Transforming growth factor beta secretion from primary breast cancer fibroblasts.

Transforming growth factor beta (TGF-beta) is a hormonally regulated growth inhibitor with autocrine and/or paracrine functions in human breast cancer. In vivo, enhanced immunohistochemical staining of extracellular TGF-beta 1 has been detected around stromal fibroblasts in response to the antiestrogen treatment. We have investigated the effects of tamoxifen on the production of TGF-beta by primary human breast fibroblast cultures in serum-free medium.

Twenty-five years of pluridisciplinary approach for melanoma patients. The European Organization on Research and Treatment of Cancer Melanoma Cooperative Group (EORTC-MCG).

The EORTC Melanoma Group was created in 1969 by people of different disciplines who were, and still are, motivated by the need for a pluridisciplinary approach to melanoma. Table 1 lists the chairmen and secretaries who have served on the organization. The core organization is devoted to treatment of melanoma.

Regional application of TNF alpha in the treatment of cancer: a preclinical-clinical interactive program.

The clinical success of the application of TNF-alpha in the setting of isolated limb perfusions in patients with advanced sarcomas, melanomas and other tumors has renewed the interest in TNF alpha as an anticancer drug in man. We have developed an interactive preclinical-clinical TNF alpha program that explores new methods to use TNF alpha in various settings or enhance its activity. Thus we have developed regional organ perfusion models and are testing the effectivity of targeting of TNF to the tumor by means systemic administration of long circulating liposomes.

Administration of high-dose tumor necrosis factor alpha by isolation perfusion of the limbs. Rationale and results.

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 effective dose in animals.

Long-term morbidity after regional isolated perfusion with melphalan for melanoma of the limbs. The influence of acute regional toxic reactions.

Objective: To determine the influence of acute regional toxic reactions on the incidence and characteristics of long-term morbidity after regional isolated perfusion with melphalan.

Design: Retrospective study.

Setting: The Amsterdam and Rotterdam perfusion centers, the Netherlands.

A retrospective comparative study evaluating the results of mild hyperthermic versus controlled normothermic perfusion for recurrent melanoma of the extremities.

The aim of this study was to investigate the role of mild hyperthermia (39-40 degrees C) in isolated cytostatic perfusion for patients with recurrent melanoma of the extremities. A total of 218 patients treated with mild hyperthermic perfusion was compared to 166 patients perfused under controlled normothermic conditions (37-38 degrees C). Only patients whose lesions had been excised before or at the moment of perfusion were eligible for this study.

Long-term neuropathy after regional isolated perfusion with melphalan for melanoma of the limbs.

The incidence of long-term (> or = 3 months) neuropathy in 350 melanoma patients treated with single normothermic or 'mild' hyperthermic perfusion with melphalan in the period 1978 to 1990 was studied. Long-term neuropathy was encountered in 14 patients; in 10/51 patients (20%) after perfusion at the axillary level and in 4/247 patients (2%) after perfusion at the iliac level. After brachial and femoro-popliteal perfusions no long-term neuropathy was observed.

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.

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.

Patient- and treatment-related factors associated with acute regional toxicity after isolated perfusion for melanoma of the extremities.

In order to gain some insight into the cause of acute regional toxicity after isolated perfusion using melphalan, 15 patient-related and perfusion-technique-related factors were tested in a logistic regression model. Acute toxicity was graded according to Wieberdink's grading system. In a group of 425 patients, 362 (85%) encountered no or slight toxicity with a grade I or II reaction, and 63 (15%) patients encountered more severe toxicity with a grade III, IV, or V reaction.

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.

Limb recurrence-free interval and survival in patients with recurrent melanoma of the extremities treated with normothermic isolated perfusion.

To date, little is known about prognostic factors for limb recurrence-free interval and survival in patients with recurrent melanoma of the limbs treated with regional isolated perfusion. Therefore, 216 such patients treated with normothermic perfusion using melphalan during the period 1978 to 1990 were analyzed for patient and tumor related variables using a Cox proportional hazard model. The five year limb recurrence-free interval was 52 percent.

Results of regional isolated perfusion for locally inoperable melanoma of the limbs.

In the period 1978-1990, 49 patients with locally inoperable melanoma of the limbs were treated with regional isolated perfusion according to four different perfusion schedules. Perfusion resulted in a complete remission in 28 patients (57%), with a median duration of 10 (1-55+) months, and a partial remission in 10 (21%), with a median duration of 3 (1-9) months. In patients treated with a double (normothermic or sequential hyperthermic) perfusion schedule the complete remission rate was higher.

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.

Is there an indication for a double perfusion schedule with melphalan for patients with recurrent melanoma of the limbs?

It has been reported that a double perfusion schedule shows a better complete remission rate than does the single procedure for recurrent melanoma of the limb. As more perfusion strategies approach the ideal of a 100% complete remission rate, the main issue now is to prolong the period of disease control in the limb, ie to reduce the limb recurrence rate. The follow up of 42 patients treated with a double perfusion schedule and of 45 patients treated with a single perfusion procedure was updated to compare the duration of limb disease control.

