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Biomedical subjects

D Liénard

Publications and source records attributed to D Liénard.

At least 73 records · Page 4Linked to original sources
PubMed1994

Early endothelium activation and polymorphonuclear cell invasion precede specific necrosis of human melanoma and sarcoma treated by intravascular high-dose tumour necrosis factor alpha (rTNF alpha).

Twenty-seven patients treated with high-dose rTNF alpha, IFN gamma and melphalan by isolated limb perfusion were histologically documented. There were 20 cases of melanoma-in-transit metastases and 7 cases of high-grade soft-tissue sarcoma. Biopsies were taken before IFN gamma, after IFN gamma, before TNF alpha and between 2 hr and 60 days after the TNF alpha perfusion. Immunohistochemistry was performed for adhesion molecules ICAM-I, ELAM-I (E selectin), VCAM-I and PECAM. During the first hours after beginning perfusion, the endothelial cells of the tumour capillaries appeared swollen. Significant tumour necrosis was already observed 3 hours after the perfusion in melanoma cases. The overall predominant feature was coagulative necrosis associated or not with haemorrhagic necrosis. TNF alpha induced increased expression of ELAM-I and VCAM-I adhesion molecules on intratumoral endothelial cells. The activated tumour vessels were progressively destroyed. Significant intravascular recruitment of polymorphonuclear cells (PMNs) was observed 3 hr after starting TNF alpha; it was followed by diapedesis and tumour colonization 3 days later. T lymphocytes and macrophages were detected during the first 7 days and B lymphocytes during the second week. Melanoma in transit metastases treated with alkylating agent alone did not show significant necrosis and did not express high levels of adhesion molecules (ELAM-I, VCAM-I) nor infiltration by PMN.

Cell Adhesion Molecules↗
PubMed1994

Rationale for using TNF alpha and chemotherapy in regional therapy of melanoma.

Recombinant tumor necrosis factor-alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side-effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the efficient dose in animals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response, compared with 52% after ILP with melphalan alone. Release of nanograms levels of TNF alpha in the systemic circulation was evident but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.

Animals↗
PubMed1994

Recreational exposure to sunlight and lack of information as risk factors for cutaneous malignant melanoma. Results of an European Organization for Research and Treatment of Cancer (EORTC) case-control study in Belgium, France and Germany. The EORTC Malignant Melanoma Cooperative Group.

This study addressed the impact of exposure to ultraviolet radiation on the risk of cutaneous malignant melanoma (CMM), as well as the behavioral components at stake in its occurrence. We performed a one-to-one unmatched case-control study among subjects aged 20 years or more with naturally non-pigmented skin in Germany, France and Belgium. Four-hundred and twenty consecutive patients with CMM diagnosed from 1 January 1991 on were derived from hospital registries; 447 controls were chosen randomly in the same municipality as cases. Subjects unaware of the dangers of exaggerated exposure to sunlight display an estimated CMM risk of 3.72% (95% confidence interval 2.63-5.26). The number of holiday weeks spent annually in sunny resorts and sunbathing during the hot hours of the day are strong risk factors in the three countries, but not the number of years spent outdoors, as farmers or building workers. Multiple logistic adjustments on the host characteristics increases the CMM risk associated with recreational exposure to sunlight, as well as the adjustment on the unawareness of the dangers of exaggerated exposure to sunlight. Recreational exposure to sunlight and sunburn early in life seem capable of fostering the proliferation of pigmented lesions of the skin. Our data support the hypothesis that most CMM develop from pigmented lesions of the skin containing initiated melanocytes, and that the cell proliferation due to brutal, intermittent exposures to solar radiation amplifies the likelihood of a melanocyte entering into a malignant process.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Clinical experience with high-dose tumor necrosis factor alpha in regional therapy of advanced melanoma.

Isolated perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response compared with 52% after ILP with melphalan alone. Leakage and release of nanograms levels of TNF alpha in the systemic circulation can be abrogated in most patients by low pump flow, continuous leak monitoring, extensive washout, and limb massage. In case of unavoidable leakage, appropriate intensive care results in minimal toxicity. The ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in humans.

Animals↗
PubMed1994

Isolated perfusion of the limb with high-dose tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and melphalan for melanoma stage III. Results of a multi-centre pilot study.

We report an update of a multi-centre pilot study previously published. Fifty-three patients (42 women, 11 men) were accrued between October 1988 and May 1992: 34 had stage IIIA, 15 had stage IIIAB, and four had stage IV melanoma. Most of them had more than five in-transit metastases; 50% had been previously treated by regional chemotherapy. Protocol included 90-min isolation perfusion at 40 degrees C with 2-4 mg rTNF-alpha, 0.2 mg rIFN-gamma and 10/13 mg/l melphalan. We prevented severe TNF systemic side effects by administration of dopamine and fluid loading. There has been no toxic death and the toxicity remained acceptable, with only one multi-organ failure (MOF) and no prolonged shock. Response rates remained very high, with 90% complete remission, 10% partial response and no failure. With a median follow-up time of 26 months, there were 12 regional recurrences, 15 distant metastases and nine local and distant recurrences. The median overall survival has been 28 months. We conclude that high-dose rTNF-alpha associated with melphalan in isolation perfusion is the therapy of choice for in-transit melanoma metastases.

