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Project HERCULES has developed a natural history model (NHM) of disease progression in Duchenne muscular dystrophy (DMD) that comprises eight ordered health states (two ambulatory states, one transfer state indicating increased caregiver burden in which patients cannot walk/run 10m or rise from floor but can still support their own weight, and five non-ambulatory states). The current study used data from nine sources (clinical trial placebo arms, one real-world dataset, and three natural history datasets) to further characterize patients with DMD according to these health states. The study included 1,173 patients across 5,306‬ visits. Patients were on average older and exhibited worse ambulatory, pulmonary, upper limb, and cardiac functions with each successive health state. Mean±SE ages increased monotonically across health states, starting with 8.47±0.07 for early ambulatory, 10.86±0.13 for late ambulatory, 11.65±0.35 for transfer state, and ranging from 13.17±0.32 to 16.84±0.37 for the non-ambulatory states. North Star Ambulatory Assessment (NSAA) total score, which measures motor function and ranges from 34 (best) to 0 (worst), was 23.7 (interquartile range [IQR]: 20–30) for early ambulatory patients, 12.7 (IQR: 9–16) for late ambulatory patients, and 3.9 (IQR: 2–5) for transfer patients. Pulmonary function as measured by mean±SE of forced vital capacity percent predicted (FVC%p) was 94.5±0.8 for early ambulatory, 89.1±1.4 for late ambulatory, and 80.2±2.8 for transfer states, and decreased from 77.2±1.7 to 20.6±1.6 across the five non-ambulatory health states. In summary, these findings further characterize health states and their interpretation in economic modeling and decision-making in DMD management. [ABSTRACT FROM AUTHOR]

Objective. To correlate 3 common presenting signs of retinoblastoma with patient and ocular survival and to assess the efficacy of current pediatric screening practices for retinoblastoma. Methods. A retrospective study was conducted of 1831 retinoblastoma patients from our center (1914-June 2000). Patient survival (excluding deaths from other primary neoplasms) and ocular survival (presenting eyes) rates were calculated and analyzed using the Kaplan-Meier method. Results. Leukocoria correlated with excellent patient survival (>86%, 5 years) but poor ocular survival in unilateral (4%, 5 years) and bilateral patients (29%, 5 years). A total of 308 (19%) of 1654 patients presented with strabismus: patient survival was excellent (90%, 5 years), and ocular survival was poor (17%, 5 years) yet better than leukocoria. Patients who had a family history of retinoblastoma and were clinically screened for retinal tumors from birth were diagnosed younger (8 months of age) and earlier (Reese Ellsworth group 1 = 26 [58%] of 45) and had better ocular survival than nonscreened patients with a family history. More patients were initially detected by family/friends (1315 [80%] of 1632) than pediatricians (123 [8%] of 1632) or ophthalmologists (156 [10%] of 1632). Conclusion. Most US children whose retinoblastoma is diagnosed initially present with leukocoria detected by a parent, despite routine pediatric screening for leukocoria via the red reflex test. Initial disease detection at the point of leukocoria or strabismus correlated with high patient survival rates and poor ocular survival rates for the presenting eye. Saving eyes and vision requires disease recognition before leukocoria, as demonstrated by the better ocular salvage rate among patients who had a positive family history and received clinical surveillance via early, routine dilated funduscopic examinations by an ophthalmologist. Pediatrics 2003;112:1248-1255; retinoblastoma, cancer, leukocoria, red reflex, strabismus., Retinoblastoma is a malignant tumor of the deeloping retina seen in young children. It is stimated that of the 5000 to 8000 new cases of retinoblastoma seen worldwide, at least [...]

