Low-dose IL-2 therapy reduces HCV RNA and HBV DNA: case report.

BACKGROUND: Patients with concomitant hepatitis C (HCV) and B (HBV) infection are difficult to treat due to lack of medicines that control these viral infections and the high risk of hepatocellular carcinoma. Currently, there are insufficient data regarding the therapeutic effect of interleukin-2 (IL-2) during chronic viral infection, but this cytokine has shown antineoplastic activity and may have also an antiviral effect. CASE REPORT: We present the case of a 44-year-old patient with hemophilia A, HBV and HCV related compensated liver cirrhosis (Child-Pugh A) with several zones in the liver, highly suspicious for hepatocellular carcinoma. The patient was treated with low-dose intermittent subcutaneous IL-2 immunotherapy, followed by standard therapy with pegasys and copegus. During 23 months' follow-up, no tumour progression occurred, and the patient remained in Child-Pugh A stage. The initial HCV and HBV loads were significant (538,207 IU/ml) and minimal (825 copies/ml), respectively. The patient was treated with intermittent subcutaneously applied low-dose IL-2 cycles for ten months. HBV DNA and HCV RNA were undetectable 3 months after the last IL-2 cycle. After cessation of IL-2 therapy, the patient received standard antiviral treatment with pegasys and copegus. Nine months later, a slight reactivation of viruses was observed: HBV DNA was 18,600 copies/ml and HCV RNA was 58 IU/ml. Twenty-three months after the last IL-2 treatment (at the time of writing), the patient is alive and in a good clinical condition. CONCLUSION: The decrease of HBV and HCV nucleic acids during immunotherapy with IL-2 predicts a possible new therapeutic option for these chronic viral infections.

Treatment of ocular squamous cell carcinomas in cattle with interleukin-2.

In total, 174 bovine ocular squamous cell carcinomas of varying sizes (20 to 2800 mm(2) in area) were treated daily with peritumoural injections of solvent, or solvent containing 5000 U, 20,000 U, 200,000 U, 500,000 U, 1 million U or 2 million U interleukin-2 (IL-2) for 10 days. The tumours were measured and clinically staged before treatment and at one, three, four, nine and 20 months after treatment. After 20 months, 14 per cent of the tumours treated with the solvent had regressed completely, a significantly smaller proportion than the 55 per cent treated with 5000 U IL-2, 52 per cent treated with 20,000 U IL-2, 58 per cent treated with 200,000 U IL-2, 50 per cent treated with 500,000 U IL-2, 69 per cent of tumours treated with 1 million U IL-2, 52 per cent treated with 2 million U IL-2. The tumours on the third eyelid and limbus were the most responsive.

A case of hepatocellular carcinoma (HCC): treatment with local application of alcohol and interleukin 2 (IL-2).

A case of an inoperable hepatocellular carcinoma due to liver cirrhosis is presented. Surgical treatment was not clinically warranted. So we decided to induce tumor necrosis by intratumoral injections of 10 mL of ethanol followed by two treatments with 9 x 10(6) U Chiron interleukin-2 with an interval of 1 month. This ethanol-interleukin-2 cycle was repeated three times with intervals of 6 months. Interleukin-2 injections were given by a fine needle, under ultrasound control in the periphery and in the center of the tumor. The initial size of the tumor was 55-60 mm. During the follow-up period of 2 years the tumor size remained relatively unchanged. The patient died due to gastric hemorrhage. The treatment elicited no adverse clinical effects. The clinical status improved greatly after this treatment. Local interleukin-2 application after alcohol-induced tumor ablation might be an alternative if surgical treatment is not warranted.

IL-2 loaded dextran microspheres with attractive histocompatibility properties for local IL-2 cancer therapy.

