Jan Willem Koten

Second primary tumors in patients with hereditary retinoblastoma: A register-based follow-up study, 1945-1994

The aim of this register‐based follow‐up study was to evaluate the long‐term cumulative incidence of second primary tumors (SPT) among survivors of hereditary retinoblastoma, with special interest for the incidence of pineoblastoma in retinoblastoma patients born after 1970. The Dutch Retinoblastoma Register was completed and updated: in the period 1945–1994, 639 retinoblastoma patients were registered. The vital status of each patient was obtained from the municipal registries and the Central Office of Genealogy. SPT were traced and histopathologically confirmed. Survival curves and cumulative incidence of SPT were calculated by the Kaplan‐Meier method. The survival of patients with hereditary retinoblastoma was significantly shorter than that of patients with non‐hereditary retinoblastoma. The cumulative incidence of SPT in hereditary patients was 3.7 and 17.7% at the ages of 10 and 35 years, respectively. Long‐term follow‐up revealed a high proportion of melanomas (7 melanomas out of 28 SPT). In the sub‐cohort of the hereditary‐retinoblastoma patient group born after 1970, the cumulative incidence of pineoblastomas at the age of 5 years was 9.3%. Our results suggest that patients with hereditary retinoblastoma should have careful follow‐up, and procedures for diagnosing SPT and pineoblastomas at an early and potentially treatable stage should be developed.

Local therapy of cancer with free IL-2

This is a position paper about the therapeutic effects of locally applied free IL-2 in the treatment of cancer. Local therapy: IL-2 therapy of cancer was originally introduced as a systemic therapy. This therapy led to about 20% objective responses. Systemic therapy however was very toxic due to the vascular leakage syndrome. Nevertheless, this treatment was a break-through in cancer immunotherapy and stimulated some interesting questions: Supposing that the mechanism of IL-2 treatment is both proliferation and tumoricidal activity of the tumor infiltrating cells, then locally applied IL-2 should result in a much higher local IL-2 concentration than systemic IL-2 application. Consequently a greater beneficial effect could be expected after local IL-2 application (peritumoralxa0=xa0juxtatumoral, intratumoral, intra-arterial, intracavitary, or intratrachealxa0=xa0inhalation). Free IL-2: Many groups have tried to prepare a more effective IL-2 formulation than free IL-2. Examples are slow release systems, insertion of the IL-2 gene into a tumor cell causing prolonged IL-2 release. However, logistically free IL-2 is much easier to apply; hence we concentrated in this review and in most of our experiments on the use of free IL-2. Local therapy with free IL-2 may be effective against transplanted tumors in experimental animals, and against various spontaneous carcinomas, sarcomas, and melanoma in veterinary and human cancer patients. It may induce rejection of very large, metastasized tumor loads, for instance advanced clinical tumors. The effects of even a single IL-2 application may be impressive. Not each tumor or tumor type is sensitive to local IL-2 application. For instance transplanted EL4 lymphoma or TLX9 lymphoma were not sensitive in our hands. Also the extent of sensitivity differs: In Bovine Ocular Squamous Cell Carcinoma (BOSCC) often a complete regression is obtained, whereas with the Bovine Vulval Papilloma and Carcinoma Complex (BVPCC) mainly stable disease is attained. Analysis of the results of local IL-2 therapy in 288 cases of cancer in human patients shows that there were 27% Complete Regressions (CR), 23% Partial Regressions (PR), 18% Stable Disease (SD), and 32% Progressive Disease (PD). In all tumors analyzed, local IL-2 therapy was more effective than systemic IL-2 treatment. Intratumoral IL-2 applications are more effective than peritumoral application or application at a distant site. Tumor regression induced by intratumoral IL-2 application may be a fast process (requiring about a week) in the case of a highly vascular tumor since IL-2 induces vascular leakage/edema and consequently massive tumor necrosis. The latter then stimulates an immune response. In less vascular tumors or less vascular tumor sites, regression may require 9–20xa0months; this regression is mainly caused by a cytotoxic leukocyte reaction. Hence the disadvantageous vascular leakage syndrome complicating systemic treatment is however advantageous in local treatment, since local edema may initiate tumor necrosis. Thus the therapeutic effect of local IL-2 treatment is not primarily based on tumor immunity, but tumor immunity seems to be useful as a secondary component of the IL-2 induced local processes. If local IL-2 is combined with surgery, radiotherapy or local chemotherapy the therapeutic effect is usually greater than with either therapy alone. Hence local free IL-2 application can be recommended as an addition to standard treatment protocols. Local treatment with free IL-2 is straightforward and can readily be applied even during surgical interventions. Local IL-2 treatment is usually without serious side effects and besides minor complaints it is generally well supported. Only small quantities of IL-2 are required. Hence the therapy is relatively cheap. A single IL-2 application of 4.5xa0millionxa0U IL-2 costs about 70 Euros. Thus combined local treatment may offer an alternative in those circumstances when more expensive forms of treatment are not available, for instance in resource poor countries.

