Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. "Alive, with good vision and no comorbidity".

Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage attempts with radiotherapy. This led to the empiric delineation of a window for conservative management subject to a "state of metastatic grace" never to be violated. Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, definitive eradication of radiotherapy and reduction of systemic chemotherapy. Here we intend to review the relevant knowledge susceptible to improve the conservative management of retinoblastoma in compliance with the "state of metastatic grace", with particular attention to (i) reviewing how new imaging modalities impact the frontiers of conservative management, (ii) dissecting retinoblastoma genesis, growth patterns, and intraocular routes of tumor propagation, (iii) assessing major therapeutic changes and trends, (iv) proposing a classification of relapsing retinoblastoma, (v) examining treatable/preventable disease-related or treatment-induced complications, and (vi) appraising new therapeutic targets and concepts, as well as liquid biopsy potentiality.

OCT-guided management of subclinical recurrent retinoblastoma.

PURPOSE: Retinoblastoma (Rb) tumor recurrence in the papillary or macular region is a threat to life and visual prognosis respectively, making early detection indispensable. This study demonstrates the value of optical coherence tomography (OCT) in the early detection of subclinical tumor recurrence. METHODS: Since June 2012, hand-held SD-OCT (spectral domain Optical Coherence Tomography) of retro-equatorial foci, the optic head nerve and macula, is systematically performed under anesthesia in children treated and followed for Rb. RESULTS: Between June 2012 and January 2017, 16 subclinical recurrent tumors in 14 children were detected only by OCT in flat pigmented scars (n = 9), in type 2 regression (n = 3), on the optic nerve head (n = 3), and as secondary retinal seeding (n = 1). CONCLUSION: OCT has become invaluable in the modern management of Rb. It allows not only early detection of a lesion before any tumor extension towards the macula or optic nerve head, but also the monitoring of the therapeutic response.

First-line intra-arterial versus intravenous chemotherapy in unilateral sporadic group D retinoblastoma: evidence of better visual outcomes, ocular survival and shorter time to success with intra-arterial delivery from retrospective review of 20†years of treatment.

PURPOSE: The introduction of intra-arterial chemotherapy (IAC) as salvage treatment has improved the prognosis for eye conservation in group D retinoblastoma. The aim of this study was to compare the outcomes of consecutive patients with advanced unilateral disease treated with either first-line intravenous chemotherapy (IVC) or first-line IAC. DESIGN: This is a retrospective mono-centric comparative review of consecutive patients. PATIENTS: Sporadic unilateral retinoblastoma group D cases treated conservatively at Jules-Gonin Eye Hospital and CHUV between 1997 and 2014. From January 1997 to August 2008, IVC, combined with focal treatments, was the primary treatment approach. From September 2008 to October 2014, IAC replaced IVC as first-line therapy. METHODS: 48 patients met the inclusion criteria, receiving only either IAC or IVC as primary treatment modality. RESULTS: Outcomes of 23 patients treated by IVC were compared with those of 25 treated by IAC; mean follow-up was 105.3 months (range 29.2-218.6) and 41.7 months (range 19.6-89.5), respectively. Treatment duration was significantly shorter in the IAC group (p<0.001). Ten eyes in the IVC group underwent enucleation. Recordable visual acuity of the salvaged eyes was significantly better in the IAC group (0.9 vs 1.4 logarithm of the minimum angle of resolution, p<0.01). No extraocular disease, metastases or long-term systemic complications were observed in either group. CONCLUSIONS: The difference in the time frame between treatment groups had an impact on the availability of intravitreal chemotherapy treatment. Despite this, the results reported here imply that eyes treated with first-line IAC will have shorter treatment period, better ocular survival and visual acuity than first-line IVC.

ranibizumab in the management of advanced Coats disease Stages 3B and 4: long-term outcomes.

BACKGROUND: Laser photocoagulation and cryotherapy to completely destroy telangiectatic vessels and ischemic retina in Coats disease is barely applicable in advanced cases with total retinal detachment, and globe survival is notoriously poor in Stages 3B and 4. Anti-vascular endothelial growth factor intravitreal injections may offer new prospects for these patients. METHODS: This study is a retrospective review of all consecutive patients with Coats disease treated with neoadjuvant or adjuvant intravitreal ranibizumab plus conventional and amblyopia treatment as appropriate. RESULTS: Nine patients (median age, 13 months) presenting Coats Stages 3B and 4 (5 and 4 eyes, respectively) were included. Iris neovascularization resolved within 2 weeks and retinal reapplication within 4 months in all patients. At last follow-up, globe survival was 100% with anatomical success in 8 of the 9 eyes. With a median follow-up of 50 months, fibrotic vitreoretinopathy was developed in 5 of the 9 cases, one leading to tractional retinal detachment and ultimately phthisis bulbi. The remaining 4 of the 9 eyes achieved some vision (range, 0.02-0.063). CONCLUSION: To the best of the authors' knowledge, this is the largest reported series of late-stage Coats undergoing anti-vascular endothelial growth factor therapy, a homogenous cohort of patients treated with a single agent and with the longest follow-up. This study supports the role of ranibizumab in advanced disease by transient restoration of the hemato-retinal barrier and suppression of neovascularization to facilitate classic treatment. At the last follow-up, the authors report unprecedented anatomical success and functional outcome.

