Peter J. Ringens

Risk of Second Malignancies in Survivors of Retinoblastoma: More Than 40 Years of Follow-up

BACKGROUND Survivors of hereditary retinoblastoma have an elevated risk of developing second malignancies, but data on the risk in middle-aged retinoblastoma survivors (ie, those with more than 40 years of follow-up) are scarce. METHODS Data from the Dutch retinoblastoma registry were used to analyze risks of second malignancies in 668 retinoblastoma survivors, diagnosed from 1945 to 2005 (median age = 24.9 years) and classified as having had hereditary or nonhereditary disease based on the presence of family history, bilateral disease, or a germline RB1 mutation. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) of subsequent cancers in patients with hereditary and nonhereditary disease were estimated by comparison with Dutch sex-, age-, and calendar year-specific rates. Multivariable Cox regression and competing risk analyses were used to determine associations of treatment with risks of second malignancies. All statistical tests were two-sided. RESULTS After a median follow-up of 21.9 years, the risk of second malignancies in survivors of hereditary retinoblastoma (SIR = 20.4, 95% confidence interval [CI] = 15.6 to 26.1) far exceeded the risk of survivors of nonhereditary retinoblastoma (SIR = 1.86, 95% CI = 0.96 to 3.24). Among patients with hereditary disease, treatment with radiotherapy was associated with a further increase in the risk of a subsequent cancer (hazard ratio = 2.81, 95% CI = 1.28 to 6.19). After 30 years of follow-up, elevated risks of epithelial cancers (lung, bladder, and breast) were observed among survivors of hereditary retinoblastoma. After 40 years of follow-up, the AER of a second malignancy among survivors of hereditary retinoblastoma had increased to 26.1 excess cases per 1000 person-years. The cumulative incidence of any second malignancy 40 years after retinoblastoma diagnosis was 28.0% (95% CI = 21.0% to 35.0%) for patients with hereditary disease. CONCLUSION Our analysis of middle-aged hereditary retinoblastoma survivors suggests that these individuals have an excess risk of epithelial cancer. Lifelong follow-up studies are needed to evaluate the full spectrum of subsequent cancer risk in hereditary retinoblastoma survivors.

A Systematic Review Of The Adverse Events Of Intravitreal Anti-vascular Endothelial Growth Factor Injections

Background: Intravitreal ranibizumab and pegaptanib are registered for neovascular age-related macular degeneration. No formal safety study has been conducted for intravitreal bevacizumab. These anti-vascular endothelial growth factor (anti-VEGF) drugs are being used on a large scale in daily practice for different ocular diseases. The objective of the present study was to systematically assess and compare the incidences of adverse events of anti-VEGFs. Methods: A systematic search was conducted in April 2009 with no date restrictions in PubMed, Embase, Toxline, and the Cochrane library. We used the terms pegaptanib, bevacizumab, ranibizumab, intravitreal, and specific and general terms for adverse events. Studies describing adverse events after anti-VEGF injections and the official safety data were included. Results: Two hundred and seventy-eight articles were included, and the incidences of adverse events were calculated separately for effect, safety, and specific side effect studies. The incidences of serious ocular and nonocular adverse events were approximately below 1 per 100 injections for intravitreal bevacizumab, intravitreal ranibizumab, and intravitreal pegaptanib. Most mild ocular adverse events were below 5 per 100 injections. Conclusion: The reported rates of serious adverse events were low after anti-VEGF injections. There is no sufficient evidence to conclude that there is a difference in incidences between the anti-VEGFs.

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.

Co-morbidity and visual acuity are risk factors for health-related quality of life decline: five-month follow-up EQ-5D data of visually impaired older patients

BackgroundCo-morbidity is a common phenomenon in the elderly and is considered to be a major threat to quality of life (QOL). Knowledge of co-existing conditions or patient characteristics that lead to an increased QOL decline is important for individual care, and for public health purposes. In visually impaired older adults, it remains unclear which co-existing conditions or other characteristics influence their health-related QOL. Our aim was to present a risk profile of characteristics and conditions which predict deterioration of QOL in visually impaired older patients.MethodsAnalyses were performed on data from an observational study among 296 visually impaired older patients from four Dutch hospitals. QOL was measured with the EuroQol-5D (EQ-5D) at baseline and at five-month follow-up. Nine co-existing condition categories (musculoskeletal; diabetes; heart; hypertension; chronic obstructive pulmonary disease (COPD) or asthma; hearing impairment; stroke; cancer; gastrointestinal conditions) and six patient characteristics (age; gender; visual acuity; social status; independent living; rehabilitation type) were tested in a linear regression model to determine the risk profile. The model was corrected for baseline EQ-5D scores. In addition, baseline EQ-5D scores were compared with reference scores from a younger visually impaired population and from elderly in the general population.ResultsFrom the 296 patients, 50 (16.9%) were lost to follow-up. Patients who reported diabetes, COPD or asthma, consequences of stroke, musculoskeletal conditions, cancer, gastrointestinal conditions or higher logMAR Visual Acuity values, experienced a lower QOL. After five months, visual acuity, musculoskeletal conditions, COPD/asthma and stroke predicted a decline in QOL (R2 = 0.20). At baseline, the visually impaired older patients more often reported moderate or severe problems on most EQ-5D dimensions than the two reference groups.ConclusionIn visually impaired older patients, visual acuity, musculoskeletal conditions, COPD/asthma and stroke predicted a relatively rapid decline in health-related QOL. With this risk profile, a specific referral by the ophthalmologist to another sub-specialty may have a beneficial effect on the patients health-related QOL. A referral by the ophthalmologist or optometrist to a multidisciplinary rehabilitation service seems appropriate for some patients with co-morbidity. The current results need to be confirmed in studies using pre-structured questionnaires to assess co-morbidity.