Adult↗
PubMed1993

Regional therapy of melanoma.

Little progress has been made in the systemic treatment of melanoma, that is for disseminated stage IV disease. However, the tumour resistance to therapy, especially chemotherapy can be overcome in melanoma by high doses of anticancer agents administered regionally. The purpose of this paper is to illustrate this concept by two modes of regional treatment namely: (1) isolation perfusion of the limbs with high doses of cytokines and chemotherapy under hyperthermia and (2) local treatment of metastatic melanoma. The third part will be devoted to the role of another regional treatment, radiotherapy, where the association with hyperthermy also looks promising.

Adult↗
PubMed1993

Disseminated melanoma, preclinical therapeutic studies, clinical trials, and patient treatment.

Disseminated malignant melanoma is a very resistant tumor to therapy. Mechanisms of resistance to chemotherapy may be due to glutathione reductase and O6 alkyltransferase, two enzymes especially able to detoxify from alkylation. An interesting model is represented by dacarbazine in the treatment of melanoma with nitrosourea derivatives. Cytokines may come to play an increasing role in the combination with chemotherapy; interferon-alpha and interleukin-2, for example, seem to potentiate the action of chemotherapy in well-designed clinical protocols. Moreover, tumor necrosis factor-alpha was shown to be active in combination therapy with interferon-gamma and chemotherapy when administered by isolation perfusion. Targeting with monoclonal antibodies or melanocyte-stimulating hormone-alpha conjugated to cytotoxic agents represents a promising area. The discovery of a gene, designated MAGE1, coding for a peptide presented by HLA-A1 and able to specifically activate cytotoxic T lymphocytes may represent a unique approach to specific active immunotherapy for melanoma. The interference with integrins and adhesion molecules may play a role in the prevention of metastases. Some preclinical models seem to validate this approach. Current treatment of disseminated malignant melanoma involves chemotherapy often associated with other cytotoxic agents or cytokines, which may potentiate the antitumor effect. Other therapeutic issues reviewed concern targeting and immunotherapy. This review ends with a survey of biologic factors that may constitute new approaches to melanoma therapy.

Antineoplastic Agents↗
PubMed1992

High serum levels of TNF-alpha after its administration for isolation perfusion of the limb.

In a phase II study, 18 patients with locally spreading melanoma or sarcoma of lower limb were treated by isolation perfusion (ILP) with hyperthermia and local infusion of high dose of recombinant human tumor necrosis factor alpha (rHuTNF-alpha) (4 mg). Bioactive TNF-alpha and interleukin 6 (IL-6) serum levels were measured serially. In the limb, TNF-alpha rapidly reached a plateau at 2 mu/ml, while IL-6 appeared later and progressively increased until the end of ILP. In the systemic circulation TNF-alpha rose up to a median concentration of 31 ng/ml after 1 hour, then decreased and became negligible after 6 hours. IL-6 peaked only after 5 hours after start of ILP (median: 36.7 ng/ml). In patients with substantial leakage towards systemic circulation, both cytokines peaked higher and earlier as compared with patients with minimal leakage. No correlation was found between cytokine levels and severity of side effects which in all cases were reversible. We conclude that high dose TNF-alpha infusion in ILP results in extremely high levels of bioactive TNF-alpha in the systemic circulation without irreversible side effect, and provokes a delayed blood release of large amounts of IL-6; there was a correlation between leakage from the limb during procedure and the magnitude of systemic cytokines levels.

Chemotherapy, Cancer, Regional Perfusion↗
PubMed1991

[Jaundice secondary to a metastasis of a malignant melanoma at the level of the common bile duct].

A patient presenting with a malignant melanoma of the skin developed obstructive jaundice. Ultrasound examination of the upper abdomen revealed dilated bile ducts and the presence of a solid mass at the hilum level. There was no evidence of biliary lithiasis. The intraluminal location of the mass was confirmed by endoscopic cholangiography. Laparoscopy disclosed a 2 cm mass within the wall of the common bile duct. Pathological diagnosis was common bile duct wall metastasis from malignant melanoma.

Cholangiopancreatography, Endoscopic Retrograde↗
PubMed1989

Results of 206 isolated limb perfusions for malignant melanoma.