Biodegradable dextran microspheres (MS) were developed as a slow-release system for interleukin-2 (IL-2) to apply them for local IL-2 therapy of cancer. We describe the tissue reactions induced by these MS without or with IL-2 in rats. Dextran MS stain bright red-purple with the periodic acid Schiff (PAS), visualising the exact spot of IL-2 release and its relation to the histological reaction pattern. Subcutaneously injected MS always form a well-circumscribed deposit. In the first 2 days there is a PMN inflammation within the MS-deposit, but the surroundings show only a scanty inflammatory reaction. The PMN reaction is replaced by an abundant macrophage reaction in particular in the MS-deposit. At day 21 a fibrous capsule of about 50 mum surrounds the deposit. The effect of IL-2 administered in its free form is mainly vascular, with vascular dilatation, vascular leakage and oedema. It is remarkable that lymphocytes are present in the injection area already at day 2. When IL-2 releasing MS were used, the various reactions induced by IL-2 and MS were amplified leading to local necrosis. We conclude that neither placebo MS nor IL-2 leads to necrosis after subcutaneous injection in rats. In contrast, when IL-2 was released from MS, then massive necrosis was induced. This might be due to increased phagocytosis or changes in the micro-niche due to the release of humoral factors by the infiltrating cells. This is probably fortuitous for local IL-2 therapy of cancer, as massive necrosis of tumour cells can be expected to lead to an increased antitumour reaction.

Non-melanoma and non-renal cell carcinoma malignancies treated with interleukin-2.

Some positive results have been observed after interleukin-2 treatment, especially in melanoma, and pulmonary metastasis of renal carcinoma. The aim of the following article is to analyze the response to interleukin-2 in patients with non-melanoma and non-renal cells malignancies. The response was studied with reference to the interleukin-2 dose, the way of application, the kind of tumor and the other treatments. A database search was performed to trace studies describing interleukin-2 tumor treatment in non-melanoma and non-renal cells malignancies, published between 1.1.1999 and 30.01.2001. We found 38 communications for the use of interleukin-2 in a total of 1030 patients. The literature review suggests that the optimal way of application of interleukin-2 in metastatic colorectal carcinoma is the local use in a low dose, with intervals between applications, for 4-6 months, after some pretreatment. In unresectable pancreatic head carcinoma a total response was 85% with twice prolonged survival. In malignant mesothelioma--stable disease was achieved in 56% with potential advantages of local application. In hematological malignancies interleukin-2 treatment was followed by remission or increase in immune defense depending on the histological type. In breast cancer interleukin-2 induced immunologically functional graft. Metastatic pulmonary carcinoma has a favorable prognosis concerning response and survival. The maintenance treatment with low doses of interleukin-2 in responders to previous chemotherapy is promising. Better results are observed with lower dose, cyclic application and combining chemotherapy. Cycles with longer duration (4-6 months) have a better effect also for patients with response to former treatment.

Comparison of the efficacy of local treatment of equine sarcoids with IL-2 or cisplatin/IL-2.

Local interleukin-2 (IL-2) is effective in a number of experimental animal models and in veterinary and human cancer patients without discomforting side effects. The primary goal of this study was to compare the therapeutic effects and side effects of the local intratumoral administration of five or ten low doses of IL-2 with those of a combination of cisplatin and a single high dose of IL-2 in the treatment of equine sarcoids. The therapeutic effect (complete and partial regression) of local cisplatin together with a single high dose of IL-2 was significantly better than the combined effect of low doses of local IL-2 administered daily over 5 or 10 days (80% and 43%, respectively; P=0.02). Cisplatin/IL-2 and low doses of IL-2 induced 53% and 14% complete regressions, respectively ( P=0.02). Histological changes after cisplatin/IL-2 treatment were far more pronounced than after IL-2 only treatment and in several cases showed an enormous eosinophilic infiltrate.

Perilesional IL-2 treatment of a VX2 head-and-neck cancer model can induce a systemic anti-tumour activity.

BACKGROUND: Head-and-neck cancer is associated with impaired cell-mediated immune reactivity. A rabbit model with VX2 Squamous Cell Carcinoma transplanted into both auricles was used to test the effects of a regimen for local Interleukin 2 (IL-2) therapy, optimal in murine tumour models. MATERIALS AND METHODS: Peri-tumoural IL-2 treatment started when one of the tumours exceeded 2 cm2 and consisted of 100,000 or 300,000 Chiron Units IL-2 or only solvent during 5 consecutive days. RESULTS: In 4 out of 12 (33%) rabbits the treated primary tumours regressed completely, simultaneously with the non-treated contra-lateral tumours. Also metastases in draining lymph nodes of both treated and untreated primary tumours regressed in three of these animals. Tumour cells injected in the cured animals were rejected. The histology of the regressing tumours in cured cases showed an active granulomatous reaction with a histiocytic response, splitting up of tumour islands, and fibrinoid obstruction of blood vessels. CONCLUSION: These findings showed local and systemic therapeutic effects of this local IL-2 regimen in a VX2 head-and-neck cancer model.