Restrictions in daily life after retinoblastoma from the perspective of the survivors.

Little is known about the impact of retinoblastoma (RB) on the health status of survivors in terms of disabilities and worries, both of which may restrict participation in activities of daily life.

Measuring the refractive properties of the diabetic eye during blurred vision and hyperglycaemia using aberrometry and Scheimpflug imaging

Purpose:  This study aimed to measure the refraction and geometry in the diabetic eye during the presence and absence of hyperglycaemia and blurred vision, using aberrometry and Scheimpflug imaging.

Precision and reliability of retinal thickness measurements in foveal and extrafoveal areas of healthy and diabetic eyes.

PURPOSE To determine the precision and reliability of retinal thickness measurements with an optical coherence tomograph (Stratus OCT 3; Carl Zeiss Meditec, Dublin, CA) and a retinal thickness analyzer (RTA; Talia Technology Ltd., Neve-Ilan, Israel) in foveal, parafoveal, and perifoveal areas. METHODS Three measurements of all areas were performed within 1 hour on the same day with each instrument in the eyes of healthy volunteers and diabetic patients. The latter group was divided into eyes with and without macular edema. RESULTS Measurement precision, expressed as the 95% limits of agreement (LA 95%), was significantly higher (i.e., a lower LA 95%, P < 0.01) for the OCT in comparison to the RTA in virtually all areas of the retina. Moreover, measurement reliability, expressed as the intraclass correlation coefficient, was high with the OCT (>0.90) and moderate to low with the RTA (0.26-0.89). A direct influence of macular edema itself on measurement precision of para- and perifoveal areas was found in the OCT measurements. CONCLUSIONS The high measurement precision and reliability of the OCT suggests that this instrument is currently the most suitable technique for detection and follow-up of diabetic macular edema. When macular edema is present, the OCT can reliably detect changes of at least 36 microm at the fovea, 55 microm in parafoveal areas below a thickness of 744 microm, and 42 microm in perifoveal areas below a thickness of 1011 microm.

Changes in the Internal Structure of the Human Crystalline Lens with Diabetes Mellitus Type 1 and Type 2

PURPOSE To investigate the effect of diabetes mellitus (DM) type 1 and type 2 on the internal structure of the lens. DESIGN Observational cross-sectional study. PARTICIPANTS AND CONTROLS One hundred seven patients with DM type 1, 106 patients with DM type 2, and 75 healthy control subjects. METHODS Scheimpflug photography was used to image the lens of the right eye of 213 patients with DM and 75 healthy control subjects. The densitogram of the Scheimpflug image was used to indicate the nucleus and the different layers of the cortex of the lens. Lenses with cataract were excluded. MAIN OUTCOME MEASURES The size of the nucleus and the different layers of the cortex of the lens. RESULTS The nucleus and the different cortical layers of the DM type 1 lenses were significantly thicker compared with those of the control group (P<0.001). A significant association was found between the duration of DM type 1 and both the anterior and posterior cortex, its different layers, and the nucleus (P<0.001). The increase in the anterior and posterior cortex with the duration of DM was comparable with that of the nucleus. No important differences in the internal structure of the lens were found between the patients with DM type 2 and the control group. CONCLUSIONS Diabetes mellitus type 1 has a significant effect on the internal structure of the lens. The difference in effect of DM type 1 and type 2 on internal lens structure suggests an essential difference in pathogenesis. Furthermore, the results of the present study may indicate that the increase in the size of the lens with DM type 1 is the result of a generalized swelling of the lens, affecting all its different parts.

The influence of chronic diabetes mellitus on the thickness and the shape of the anterior and posterior surface of the cornea.

Purpose: To determine the influence of diabetes mellitus (DM) type 1 and type 2 on the thickness, radius of curvature, power, and asphericity of the cornea. Methods: In this observational cross-sectional study, 102 patients with DM type 1, 101 patients with DM type 2, and 69 healthy subjects were measured by means of Scheimpflug imaging to determine central corneal thickness and the radius and asphericity of the anterior and posterior corneal surfaces. Corneal power was calculated from these parameters. Several systemic parameters (eg, duration of diabetes, glycated hemoglobin, blood glucose levels, and type of medication) and ocular comorbidity (eg, stage of retinopathy) were recorded. Results: Patients with DM type 1 and 2 had significantly smaller posterior corneal radii (P < 0.05) than those of healthy subjects (men: 6.49/6.48/6.64 mm; women: 6.36/6.30/6.49 mm). As a result, the optical power of the posterior corneal surface of the patients with diabetes differed from that of the healthy subjects (P < 0.01; men: DM, −6.2 D; healthy, −6.0 D; women: DM, −6.3 D; healthy, −6.2 D). However, corneal thickness, anterior radius and asphericity, and overall corneal power did not differ significantly between the groups. Furthermore, none of the systemic factors or ocular comorbidity had any influence on the corneal thickness or shape. Conclusions: DM affects the posterior corneal radius, resulting in a small change in posterior corneal power. However, chronic DM does not seem to significantly influence the overall corneal power.