Risk of third malignancies and death after a second malignancy in retinoblastoma survivors.

Retinoblastoma patients have a strongly increased risk of second malignancies, and survivors with a third or subsequent malignancy are increasingly observed. However, it has not been examined whether survivors who developed a second malignancy have a greater risk of a subsequent malignancy. On the basis of the Dutch retinoblastoma registry, the risk of a third malignancy was compared with cancer risk in the Dutch population. Cox model analysis with a time-dependent covariate was used to compare the subsequent malignancy risk and survival among patients with and without a second malignancy. Risk of a third malignancy was increased 8-fold compared with the general population. The hazard ratio (HR) of a third malignancy after a second malignancy was more than 7-fold increased compared to the risk of a second malignancy after retinoblastoma. Radiotherapy increased the risk 3-fold. A third malignancy was associated with worse survival compared with survival of patients only diagnosed with a second malignancy (HR=5.0). Survivors of retinoblastoma who already developed a second primary malignancy have an even higher risk of subsequent primary malignancies than retinoblastoma survivors without a second malignancy. Treating physicians and patients should be aware of this higher risk.

Incidence of retinoblastoma in Dutch children conceived by IVF: an expanded study.

BACKGROUND: In 2003, we reported an increased risk of retinoblastoma in children conceived by IVF between 1995 and 2002. However, population-based studies among children conceived by IVF did not find an elevated risk of retinoblastoma. METHODS: From nationwide estimates of numbers of live births conceived by IVF (n = 40 330), we estimated the expected numbers of patients with retinoblastoma conceived by IVF in the period 1995-2007. The observed number of retinoblastoma diagnoses in children conceived by IVF was obtained by questionnaires sent to the parents of children with retinoblastoma diagnosed between 1995 and 2005. For non-responders and patients diagnosed after 2005, information was available through the medical files, in which information on fertility treatment has been routinely recorded since 2000. The relative risk (RR) of retinoblastoma among children conceived by IVF was calculated for the total study period (1995-2007) and for the expanded study period (2002-2007). RESULTS: Of all eligible patients with retinoblastoma (n = 162) diagnosed in the period 1995-2007, seven were conceived by IVF. In the total study period (1995-2007) the risk was significantly elevated [RR = 2.54, 95% confidence interval (CI) = 1.02-5.23]. In the expanded study period (2002-2007), no significantly elevated risk (RR = 1.29, 95% CI = 0.16-4.66) was found. CONCLUSIONS: We found a significantly increased risk of retinoblastoma in children conceived by IVF in the total study period 1995-2007. However, this increased risk was mostly based on the much stronger risk increase observed previously, for 1995-2002. Caution and awareness on the one hand and avoiding unnecessary worries on the other hand are important at this stage of our knowledge.

Cancer mortality in long-term survivors of retinoblastoma.

This study examined long-term cause-specific mortality among 998 Dutch retinoblastoma survivors, diagnosed from 1862 to 2005, according to follow-up time, treatment and heredity. After a median follow-up of 30.8 years, only cause-specific mortality for second malignancies among hereditary retinoblastoma survivors was statistically significantly increased with 12.8-fold. Risk of death from second malignancies among non-hereditary survivors was not increased. Mortality rates of second malignancy among hereditary patients were non-significantly elevated with 1.6-fold for treated with radiotherapy, compared to those treated otherwise. Standardised mortality ratios (SMRs) for second malignancy among hereditary patients increased during the first three decades after retinoblastoma diagnosis. Whereas these risks decreased after three decades, the absolute excess risk (AER) increased significantly, up to 23.2 excess cases per 1000 patients/year after five decades of follow-up. Fifty years after retinoblastoma diagnosis the cumulative mortality from any second malignancy was 17.3% for hereditary patients. Very long-term follow-up of retinoblastoma patients revealed an emerging excess risk of mortality in hereditary retinoblastoma survivors. This implies that lifelong follow-up is needed, whereas at the same time, patients and their physicians must be alerted to the increased second malignancy risks.

[Revised guideline 'Diabetic retinopathy: screening, diagnosis and treatment']. / Richtlijn 'diabetische retinopathie: screening, diagnostiek en behandeling' (herziening).

The revised evidence-based guideline 'Diabetic retinopathy: screening, diagnosis and treatment' contains important recommendations concerning screening, diagnosis and treatment of diabetic retinopathy. Regular screening and the treatment of risk factors, such as hyperglycemia, hypertension, adipositas and dyslipidemia, can prevent retinopathy and slow down its development. Fundus photography is recommended as a screening method. If necessary, diagnosis by biomicroscopy and a treatment consisting of photocoagulation and/or vitrectomy should be performed by the ophthalmologist. The reassessment of responsibilities is a vital component of the implementation of the guideline bearing in mind that the screening in particular, can be performed by personnel other than ophthalmologists.

Follow-up of functionally lost eyes after vitrectomy and silicone oil tamponade for tractional retinal detachment.

