Interferon and interferon inducers in the treatment of cancer : experimental studies in mice, rats and humans

Biological response modifiers are agents that · exert their antitumor effects mainly or exclusively through modulation of host immune defense mechanisms. A common feature of these agents is their capacity to induce the production of endogenous interferons and/ or other lymphokines in vivo, and their capacity to activate various subsets of lymphocytes and monocytes that can lyse tumor cells in vitro and in vivo. Antiproliferative and immunomodulative effects as well as toxicity and side-effects observed in connection with the admin

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. During the 35-day experiment doxorubicin treatment caused dose-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppression (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulting in ascites, pleural effusion, hypercholesterolaemia and hypertriglyceridaemia. These toxicities were enhanced by the addition of the chemosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no signs of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrenal gland and large intestine. CsA had a low toxicity profile, as it only caused a transient rise in bilirubin. In conclusion, the chemosensitizer CsA enhanced the side-effects of the anticancer drug doxorubiein without altering the toxicity pattern. There was no evidence of a therapeutic gain by adding CsA to doxorubicin, compared to single-agent treatment with doxorubicin in 25%-33% higher doses, because of the enhanced toxicity of the combination treatment

Fifty tumor necrosis factor-based isolated limb perfusions for limb salvage in patients older than 75 years with limb-threatening soft tissue sarcomas and other extremity tumors

BACKGROUND: Isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan is highly effective in treating limb-threatening soft tissue sarcoma (STS) and other bulky tumors. Because of fear of TNF-associated toxicity, ILP with TNF is not offered to older patients in some cancer centers, although especially in older patients, every attempt to avoid an amputation that may end their independence must be considered. METHODS: Out of 306 TNF-based ILPs, 50 ILPs were performed for limb salvage in 43 patients >75 years old (range, 75-91 years): 29 STS and 14 melanoma patients. RESULTS: In the STS patients, a response rate of 76% and a limb-salvage rate of 76% were achieved; in the melanoma patients, a 100% response rate and a 93% limb-salvage rate were achieved. Local toxicity was mild. The three postoperative deaths that occurred in the total series of 306 TNF-based ILPs in Rotterdam (75 years old after leakage-free perfusions and were not related to TNF but to extremely high-risk profiles in these three patients. CONCLUSIONS: Older patients should not be withheld a TNF-based ILP for limb salvage, because the procedure is safe and highly effective in these patients

Systemic toxicity and cytokine/acute phase protein levels in patients after isolated limb perfusion with tumor necrosis factor-alpha complicated by high leakage

BACKGROUND: Since the introduction of high-dose tumor necrosis factor-alpha (TNFalpha) in the setting of isolated limb perfusion (ILP) in the clinic, prevention of leakage to the body of the patient is monitored with great precision for fear of TNF-mediated toxicity. That we observed remarkably little toxicity in patients with and without leakage prompted us to determine patterns of cytokines and acute phase proteins in patients with high leakage and in patients without any leakage. METHODS: TNFalpha, interleukin (IL)-6, IL-8, C-reactive protein, and secretory (s)-phospholipase A2 were measured at several time points during and after (until 7 days) ILP in 10 patients with a leakage to the systemic circulation varying in percentage from 12% to 65%. As a control, the same measurements, both in peripheral blood and in perfusate, were performed in nine patients without systemic leakage. RESULTS: In patients with systemic leakage, levels of TNFalpha increased during ILP, reaching values to 277 ng/ml. IL-6 and IL-8 peaked 3 hours after ILP with values significantly higher compared with patients without systemic leakage. C-reactive protein and s-phospholipase A2 peaked at day 1 in both patient groups, s-phospholipase A2 with significant higher levels and C-reactive protein, in contrast, with lower levels in the leakage patients. CONCLUSIONS: High leakage of TNFalpha to the systemic circulation, caused by a complicated ILP, led to 10-fold to more than 100-fold increased levels of TNFalpha, IL-6, and IL-8 in comparison with patients without leakage. The increase of the acute phase proteins was limited. Even when high leakage occurs, this procedure should not

Pharmacokinetics, Tissue Distribution and Therapeutic Effect of Cationic Thermosensitive Liposomal Doxorubicin Upon Mild Hyperthermia

Purpose: To evaluate pharmacokinetic profile, biodistribution and therapeutic effect of cationic thermosensitive liposomes (CTSL) encapsulating doxorubicin (Dox) upon mild hyperthermia (HT). Methods: Non-targeted thermosensitive liposomes (TSL) and CTSL were developed, loaded with Dox and characterized. Blood kinetics and biodistribution of Dox-TSL and Dox-CTSL were followed in B16BL6 tumor bearing mice upon normothermia (NT) or initial hyperthermia conditions. Efficacy study in B16BL6 tumor bearing mice was followed with Dox-TSL or Dox-CTSL upon NT or HT. Efficacy study in LLC tumor bearing mice was performed upon two HT conditions. Intravital microscopy was performed on B16BL6 tumors implanted in dorsal-skin fold window-bearing mice. Results: Targeting did not cause faster blood clearance of CTSL compared to TSL. Highest uptake of liposomes was observed in spleen, kidneys and liver. Applying HT prior to CTSL administration increased drug delivery to the tumor and CTSL delivered ∼1.7 fold higher Dox concentration compared to TSL. Efficacy in B16BL6 murine melanoma showed that HT had a significant effect on CTSL in tumor suppression and prolonged survival. Efficacy in LLC Lewis lung carcinoma tumor model demonstrates that two HT treatments hold promises for a successful treatment option. Conclusion: CTSL have potency to increase drug efficacy in tumors due to their targeted and drug release functions