Local low-dose IL-2 therapy.

Interleukin-2 (IL-2) is a powerful drug for treating cancer. However, it is only powerful if it is properly applied. That is, IL-2 should be applied at the tumor site, because at the transition of normal and malignant tissue are the tumor infiltrating cells. These should be activated by IL-2. Local application implies that IL-2 can be used in relatively low doses. It is becoming clear that even a single injection of IL-2 can cure cancer. IL-2 can also enhance the therapeutic effects of irradiation and Cisplatin. Locally applied IL-2 therapy is virtually non-toxic.

Interleukin 2 (IL-2) therapy: potential advantages of locoregional versus systemic administration.

There has been an apparent discrepancy between the results obtained with IL-2 based immunotherapy in animal tumour models, including veterinary cancer patients, and human cancer patients. We argue that this is due to differences in the therapeutic regimens used to treat human and veterinary cancer patients. The main differences are systemic therapy and surgical removal of the primary tumour in case of human cancer patients, whereas these treatment modalities are not used in IL-2 treated veterinary cancer cases. We have developed a treatment protocol, in which IL-2 is applied locally, that has been successful against transplanted tumours as well as spontaneous tumours of varying origin and immunogenicity. In view of immunobiological considerations we conclude that local treatment of cancer with IL-2 makes more sense than systemic treatment, as usually applied in the clinic, and that surgical removal of tumours may be detrimental to successful IL-2 therapy.

History of cancer research in nosological perspective.

Contrary to conventional wisdom progress in cancer research has not followed a linear course, but rather a torturous capricious path, often guided by the prevailing concepts of disease (nosology). Various theories appear, disappear and reappear all the time. Periods with rapid progression alternate with periods of stagnation. Really new ideas emerge rarely in oncology. Most of the so-called new ideas are modifications of older concepts i.e. old wine in new skins. Moreover existing oncological theories brought under the umbrella of a new nosological paradigm may change drastically and often get a totally new meaning. As a consequence older theories may linger on over centuries but may be modified to such an extent that the original concepts are barely recognisable. Progress in oncology is characterised by periods of rapid progress alternating with periods of apparent stagnation which with hindsight were nevertheless periods in which new concepts were in statu nascendi. The history of oncology provides still a source of inspiration, since older ideas may be worth reconsidering.

A 4-mutation model of carcinogenesis for tumour suppressor genes.

Human life can be described as the clonal development of a fertilized egg. During cell proliferation in this clone among others cancer-specific mutations arise. Supposing that about 10(16) cells are produced in a lifetime; that the mutation frequency is about 10(-6) per gene per cell generation; that cells can go through about 60 cell divisions; and that cancer arises about once in a lifetime, carcinogenesis is likely to depend on 4 cancer-specific mutations. The advantage of a 4-mutation model over a multimutational model is that it implies far more predictions that can be tested. The 4-mutation model accurately predicts the age/incidence relation of tumors and the prevalence of cancer in the various organs. It further explains the increased tumor incidence in persons with an inherited cancer gene; and the well-known histological stages of carcinogenesis.

Distribution of tumors in the retina in hereditary retinoblastoma patients.

We have compared the location of the ocular tumors in hereditary retinoblastoma in relation to the age of the patients at time of diagnosis. Eighty fundus drawings were analyzed from 59 hereditary patients containing I 59 tumors. At the time of diagnosis, indirect ophthalmoscopy was performed under general anaesthesia in all patients and standard drawings of the retina were made depicting the number and relative location of all tumors. The distance between the center of the tumor and the center of the macula was measured and plotted against the age of the patients at time of diagnosis. The results show that the distance between the center of the tumor and the center of the macula at time of diagnosis increases with age during the first seven months after birth.