BACKGROUND: Is there any association between, on the one hand, retention or removal of silicone oil or any specific ocular finding in patients with functionally lost eyes after vitrectomy and silicone oil tamponade for tractional retinal detachment and, on the other, a greater chance of preservation of the eye? This information is important in deciding whether to remove silicone oil, as well as in counseling patients about their individual chances of preserving their eye. METHODS: Seventy-three consecutive patients with a functionally lost eye with a minimum follow-up of 3 years were retrospectively studied. The relation between the variables at study entry or the removal of silicone oil during the follow-up period and a subsequent intervention (enucleation, evisceration or conjunctival cover with a scleral shell) were tested for statistical significance with Cox proportional hazards analysis. RESULTS: The absence or removal of silicone oil was not associated with a greater chance of finally preserving the eye. Nor could we identify other factors which predicted better chances of preservation. CONCLUSION: The notion that functionally lost eyes after treatment with vitrectomy and silicone oil tamponade for complicated tractional retinal detachment have better chances of preservation of the eye without silicone oil is not supported by our study.

Endophthalmitis: incidence, therapy and visual outcome in the period 1983-1992 in the Rotterdam Eye Hospital.

From 1983 to 1992, 134 patients were treated for clinically suspected endophthalmitis. 61% of this endophthalmitis population consisted of cases that were referred to our clinic. In this nine year period antibiotic treatment was carried out according to three consecutively used guidelines. These three treatment schemes differed in antibiotic spectrum and mode of antibiotic delivery. In 68 patients we performed vitrectomy on account of clinical deterioration under antibiotic treatment. We did not find significant differences in visual outcome between the three treatment groups. The incidence of endophthalmitis following cataract or vitreous surgery did not change throughout the study period. There was however a dramatic decrease in incidence of post-traumatic endophthalmitis following the introduction of a prophylactic antibiotic treatment scheme consisting of fortified gentamicin and cefazolin eyedrops, and intravenously and subconjunctivally administered gentamicin, cefazolin, and clindamycin. In 55 of 68 cases in which vitrectomy was performed in conjunction with intravitreal antibiotics, a vitreous or anterior chamber specimen was cultured. 36 patients had a positive culture result. In the group with positive culture result 42% had better visual acuity in the post-treatment period than before treatment. In the group with a sterile culture result 79% had better vision after treatment.

In-toto removal of a subretinal Cysticercus cellulosae by pars plana vitrectomy.

A case of subretinal cysticercosis was treated with laser coagulations round the cyst prior to surgery. In-toto removal of the living cysticercus was performed by pars plana vitrectomy. Two weeks after surgery 25/20 vision was regained. Histopathology of the cyst confirmed the clinical diagnosis.

Analysis of genes coding for S-antigen, interstitial retinol binding protein, and the alpha-subunit of cone transducin in patients with retinitis pigmentosa.

We screened 526 unrelated patients with autosomal dominant, autosomal recessive, or simplex retinitis pigmentosa for evidence of mutations of the genes encoding S-antigen (S-Ag), interstitial retinol binding protein (IRBP), and the alpha-subunit of cone-specific transducin. Restriction fragment length polymorphisms (RFLPs) were identified at each of these loci. Within each set of patients with a particular genetic type of retinitis pigmentosa, RFLP alleles at each of these loci showed no departure from Hardy-Weinberg equilibrium. No gene deletions or rearrangements could be detected in any patient. Furthermore, in each of six pedigrees (one autosomal dominant, one autosomal recessive, three Usher's syndrome type I, and one Laurence-Moon-Bardet-Biedl syndrome) there was no co-segregation of the disease with alleles determined by RFLPs at the locus for S-antigen. At the IRBP locus, lack of co-segregation was seen in one autosomal dominant, two autosomal recessive, and three Usher's syndrome type I pedigrees. Finally, one pedigree with autosomal recessive retinitis pigmentosa showed no co-segregation of the disease with alleles at the locus for the alpha-subunit of the cone-specific transducin. These data support the idea that the genes coding for S-Ag, IRBP, and the alpha-subunit of the cone-specific transducin do not play an etiologic role in the families with retinitis pigmentosa so far studied.

Analysis of the DNA of patients with retinitis pigmentosa with a cellular retinaldehyde binding protein cDNA.

We used a cDNA fragment corresponding to the human cellular retinaldehyde binding protein (CRALBP) gene to search for mutations at this locus in patients with autosomal dominant, autosomal recessive, or isolate retinitis pigmentosa, and Usher's syndrome, type I. No gene deletions or rearrangements could be detected in any patient by Southern blotting. We identified a Pvu II restriction fragment length polymorphism (RFLP) defining two alleles at the CRALBP locus in the normal population. We used this RFLP to analyze the genomic DNA of large sets of unrelated patients with autosomal dominant, autosomal recessive, or isolate retinitis pigmentosa. Within each of these groups, RFLP alleles at the CRALBP locus showed no linkage disequilibrium (departure from Hardy-Weinberg equilibrium). In addition, two autosomal dominant, two autosomal recessive, and three Usher's syndrome, type I pedigrees each showed no cosegregation of the CRALBP locus and the disease locus. We could find no evidence that mutations of the CRALBP gene are associated with the common forms of retinitis pigmentosa or Usher's syndrome, type I.

