of MCM4 (hazard ratio [HR] of death = 4.04, 95% confidence interval [CI] = 1.39 to 11.76; P = .010) and MCM6 (HR of death = 7.42, 95% CI = 1.99 to 27.64; P = .003) proteins was still statistically significantly associated with overall survival. CONCLUSION: We identified 254 genes whose expression was associated with metastatic dissemination of cutaneous melanomas. These genes may shed light on the molecular mechanisms underlying poor prognosis in melanoma patients.

Adolescent↗

The palliative value of tumor necrosis factor alpha-based isolated limb perfusion in patients with metastatic sarcoma and melanoma.

BACKGROUND: Both patients with soft tissue sarcoma (STS) and patients with melanoma have limited treatment possibilities once the tumor has metastasized systemically. In patients with extremity STS or bulky melanoma in-transit metastases, the local tumor burden may be so problematic that, even in patients with systemically metastasized disease, an amputation may be inevitable. Isolated limb perfusion (ILP) has proven to be an excellent, local, limb-saving treatment option in patients with locally advanced extremity tumors. In this study, the authors investigated the palliative value of the ILP procedure to avoid amputation in patients who had Stage IV STS and melanoma. METHODS: From 1991 to 2003, of 339 tumor necrosis factor alpha (TNF)-based ILPs, 51 procedures were performed for either Stage IV STS (n = 37 patients) or Stage IV melanoma (n = 14 patients). All patients underwent an ILP with TNF and melphalan of the upper limb (n = 4 patients) or the lower limb (n = 47 patients) with 26-140 mg melphalan and 2-4 mg TNF. RESULTS: The overall response in patients with Stage IV STS was 84%, and their median survival was 12 months after ILP. Limb salvage was achieved in 36 of 37 patients, with 1 patient undergoing amputation due to treatment toxicity. In the patients with Stage IV melanoma, the complete response rate was 43%. All patients with melanoma preserved their limb during a median survival of 7 months. CONCLUSIONS: TNF-based ILP is an excellent procedure that provided tumor control and limb salvage for the short survival of patients with metastasized, very bulky, limb-threatening tumors of the extremity.

Adolescent↗

Value of intraoperative radiotherapy in locally advanced rectal cancer.

PURPOSE: This study was designed to analyze the results of a multimodality treatment using preoperative radiotherapy, followed by surgery and intraoperative radiotherapy in patients with primary locally advanced rectal cancer. METHODS: Between 1987 and 2002, 123 patients with initial unresectable and locally advanced rectal cancer were identified in our prospective database, containing patient characteristics, radiotherapy plans, operation notes, histopathologic reports, and follow-up details. An evaluation of prognostic factors for local recurrence, distant metastases, and overall survival was performed. RESULTS: All patients were treated preoperatively with a median dose of 50 Gy radiotherapy. Surgery was performed six to ten weeks after radiotherapy. Twenty-seven patients were treated with intraoperative radiotherapy because margins were incomplete or </=2 mm. Postoperative mortality was 2 percent. The median follow-up of all patients was 25.1 months. The overall five-year local control was 65 percent and the overall five-year survival was 50 percent. Positive lymph nodes and incomplete resections negatively influenced local control and overall survival. Intraoperative radiotherapy improved five-year local control (58 vs. 0 percent, P = 0.016) and overall survival (38 vs. 0 percent, P = 0.026) for patients with R1/2 resections. CONCLUSIONS: The presented multimodality treatment is feasible with an acceptable mortality and a five-year overall survival of 50 percent. Addition of intraoperative radiotherapy for patients with a narrow or microscopic incomplete resection seems to overrule the unfavorable prognostic histologic finding.

Adenocarcinoma↗

EMAP-II facilitates TNF-R1 apoptotic signalling in endothelial cells and induces TRADD mobilization.

Endothelial monocyte-activating polypeptide-II (EMAP-II), a proinflammatory cytokine with antiangiogenic properties, renders tumours sensitive to tumour necrosis factor-alpha (TNF) treatment. The exact mechanisms for this effect remain unclear. Here we show that human endothelial cells (EC) are insensitive to TNF-induced apoptosis but after a short pre-treatment with EMAP-II, EC quickly undergo TNF-induced apoptosis. We further analysed this EMAP-II pre-treatment effect and found no increase of TNF-R1 protein expression but rather an induction of TNF-R1 redistribution from Golgi storage pools to cell membranes. In addition, we observed EMAP-II induced mobilization and membrane expression of the TNF-R1-Associated Death Domain (TRADD) protein. Immunofluorescence co-staining experiments revealed that these two effects occurred at the same time in the same cell but TNF-R1 and TRADD were localized in different vesicles. These findings suggest that EMAP-II sensitises EC to apoptosis by facilitating TNF-R1 apoptotic signalling via TRADD mobilization and introduce a molecular and antiangiogenic explanation for the TNF sensitising properties of EMAP-II in tumours.

Apoptosis↗

Randomized trials in melanoma: an update.

No effective therapy for metastatic melanoma exists. Polychemotherapy or chemoimmunotherapy have not shown survival benefits. Vaccines have shown little activity in stage IV disease. To advance the identification of effective agents, new drugs can and should be offered as first-line treatment. Efforts must be made to improve understanding of the biology of malignant melanoma. Too many phase III trials have been conducted with a poor understanding of the mechanism of action of the involved drugs.

Antineoplastic Agents↗

Technology insight: Utility of TNF-alpha-based isolated limb perfusion to avoid amputation of irresectable tumors of the extremities.

Isolated limb perfusion (ILP) with melphalan is effective in the treatment of small multiple melanoma intransit metastases and is utilized widely for this indication. The treatment is much less effective against bulky melanoma metastases and has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor-necrosis factor-alpha (TNF-alpha) to this treatment approach has changed the situation dramatically. High response rates and limb-salvage rates have been reported in multicenter trials that combined ILP with TNF-alpha plus melphalan; these trials resulted in the approval of TNF-alpha for bulky melanoma metastases and soft tissue sarcomas in Europe in 1998. Subsequently, many doctors working in European centers have been trained, and a series of confirmatory reports from single institutions have now been published regarding the efficacy of the procedure. TNF-alpha has an early and a late effect; it enhances tumor-selective drug uptake during the perfusion, and plays an essential role in the subsequent selective destruction of the tumor vasculature. These effects result in a high response rate in bulky tumors, soft tissue sarcomas, bulky melanomas, and various other tumor types. This induction therapy therefore allows tumor remnants to be resected some 3 months after ILP thus avoiding limb amputation. TNF-alpha-based ILP is a well-established treatment that aims to avoid amputations regardless of the tumor size and type. It represents an important example of combination therapy that modulates the tumor vasculature and should be offered in high-volume tertiary referral centers.

Amputation, Surgical↗