Between 1976 and 1988, 182 patients--135 females (74.3%) and 47 males (25.7%)--were submitted to 206 isolation perfusions, using melphalan and mild hyperthermia for 34 upper and 172 lower limbs. Stage I melanoma represented 37.4% including 75.4% greater than 1.5 mm Breslow thickness or with regression, ulceration or incisional biopsy. Stage II melanoma included 62.6% of the cases. Peri-operative mortality occurred in 2/182 patients. Amputation was performed within 1 month for toxic reasons in three patients and delayed in six for progressive disease. Regional toxicity consisted in oedema (76%), pain (61%), nerve palsy (24%), thrombosis (7%), septicemia (3%), thrombocyto-granulopenia (1.5%), minor miscellaneous (52%). Mean peripheral leakage was 1.0, 7.8 and 12.4% at respectively 5, 10 and 60 minutes. Projected 5-year disease-free survival was 79% for Stage I and 27% for Stage II. Survival at 5 years was 92% in Stage I and 53.5% in Stage II. Twenty-five patients were perfused twice for recurrence or incomplete response. Although the median disease-free interval was only about 8 months, the 5-year survival was 67%. This may indicate that isolation perfusion renders melanoma metastases less aggressive despite the fact they may recur at a high rate.

Adolescent↗
PubMed1989

Resection of lung metastases from sarcomas.

Between 1977 and 1987, 19 patients were candidates for resection of lung metastases from pretreated extrathoracic primary tumours. Primary tumours comprised 10 osteosarcomas, one Ewing sarcoma and eight soft tissue sarcomas. All 19 patients presented with metachronous metastases. Twenty-eight thoracotomies were performed in these 19 patients. Nine patients underwent multiple surgical explorations. All the metastases were removed by wedge resection. Seven out of 10 patients treated for osteosarcoma received pre- and postoperative chemotherapy, and three out of 10 postoperative chemotherapy only. The projected survival rate at 3 years is 33%. Seven out of 19 patients survived more than 2 years; four of them were free of disease at 33, 54, 56 and 137 months. Good prognosis appears to be long metastases-doubling time, metachronous metastases, small number of lung metastases, pathological evidence of tumour necrosis and/or fibrosis after chemotherapy and, of course, complete control of the primary tumour and no extrathoracic metastases.

Adolescent↗
PubMedDate not supplied

Isolated limb perfusion in primary and recurrent melanoma: indications and results.

In advanced melanoma of the limbs with in-transit metastasis, melphalan with isolated limb perfusion (M-ILP) produces around 50% complete remissions (CR). The combination of melphalan with tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) in isolated limb perfusion (TIM-ILP) gives around 80% CR. A prospective randomised phase II study compared 32 patients who received TIM-ILP with 32 patients who received TM-ILP (without IFNgamma). The overall remission rate (ORR) and the CR rate were superior with TIM-ILP as compared to TM-ILP, 100% vs. 91% and 78% vs. 69% respectively, but the differences are not significant. Given the efficacy of M-ILP on in-transit metastasis, the procedure was tested as an adjunct to surgery in high-risk (Breslow > or = 1.5 mm) primary melanoma of the limbs. Through the combined effort of the melanoma groups of the European Organization for Research and Treatment of Cancer (EORTC), the World Health Organization (WHO), and the North American Perfusion Group, 832 evaluable patients from 16 centres were entered in a phase III study. Median followup is 6.4 years. There was a trend for a longer disease-free interval after M-ILP. The difference is significant if the patients without elective lymph node dissection (ELND) are separately analysed, with a high significance in the 1.5 to 3 mm thickness subgroup. The occurrence of in-transit metastases was reduced from 6.6% to 3.3% by M-ILP. There was, however, no benefit of M-ILP in terms of survival. Prophylactic M-ILP cannot be recommended as a standard adjunct to surgery in high-risk primary limb melanoma. TIM-ILP or TM-ILP is a regional therapy with a very high regional response rate on melanoma in-transit metastasis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Hyperthermic isolated limb perfusion for the treatment of soft tissue sarcomas.

Hyperthermic isolated limb perfusion (HILP) with various chemotherapeutic agents has been used for the local treatment of high-grade soft tissue sarcomas (STS) of the extremities, but in most cases, with a disappointing result. Most such regimens certainly should not be considered superior to surgery plus radiotherapy. Although the majority of extremity STS can be resected locally, some are very large and are in close proximity to bone, nerve or blood vessels. In these cases, amputation is the only means of resecting the tumour. A new combination of drugs used in the set-up of HILP with tumour necrosis factor-alpha and melphalan has emerged as a very promising option for the limb-saving management of locally advanced STS. In recent studies, complete response rates of approximately 30% and partial remission rates of 50% have been achieved, while the overall limb-salvage rate is more than 80%.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Surgical management of distant melanoma metastases.

Disseminated melanoma remains a tumour that is poorly responsive to chemotherapy and radiotherapy. However, this review demonstrates that surgical removal of visceral metastases such as at the, lung or digestive sites, as well as the brain, yields consistent median survivals, often longer than 12 months, and long-term survivors. Such surgery is followed by little complication cost and low perioperative mortality. Our experience tends to confirm that complete debulking offers longer survivors as compared to partial. Also, one site of metastases, whatever its anatomical location, when operated on, gives a better chance for survival than when there are multiple sites.

Brain Neoplasms↗