Parental Age in Sporadic Hereditary Retinoblastoma

Of 104 children with sporadic hereditary retinoblastoma born between 1945 and 1970, we studied the age of their parents at the birth and compared this age with the mean age of parents at the birth of their children during the same period in The Netherlands. The mean age of fathers at the birth of their children with sporadic hereditary retinoblastoma (33.7 years) was significantly higher than the mean age of fathers at the birth of their children in the general population (32.5 years) (P less than .05, one sided). Similarly, the mean age of mothers at the birth of their children with sporadic hereditary retinoblastoma (31.2 years) was significantly higher than the mean age of mothers at the birth of their children in the general population (29.5 years) (P less than .05, one sided). We further analyzed this parental age factor by measuring the relative risk of age groups and comparing the incidence of sporadic hereditary retinoblastoma in the various parental age groups with the incidence of sporadic hereditary retinoblastoma in the total population. Mothers 35 years of age or older had a relative risk of 1.7 to have a child with sporadic hereditary retinoblastoma compared with mothers in the population in general (P = .006, one sided). Similarly, fathers 50 years of age or older had a relative risk of 5.0 to have a child with sporadic hereditary retinoblastoma compared with fathers in the population in general (P = .04, one sided). No parental age effect was found in children with nonhereditary retinoblastoma. We conclude that a high paternal and a high maternal age are significant risk factors for sporadic hereditary retinoblastoma.

Treatment of stage III-IV nasopharyngeal carcinomas by external beam irradiation and local low doses of IL-2.

The therapeutic effect of intratumoural application of Interleukin-2 (IL-2) was studied in patients with stage III–IV nasopharyngeal carcinoma (NPC) that received radiotherapy. Patients with stage III–IV NPC receiving a standard treatment of 7,000xa0cGy external beam irradiation have a mean disease-free survival of about 1.5xa0years. In this paper, we describe ten of these patients who were treated with additional peritumoural and intratumoural injections with 3×104xa0U IL-2 on 5xa0days in weeks 2, 4, and 6 of the 7-weeks’ irradiation period. This combined treatment group was compared with a historical group of patients treated with standard irradiation alone. Local IL-2 therapy showed a marked clinical and statistical significant improvement of disease-free survival. After 5xa0years, 63% of the IL-2 treated patients were disease-free versus 8% of the control patients. These results suggest that the therapeutic results of radiotherapy can be significantly improved by combining it with local IL-2 treatment. To our knowledge, this is the first clinical report showing that local IL-2 therapy is effective against an infiltrative and locally metastasizing tumour in human patients.

Non-ocular cancer in hereditary retinoblastoma survivors and relatives.

An epidemiological survey has been carried out to establish the incidence of second malignant neoplasms in hereditary retinoblastoma survivors in The Netherlands and the relative risk of cancer in non-affected relatives. The cumulative incidence of second neoplasms was 19% at the age of 35 years. Fathers, unaffected by retinoblastoma, were at risk for pancreatic cancer, the relative risk being 8.3.

Histopathologic studies of the below-the-knee great saphenous vein after endovenous laser ablation.

BACKGROUND There has been hesitation to use endovenous laser ablation (EVLA) for the treatment of incompetence of the below‐the‐knee great saphenous vein (GSV). OBJECTIVE To assess early pathologic changes in the below‐the‐knee nonvaricose GSV and adjacent tissue after EVLA in legs scheduled for below‐the‐knee amputation. METHODS The below‐the‐knee GSV in five patients was exposed to EVLA using 14‐, 12‐, and 10‐watt laser power with continuous or intermittent laser exposure using a 600‐nm core, bare tip fiber. Six segments (3 × 3 cm) of GSV with adjacent tissue were excised, examined histologically, and compared with non‐laser‐exposed parts of the vessel. RESULTS Histologic evaluation revealed thermal damage of the intima and the internal part of the media. At the site of the laser tip, carbonization and necrosis was observed. Vascular perforation with subsequent perivascular bleeding was occasionally (<10%) seen in cases treated with 40 to 80 J/cm and in all cases treated with 110 to 200 J/cm. The saphenous nerve was not damaged. CONCLUSION Based on this histopathologic study, acute thermal damage of the below‐the‐knee GSV after EVLA was limited to the intima and the inner third of the media. No acute damage of perivascular nerve tissue was observed.

Histological analysis of IL-2 induced regression of murine solid SL2-tumors

When DBA/2 mice are inoculated both intraperitoneally (i.p.) and subcutaneously (s.c.) with syngeneic SL2 lymphoma cells and treated i.p. on day 10–14 with 20,000 units IL-2/day, about 50% of the mice reject both the ascitic tumour and the s.c. tumour. During IL-2 therapy large areas of necrosis appear in the solid SL2 tumours between day 12 and 15. Immunohistochemical studies show that only a small number of infiltrating cells is present in the tumours. The percentage of macrophages (MHC-II+)in the tumours is about 1 and the percentage of T-lymphocytes (αβ-TCR+) about 0.5. No differences in the numbers of infiltrating cells are seen in untreated and IL-2 treated tumour bearing mice. The tumoursurrounding infiltrate consists mainly of mononuclear cells: about 50% macrophages, 20% CD8+ cells, and 15% CD4+ cells. No tumour-infiltrating cells were found that express the IL-2 receptor.We conclude that direct cytotoxic activity of tumour infiltrating cells cannot account for the rapid occurrence of necrosis.When L3T4+ cells were eliminated by treating the mice withα-L3T4 monoclonal antibodies before tumor inoculation and treatment with rIL-2, tumor eradication did not occur. So, L3T4+ helper T-cells are essential for IL-2-mediated tumour regression. Exogenous rIL-2 is not directly responsible for the induced tumour regression. A significant stagnation of intratumoural bloodflow is observed after histological analysis; yet it still needs to be determined whether this is the primary cause or consequence of the observed necrosis.