Intravesical interleukin-2 in T1 papillary bladder carcinoma: regression of marker lesion in 8 of 10 patients.

PURPOSE: We evaluate the therapeutic effect of intravesical interleukin-2 (IL-2) on T1 papillary bladder carcinoma after incomplete transurethral resection. MATERIALS AND METHODS: After incomplete transurethral resection we treated 10 patients in whom the marker lesion was left in place with 3 x 10(6) Chiron units IL-2 in 50 ml. saline plus 0.1% human serum albumin. The solution remained in the bladder for 2 hours and it was instilled on 5 consecutive days. The effect of IL-2 treatment on the marker lesion was evaluated by cystoscopy and repeat biopsy of the marker site 2 months after treatment. In addition, the effect on the recurrence of bladder tumors was studied. RESULTS: At 2 months 8 of the 10 marker lesions (80%) had completely regressed and there were no tumor cells on repeat biopsy. Four patients remained tumor-free after 30 to 54 months. We noted no toxic effects. In 1 patient with a 7-year history of bladder cancer the marker was only partially regressed after 2 months. After removal of the marker this patient remained tumor-free at a followup of 54 months. CONCLUSIONS: To our knowledge this report represents the first study of the effect of IL-2 on marker lesions left in place after transurethral resection. The results indicate that IL-2 instillations are feasible, and the combination of transurethral resection and IL-2 instillation may have a powerful antitumor effect. The therapeutic effects may not simply be due to intravesical IL-2, because previous transurethral resection probably caused some influx of infiltrating cells and the marker may have had tumor associated antigens. Consequently these effects may be due to the interaction of tumor associated antigens, infiltrating cells and IL-2.

Incidence and survival of retinoblastoma in The Netherlands: a register based study 1862-1995.

AIM: The aim of this study was to determine the (time trends in) incidence and survival of hereditary (familial and sporadic) and non-hereditary retinoblastoma for male and female patients born in the Netherlands between 1862 and 1995. METHOD: The national retinoblastoma register was updated and now consists of 955 patients. The missing dates of death were obtained from the municipal registers and the Central Bureau of Genealogy in The Hague. Mortality was compared with the Dutch vital statistics. RESULTS: From 1862 to 1995 no significant differences in incidence for retinoblastoma were found in the hereditary subgroups. Further, no significant differences between males and females were found, both overall and in the hereditary subgroups. The average incidence of retinoblastoma increased until 1944, probably due to incompleteness of the register, and stabilised after 1945 (1 per 17000 live births). From 1900 to 1995 the standardised mortality ratio increased for hereditary retinoblastoma patients from 2.9 to 9.0 and decreased for non-hereditary retinoblastoma patients from 1.9 to 1.0. CONCLUSION: Although survival for retinoblastoma was significantly better after 1945 than before, in comparison with the Dutch population the mortality between 1900 and 1990 increased for the hereditary and decreased for the non-hereditary retinoblastoma patients.

Three histopathological types of retinoblastoma and their relation to heredity and age of enucleation.

The histopathology of 61 eyes was studied with special attention to the morphology of the retina adjacent to the main tumour. Three retinal types were distinguished. Retina type 1 (RT-1, 28 specimens) contained a single tumour that was sharply demarcated from surrounding normal retina. In retina type 2 (RT-2, 29 specimens) large parts of the retina were affected and the main tumour mass gradually blended with the adjacent pathological retina. Retina type 3 (RT-3, four specimens) was characterised by a retina almost entirely affected by diffuse tumour growth. RT-1 correlated significantly with early enucleation (0-3 years) both in hereditary and non-hereditary cases. RT-2 was seen in eyes enucleated later (2-5 years). The progressing tumour may release growth factors in the intraocular space that stimulate the cells of the adjacent retina and lead to multiple new primary tumours in the adjacent retinal area. RT-3 was only present in non-hereditary cases with late enucleation (at 2-5 years). Hereditary retinoblastoma cases are usually detected early. Therefore in hereditary cases RT-1 is significantly more common than RT-2. In 25 eyes of the 44 patients with unilateral sporadic retinoblastoma, multifocal tumours of the retina were observed. Such cases should not mistakenly be classified as hereditary cases on the basis of the histological pattern of multifocality of the tumour process.