Monoclonal antibodies in detection of choroidal melanoma.

Three monoclonal antibodies (MoAbs) prepared against cutaneous melanomas were tested against one group of 12 choroidal melanomas with indirect immunofluorescence in frozen sections. A fourth MoAb was tested in paraffin sections of a second group of 47 choroidal melanomas. One MoAb (NKI-M7) did not react with choroidal melanoma, even though it had a high sensitivity for cutaneous melanoma. A second MoAb (NKI-M6) showed a positive reaction with only 2/12 choroidal melanomas. The third MoAb (NKI/beteb) reacted with all choroidal melanomas, regardless of the cell type. MoAb NKI/C-3 was positive with 38/47 (81%) choroidal melanomas. We conclude that NKI/C-3 and NKI/beteb have a high sensitivity for both cutaneous and choroidal melanomas in frozen sections. Of these two antibodies NKI/beteb was the most specific for cutaneous naevi and melanomas.

A monoclonal antibody specific for cells of the melanocyte lineage.

A monoclonal antibody, NKI/beteb, was prepared against membranes from a human melanoma metastasis, and in immunoprecipitates of melanoma cell lysates specific 100- and 7-kd glycoproteins were found. The large glycoproteins were also present in conditioned medium of melanoma cell lines. The antigen is located on the inner side of membranes of (pre)melanosomes and premelanosomelike vesicles. The antibody reacted in the immunoperoxidase test on frozen tissue sections with 27 of 28 nevocellular nevi (15/16 common, 12/12 dysplastic), 39/39 primary melanomas (3 intraepidermal, 24 cutaneous, 12 choroidal), 56/63 melanoma metastases, and 4/4 clear-cell sarcomas (melanoma of soft tissue). With sections of formalin-fixed paraffin-embedded tissues, the reaction was less sensitive. No reactivity was detected with frozen sections of 185 other tumors, except for 1 case of non-Hodgkin's lymphoma in which macrophages were positive. With the exception of melanocytes, all frozen sections of adult tissues that were tested were negative with NKI/beteb. On the basis of its tissue distribution so far, the antigen recognized by NKI/beteb seems to be a specific and sensitive diagnostic marker for cells of the melanocyte lineage.

Heterogeneous expression of melanoma-associated antigens in uveal melanomas.

Twenty-five uveal melanomas were stained with seven monoclonal antibodies (MoAbs) recognizing different antigens on cutaneous melanomas. A two step immuno-peroxidase procedure was used. Phenotypic heterogeneity was observed for four MoAbs (M.2.2.4, AMF-7, 225.28S, PAL-M1) while two MoAbs (NKI-beteb, CL203.4) reacted strongly with most (85%) uveal melanomas, and one MoAb (R-24) showed very low reactivity. Despite heterogeneity, co-expression of some antigens was observed. Expression of the antigen recognized by MoAb M.2.2.4. was significantly lowered by pre-enucleation irradiation while the other antigens remained unchanged. Expression of antigens on uveal melanomas differed markedly from primary cutaneous melanomas. The clinical relevance of these findings awaits further study.

The pattern-elicited electroretinogram. I. A tool in the early detection of glaucoma?

The pattern-elicited electroretinogram (PERG) was recorded in 75 patients known with glaucoma, each one of them having a normal visual acuity, and compared with the results in normal test subjects. Although there is a great overlap between normal and glaucomatous eyes, a lower average amplitude and a delay in latency is recorded in the case of glaucoma. A correlation was sought between the PERG outcome on the one hand and different glaucomatous parameters (visual field loss, intraocular pressure, cup disc/ratio) on the other; this could only be confirmed for the cup/disc ratio. In beginning glaucoma the PERG is more often disturbed than the VECP.

Lens proteins in intumescent cataract.

Intumescent cataractous lenses were investigated as to their water content and protein composition. Nuclei were separated from cortices. Water-soluble, water-insoluble, urea-soluble and urea-insoluble portions were quantified and the subunit composition of the water-soluble crystallin fraction was looked at on SDS-gel electrophoresis. Compared to normal lenses it is observed that the water content in intumescent cataract is increased, water-soluble and urea-soluble fractions are diminished, whereas the urea-insoluble portions are augmented. No major changes are noted in the subunit composition of the soluble protein fractions. Particularly, the relative amount of gamma-crystallins is diminished in intumescent cataractous lenses.

The pattern-elicited electroretinogram. II. Retinal responses in retrobulbar neuritis.

The pattern ERG is recorded in 54 patients in the acute phase of an optic neuritis. No differences could be recorded between the group of patients and a group of normal test subjects.

A standardized method for recording pattern-elicited electroretinograms in normal human subjects.

The pattern-elicited electroretinogram may be a useful tool for a further refinement of electro-ophthalmological diagnosis. Before being able to detect abnormalities under various pathological conditions, it is necessary to standardize the procedure and calculate the values for normal human test subjects. The routine procedure for these experiments is described and the data obtained are presented. This method appears to be reproducible and useful and is little time consuming in a diagnostic laboratory set-up.