J. W. Koten

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 untill 1944, probably due to incompleteness of the register, and stabilised after 1945 (1 per 17 000 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.

Therapeutic efficacy of IL-2-loaded hydrogels in a mouse tumor model.

Interleukin‐2 (IL‐2) is a highly effective anticancer drug if it is applied locally for 5 consecutive days. In most cases this requires 5 invasive treatments, which is not usually acceptable for either the patient or the clinician. For this reason we have developed dextran‐based hydrogels from which the required amount of encapsulated IL‐2 (1–4 × 106 IU of IL‐2) is gradually released during 5–10 days. Initially IL‐2‐containing macroscopic cylinder‐shaped gels (implants), and later IL‐2‐containing injectable microspheres, were developed. These preparations were characterized in vitro, and the therapeutic activity was tested in DBA/2 mice with SL2 lymphosarcoma. The therapy was given to mice with a large and extensively metastasized tumor load (at least 5% of the body weight). If 1–4 × 106 IU of IL‐2 was slowly released from the hydrogels over a period of 5–10 days, the therapeutic effects were very good and comparable to the effects of free IL‐2 injections for 5 consecutive days. In conclusion, dextran‐based hydrogels are promising systems for the controlled release of IL‐2.

Therapy of bovine ocular squamous-cell carcinoma with local doses of interleukin-2: 67% complete regressions after 20 months of follow-up

We have tested the therapeutic potency of peritumorally injected low doses of interleukin-2(IL-2). Seventy tumours of the bovine ocular squamous-cell carcinoma (BOSCC), 1–3 cm in diameter, were treated with 5000, 20 000 or 200 000 U IL-2 from Eurocetus (Chiron) to find the optimal dose for treatment. Injections were given peritumorally on Monday to Friday on 2 consecutive weeks. The size of the tumours was measured before treatment and 1, 3, 4, 9 and 20 months after treatment. After 9 months complete regression was observed in 89% of the tumours treated with 5000 U IL-2, 80% treated with 20 000 U and 67% treated with 200 000 U. After 20 months, there was complete regression of 35%, 31% and 67% of the tumours respectively. The 9-and 20-month results of the 200 000-U treatment are significantly better than those of the 5000-U and 20 000-U treatments taken together. This protocol may be useful to treat advanced inoperable tumours (e.g. of the nasopharynx or skin) of human patients.

The mechanism of regression of solid SL2 lymphosarcoma after local IL-2 therapy

Abstract. Treatment of cancer by the administration of interleukin-2 (IL-2) at the tumour site is a very effective approach. The mechanism of this tumour regression is not clear, although it is generally assumed that it involves an IL-2-stimulated immune reaction. There are, however, no immune parameters that consistently correlate with the therapeutic effect. We have studied the histopathological events in a subcutaneously (s.c.) growing SL2 lymphosarcoma (transplantation of tumour cells at day 0) treated with peritumoural IL-2 injections at days 10–14. Most IL-2-treated tumours had already begun to regress from day 12 onwards, showing that local IL-2 therapy was also effective in the present study. The immediate reaction after local IL-2 administration is vascular leakage from the surrounding circulation, causing oedema within the tumour and in a broad zone surrounding it. The presence of oedema is always accompanied by markedly increased tumour necrosis. After a few days extensive angiogenesis occurs at the border between the oedematous area and the healthy connective tissue. Leucocytes, mainly macrophages, migrate via the newly formed blood vessels to gain access to the necrotising tumour site, where they form a granuloma. These macrophages phagocytose the dead tumour material. During growth, the SL-2 tumours infiltrate the surrounding tissue. The infiltrating tumour strands are apparently attacked by macrophages, as the tumour cells in close proximity to the latter are progressively destroyed. Therefore, the body of the tumour and the infiltrating tumour strands are attacked in different ways. The primary effect of IL-2 administration at the tumour site is vascular leakage that causes oedema in and around the tumour. This is followed by extensive angiogenesis, with the resulting migration of white cells from the circulation, which form a granuloma around the tumour. Both the oedema and the granuloma cause tumour regression.

Antitumor effect of locally injected low doses of recombinant human interleukin-2 in bovine vulval papilloma and carcinoma

In many human clinical trials and in various animal tumor models, the antitumor effect of high doses of systemically applied interleukin-2 (IL-2) is tested. Our studies focused on the effects of low doses of locally injected IL-2. In this paper, the effect of local injection of low doses of IL-2, i.e. a total dose of 25,000-50,000 units, into papillomas or carcinomas of the bovine vulva is described. In 19 out of 23 (83%) cows treated with IL-2 an effect on the tumor load was observed; in three of these animals, complete regression was obtained. In the majority of cases, regression was not restricted to the tumors injected with IL-2.

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 mm2 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.

Are omental milky spots an intestinal thymus

Abstract It is suggested that omental milky spots in young children, which in later life gradually transform into fatty tissue and only reappear during intraperitoneal infection, might influence the development of gastrointestinal immunity.

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.

A Macrophage Factor Enhancing the Systemic Anti-Tumour Effect of T Lymphocytes

Spleen cells sensitized to tumour cells have an anti-tumour effect on injected syngeneic lymphosarcoma cells in mice. This study shows that this anti-tumour effect can be enhanced by induced peritoneal macrophages and by macrophage-like tumour cells (macrophages). Addition of macrophages to the intraperitoneally injected sensitized spleen cells stimulated the anti-tumour effect. This was observed both with intraperitoneally injected tumour cells and with subcutaneously transplanted tumour cells. The anti-tumour effect is the result of a cooperation between T cells and macrophages. In vitro incubation of immune T-cells with macrophages or macrophage-like cells enhanced the in vivo anti-tumour activity of the sensitized T-lymphocytes. Neither the presence of antigen nor the proliferation of the immune T-cells were a prerequisite to enhance this anti-tumour effect. Our experiments suggest that a macrophage factor is responsible for the enhancement of the anti-tumour effect. Based on the results of this paper and other studies we propose the following sequence of events to explain the anti-tumour effect of injected sensitized T-lymphocytes and macrophages: injected macrophages enhance the anti-tumour effect of sensitized lymphocytes. These stimulated lymphocytes migrate to the tumour located elsewhere and recognize the tumour antigens. Subsequently, the lymphocytes render (host) macrophages in the tumour cytotoxic to tumour cells.

Causes of zonal distribution of glycogen in the liver acinus after a fat-rich diet

Nachweis, dass nach fettreicher Diät Glykogen hauptsächlich in der Zone 1 des Rappaportschen Leberacinus abgelagert wird, was durch den Abbau von Enzymen, die in den Zonen 2 und 3 am Glykogenaufbau beteiligt sind und durch die physiologische Regeneration in der Zone 1 verursacht wird.