We investigated the epigenetic silencing and genetic changes of the RAS-associated domain family 1A (RASSF1A) gene and the O6-methylguanine-DNA methyltransferase (MGMT) gene in retinoblastoma. We extracted DNA from microdissected tumor and normal retina tissues of the same patient in 68 retinoblastoma cases. Promoter methylation in RASSF1A and MGMT was analyzed by methylation-specific PCR, RASSF1A sequence alterations in all coding exons by direct DNA sequencing, and RASSF1A expression by RT-PCR. Cell cycle staging was analyzed by flow cytometry. We detected RASSF1A promoter hypermethylation in 82% of retinoblastoma, in tumor tissues only but not in adjacent normal retinal tissue cells. There was no expression of RASSF1A transcripts in all hypermethylated samples, but RASSF1A transcripts were restored after 5-aza-2′-deoxycytidine treatment with no changes in cell cycle or apoptosis. No mutation in the RASSF1A sequence was found. MGMT hypermethylation was present in 15% of theretinoblastoma samples, and the absence of MGMT hypermethylation was associated (P = .002) with retinoblastoma at advanced Reese-Ellsworth tumor stage. Our results revealed a high RASSF1A hypermethylation frequency in retinoblastoma. The correlation of MGMT inactivation by promoter hypermethylation with lower-stage diseases indicated that MGMT hypermethylation provides useful prognostic information. Epigenetic mechanism plays an important role in the progression of retinoblastoma. [ABSTRACT FROM AUTHOR]

: PurposeTo determine the extent of expansion of laser scars after single treatment with transpupillary thermotherapy (TTT) for retinoblastoma.: DesignWe retrospectively reviewed medical records and RetCam (Massie Industries, Dublin, CA) digital fundus photographs of patients with retinoblastoma who received TTT by use of an 810-nm diode laser with large-spot indirect ophthalmoscope. Digital images were measured by use of RetCam software beginning immediately after treatment. Lesions were measured in both linear size and area by 2 observers. In addition, optic disc diameters were also measured for each image.: ParticipantsWe identified 9 patients with hereditary retinoblastoma who were treated from 1997 to 2000.: Main outcome measuresLinear and area expansion of laser scars as a function of time.: ResultsFourteen tumors in 10 eyes were treated successfully with 1 session of TTT. Follow-up for all eyes was at least 16 months. Scars of 12 of the 14 lesions increased beyond their original borders (mean starting linear diameter, 2.02 mm; range 1.46–2.59 mm; mean increase, 0.72 mm [36%]) over time, most within 6 months to 1 year after treatment.: ConclusionsScars from TTT for retinoblastoma may increase in size after treatment. This expansion must be considered when applying TTT to tumors near vital macular structures, such as the fovea and optic nerve. [Copyright &y& Elsevier]

Purpose: To investigate the link between microsatellite instability and epigenetic silencing of the MLH1 gene in the human retinoblastoma genome., Methods: Methylation at the 5' region of MLH1 was studied, along with its protein expression level by using immunohistochemical staining in 51 retinoblastoma tumors and 2 retinoblastoma cell lines. Also assessed was the genomic stability of 26 retinoblastoma DNAs from microdissected tumor tissue and matched normal retina tissue obtained from the same patient by microsatellite instability (MSI) analysis. The National Cancer Institute-designed reference panel, and 85 markers on chromosomes 1, 6, 9, and 13 were used., Results: Hypermethylation of the MLH1 promoter was detected in the WERI-Rb1 cell line and in 34 (67%) of the 51 tumors, but not in cell line Y79 and the other 17 tumors. MLH1 hypermethylation was associated with null MLH1 protein expression (P < 0.0005) and with well-differentiated histology (P < 0.05). MSI at three markers (D2S123, D6S470, and D13S265) was frequently identified among 26 retinoblastoma specimens with matched normal DNA. Among these 26 retinoblastomas, high-frequency MSI (MSI-H) tumors were detected in 19% (5/26) and low-frequency MSI (MSI-L) in another 19% (5/26). The remaining 62% (15/26) were genetically stable (MSS). MSI status (MSS, MSI-L, and MSI-H) was not associated with MLH1 promoter hypermethylation (P = 0.088; Kruskal-Wallis test)., Conclusions: Epigenetic silencing of the DNA repair gene MLH1 by promoter hypermethylation is a frequent event in retinoblastoma. The results showed that somatic genetic changes involving MSI occur in a subset of retinoblastoma and implicated the presence of a defective DNA mismatch repair pathway resulting in MSI in retinoblastoma.