Unhealthy drinking patterns in older adults: prevalence and associated characteristics.

OBJECTIVES: To examine the prevalence of unhealthy drinking patterns in community-dwelling older adults and its association with sociodemographic and health characteristics. DESIGN: Cross-sectional analysis of nationally representative survey data. SETTING: The data source was the 2003 Access to Care file of the Medicare Current Beneficiary Survey, which represents the continuously enrolled Medicare population. PARTICIPANTS: Community-dwelling Medicare beneficiaries aged 65 and older (N=12,413). MEASUREMENTS: The prevalence of unhealthy alcohol use by older adults defined in relation to two parameters of recommended limits: monthly use exceeding 30 drinks per typical month and "heavy episodic" drinking of four or more drinks in any single day during a typical month in the previous year. Sociodemographic and health status variables were also included. RESULTS: Nine percent of elderly Medicare beneficiaries reported unhealthy drinking, with higher prevalence in men (16%) than women (4%). In logistic regression analyses with the full sample, higher education and income; better health status; male sex; younger age; smoking; being white; and being divorced, separated, or single were associated with higher likelihood of unhealthy drinking. Among drinkers, in addition to sociodemographic variables, self-reported depressive symptoms were positively associated with unhealthy drinking. Among unhealthy drinkers, race and ethnicity variables were associated with likelihood of heavy episodic drinking. CONCLUSION: Almost one in 10 elderly Medicare beneficiaries report exceeding recommended drinking limits. Several distinct unhealthy drinking patterns were identified and associated with sociodemographic and health characteristics, suggesting the value of additional targeted approaches within the context of universal screening to reduce alcohol misuse by older adults.

Shorter time to diagnosis and improved stage at presentation in Swiss patients with retinoblastoma treated from 1963 to 2004.

OBJECTIVES: Retinoblastoma is the most frequent intraocular malignancy in children. Early diagnosis is essential for globe salvage and patient survival. The aim of our study was to determine how time to diagnosis of retinoblastoma has evolved over a 40-year period in Switzerland. METHOD AND PATIENTS: A retrospective study of 139 Swiss patients with retinoblastoma was performed comparing 3 periods: (1) 1963-1983; (2) 1984-1993; and (3) 1994-2004. Factors taken into account were gender, laterality of retinoblastoma, age at first symptoms, type and first observer of symptoms, time to diagnosis, age at diagnosis, disease stage, and family history. RESULTS: Thirty-seven patients (26.6%) were treated in period 1, 44 (31.7%) in period 2, and 58 (41.7%) in period 3. Overall, the diagnostic interval decreased in a significant way from 6.97 months in period 1 to 3.58 in period 2 and to 2.25 in period 3. When looking separately at unilateral and bilateral disease, the decrease of the diagnostic interval remained statistically significant in unilateral retinoblastoma; there was also a significant reduction in the number of patients with advanced group E disease (Murphree classification) (61.5% in period 1, 46.7% in period 2, 22.2% in period 3). In bilateral disease, the same observations were made to a lesser extent. However, there were no cases with group E disease in 10 patients with positive family history. Leukocoria (48.2%) and strabismus (20.1%) were the 2 most frequent symptoms throughout the 3 periods. The only factors that statistically influenced the chances of having a diagnosis of group E disease were the diagnostic interval and period of diagnosis. CONCLUSIONS: Progress has been made in the diagnosis of retinoblastoma in Switzerland, notably in unilateral disease. Improvement to a lesser extent has also been observed in bilateral cases but without statistical significance. Greater effort is needed to teach physicians-in-training to recognize the importance of ocular symptoms and refer patients earlier.

Undergraduate public health education: a workforce perspective.

OBJECTIVE: To describe the career paths of students who majored in public health at the undergraduate level and to assess the skills and knowledge these graduates believed were most useful to them in the public health workforce. METHOD: A telephone survey was conducted of all graduates from Adelaide University's Bachelor of Health Sciences degree from 1992-99 who had majored in public health (124 graduates). RESULTS: The response rate to the graduate survey was 71%. Using the definition of public health functions from the National Delphi Study on Public Health Functions to delineate the public health workforce, 59% of respondents were employed in public health. Graduates working in public health valued generic skills such as communication and collaboration more highly than more specific public health skills and knowledge areas. However, they also believed their undergraduate course would have been improved by a more practical orientation. CONCLUSIONS: A high proportion of graduates from this generalist degree who major in public health find employment in the public health workforce. They greatly value the generic skills associated with their undergraduate public health education and believe their entry into the workforce would have been further facilitated by stronger links between their academic program and the working environment of public health professionals. IMPLICATIONS: Studies of workforce training programs in public health must differentiate between the educational needs of undergraduate and postgraduate students. In particular, strategies need to be developed to provide stronger links between undergraduate students and the public health workforce.