The infiltration of experimentally induced lung metastases of colon carcinoma CC531 by adoptively transferred interleukin-2-activated natural killer cells in Wag rats.

The number of IL-2-activated natural killer (A-NK) cells reaching the tumor site in vivo may be crucial for their anti-tumor effect following adoptive immunotherapy. We investigated in a syngeneic rat model the infiltration of established lung metastases by adoptively transferred A-NK cells. The Wag rat colon carcinoma CC531 was injected via a tail vein to induce pulmonary metastases.

Immunotherapy in a human ovarian cancer xenograft model with two bispecific monoclonal antibodies: OV-TL 3/CD3 and OC/TR.

The bispecific antibodies (bs-mAbs) OV-TL 3/CD3 and OC/TR (MOv18/CD3) efficiently mediate ovarian tumor cell lysis by cytotoxic T cells and activated peripheral blood lymphocytes (PBL) in vitro. OV-TL 3/CD3 and OC/TR are reactive with tumor-associated antigens on ovarian carcinoma cells (OA3 and CA-MOv18, respectively), and CD3 on activated PBL, bridging both cells and simultaneously inducing activation of the effector cells. In a comparative study we investigated the therapeutic efficacy of OV-TL 3/CD3 and OC/TR by targeting activated PBL with the bs-mAbs against intraperitoneally growing NIH:OVCAR-3 human ovarian carcinoma cells.

Soluble factors produced by macrophages/monocytes inhibit lymphokine-activated killer activity in rat splenocyte cultures.

In the present study we investigated the inhibition of interleukin-2(IL-2)-induced lymphokine-activated killer (LAK) activity in rat splenocyte cultures in relation to the presence of 2-mercaptoethanol and macrophages/monocytes. The presence of 2-mercaptoethanol is necessary for induction of LAK activity in rat splenocyte cultures. Removal of macrophages/monocytes from rat splenocytes by plastic or nylon-wool adherence, or iron ingestion resulted in LAK induction by IL-2 in the absence of 2-mercaptoethanol.

Prognostic factors for tumor response and limb recurrence-free interval in patients with advanced melanoma of the limbs treated with regional isolated perfusion with melphalan.

Background: At this time little is known about prognostic factors for tumor response and subsequent limb recurrence-free interval in patients suffering from advanced melanoma of the limbs who were treated with regional isolated perfusion.

Methods: A retrospective analysis was done, with a logistic regression model and a Cox proportional hazard analysis, looking at possible patient-, tumor-, and treatment-related prognostic factors in all 120 patients with advanced melanoma of the limbs who were treated with regional isolated perfusion with melphalan in the period 1978 to 1990 at our institutions.

Results: Complete remission was achieved in 65 patients (54%) with a median duration of 9+ months (range, 1 to 97+ months), and partial remission was seen in 30 patients (25%).

The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat.

The feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimental design we investigated the side-effects of the combination treatment.

Rat interleukin-2-activated natural killer (A-NK) cell-mediated lysis is determined by the presence of CD18 on A-NK cells and the absence of major histocompatibility complex class I on target cells.

The precise mechanism by which target cells are recognized and subsequently lysed by interleukin-2-activated natural killer (A-NK) cells is poorly understood. In this study the role of major histocompatibility complex (MHC) class I and adhesion molecules in the recognition and lysis of tumor cells was investigated in a syngeneic Wag rat model. Preincubation of tumor cells with F(ab')2 fragments of anti-MHC class I monoclonal antibody (mAb) OX18 strongly enhanced the A-NK cell-mediated lysis.

5'-Deoxy-5-fluorouridine increases daunorubicin uptake in multidrug-resistant cells and its activity is related with P-gp 170 expression.

Most anticancer agents fail to induce clear responses in the treatment of colorectal cancer. This can be explained by involvement of overexpression of the membrane glycoprotein, P-gp 170, which is associated with multidrug resistance (MDR), and/or with involvement of ras. Fluoropyrimidines are amongst the few options in the chemotherapeutic treatment of colorectal cancers.

Effects of recombinant tumour necrosis factor (rTNF-alpha) in cancer. Observations on the acute phase protein reaction and immunoglobulin synthesis after high dose recombinant TNF-alpha administration in isolated limb perfusions in cancer patients.

To obtain insight in the effect of TNF on the synthesis of acute phase proteins like CRP, alpha 1-antitrypsine, alpha 1-acidglycoprotein, C3 and C4 and the immunoglobulins (IgG-M-A), nine cancer patients who were treated with an isolated limb perfusion (ILP) with high dose recombinant TNF-alpha (rTNF-alpha) were investigated during a 7-day period after the end of the perfusion. Resorption of rTNF-alpha from out of these limbs into the circulation after the ILP induced within 30 min to 6 h in all patients elevated serum levels of IL-6. At the same time C-reactive protein became detectable in serum.