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. Also normal syngeneic cells such as T cells and A-NK cells became highly sensitive for lysis by A-NK cells after preincubation with mAb OX18. Two other mAb against MHC class I had no effect on lysis of target cells. These data indicate that masking of MHC class I on syngeneic tumor and normal cells by mAb OX18 is sufficient for A-NK cells to recognize target cells as non-self, resulting in lysis. In addition, we found that the presence of mAb against the β2 (CD18)-integrins blocked the lysis of all tumor cell lines by A-NK cells in 51Cr-release assays, also when target cells were preincubated with mAb OX18. Because of the absence of CD18 on most tumor cells we concluded that a CD18-associated integrin on A-NK cells is essential for lysis of target cells. These results show that in this syngeneic rat model CD18 on A-NK cells together with MHC class I on tumor cells determine A-NK cell-mediated lysis. Furthermore, we hypothesize that the anti-MHC class I OX18 recognizes an epitope on rat MHC class I which is, or is very close to, the restriction element determining A-NK cell-mediated lysis

One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases

OBJECTIVE: The aim of this study is to describe the experience with 100 TNF-based ILP for locally advanced melanoma and to determine prognostic factors for response, time to local progression, and survival. METHODS: One hundred TNF-based ILPs were performed between 1991 and 2003 in 87 patients for whom local control by surgery of in-transit melanoma metastases was impossible. In total, 62 iliac, 33 femoral, and 5 axillary ILPs were performed in mild hyperthermic conditions with 2 to 4 mg of TNF and 10 to 13 mg of melphalan per liter of limb volume. RESULTS: Overall response was 95%, with 69% complete response, 26% partial response, and 5% no change. Complete response rate differed significantly for patients with IIIA disease versus IIIAB and IV. Local and systemic toxicity was mild to moderate in almost all cases, with no treatment-related death and one treatment-related amputation. Five-year overall survival was 32%; local progression occurred in 55% after a median of 16 months. In complete response patients, 5-year survival was 42% with local progression in 52% at a median of 22 months. Response rate and survival were significantly influenced by stage of disease; (local progression free) survival was influenced by response rate. CONCLUSIONS: TNF-based ILP results in excellent response rates in this patient population with unfavorable characteristics. Response on ILP predicts outcome in patients and reflects aggressiveness of the tumor

Mastectomy by inverted drip incision and immediate reconstruction: data from 510 cases

BACKGROUND: Immediate reconstruction of the breast can be performed in selected cases after mastectomy for breast cancer or after prophylactic mastectomy in patients with a high risk of developing breast cancer. Despite the frequency with which these procedures are performed, data from large series of subpectoral implantation of silicone prostheses in combination with a skin-saving approach are lacking. METHODS: In this retrospective study, data on complications and late surgical interventions in 356 patients who underwent 510 mastectomies with an inverted drip incision and immediate reconstruction (MIDIIR) were analyzed to determine potential prognostic factors of early complications. RESULTS: In 82% of the MIDIIRs, the postoperative course was uneventful. In 18%, the complications were infection (32 cases), necrosis of the skin flap (29 cases), bleeding (31 cases), and protrusion of the prosthesis (20 cases), resulting in surgery in 9, 12, 15, and 20 cases, respectively. At the end of the follow-up period, 30 (6%) prostheses were definitively removed. Age, size of the prostheses, radiotherapy, previous lumpectomy, and indication for mastectomy were not significant factors for the prognosis of early complications. CONCLUSIONS: With the right technique and indications, MIDIIR is a very safe procedure and should be one of the surgical treatments that can be offered in the overall management of patients with, or at high risk for, breast cancer

The teaching practices with GIS in Hyogo Prefecture, Japan

This study aims to quantify the heterogeneity of tumour enhancement in dynamic contrast-enhanced MRI (DCE-MRI) using texture analysis methods. The suitability of the coherence and the fractal dimension to monitor tumour response was evaluated in 18 patients with limb sarcomas imaged by DCE-MRI pre- and post-treatment. According to the histopathology, tumours were classified into responders and non-responders. Pharmacokinetic (K(trans)) and heuristic model-based parametric maps (slope, max enhancement, AUC) were computed from the DCE-MRI data. A substantial correlation was found between the pharmacokinetic and heuristic model-based parametric maps: ρ = 0.56 for the slope, ρ = 0.44 for maximum enhancement, and ρ = 0.61 for AUC. From all four parametric maps, the enhancing fraction, and the heterogeneity features (i.e. coherence and fractal dimension) were determined. In terms of monitoring tumour response, using both pre- and post-treatment DCE-MRI, the enhancing fraction and the coherence showed significant differences between the response group and the non-response group (i.e. the highest sensitivity (91%) for K(trans), and the highest specificity (83%) for max enhancement). In terms of treatment prediction, using solely the pre-treatment DCE-MRI, the enhancing fraction and coherence discriminated between responders and non-responders. For prediction, the highest sensitivity (91%) was shared by K(trans), slope and max enhancement, and the highest specificity (71%) was achieved by K(trans). On average, tumours that responded showed a high enhancing fraction and high coherence on the pre-treatment scan. These results suggest that specific heterogeneity features, computed from both pharmacokinetic and heuristic model-based parametric maps, show potential as a biomarker for monitoring tumour response