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Recent documents in eScholarship@UMMS
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Defining functional DNA elements in the human genome

Mon, 06/23/2014 - 3:50pm

With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.

Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription

Mon, 06/23/2014 - 3:49pm

A new level of chromosome organization, topologically associating domains (TADs), was recently uncovered by chromosome conformation capture (3C) techniques. To explore TAD structure and function, we developed a polymer model that can extract the full repertoire of chromatin conformations within TADs from population-based 3C data. This model predicts actual physical distances and to what extent chromosomal contacts vary between cells. It also identifies interactions within single TADs that stabilize boundaries between TADs and allows us to identify and genetically validate key structural elements within TADs. Combining the model's predictions with high-resolution DNA FISH and quantitative RNA FISH for TADs within the X-inactivation center (Xic), we dissect the relationship between transcription and spatial proximity to cis-regulatory elements. We demonstrate that contacts between potential regulatory elements occur in the context of fluctuating structures rather than stable loops and propose that such fluctuations may contribute to asymmetric expression in the Xic during X inactivation.

A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways

Mon, 06/23/2014 - 3:49pm

Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models.

Multiple transcription factors directly regulate Hox gene lin-39 expression in ventral hypodermal cells of the C. elegans embryo and larva, including the hypodermal fate regulators LIN-26 and ELT-6

Mon, 06/23/2014 - 3:49pm

BACKGROUND: Hox genes encode master regulators of regional fate specification during early metazoan development. Much is known about the initiation and regulation of Hox gene expression in Drosophila and vertebrates, but less is known in the non-arthropod invertebrate model system, C. elegans. The C. elegans Hox gene lin-39 is required for correct fate specification in the midbody region, including the Vulval Precursor Cells (VPCs). To better understand lin-39 regulation and function, we aimed to identify transcription factors necessary for lin-39 expression in the VPCs, and in particular sought factors that initiate lin-39 expression in the embryo.

RESULTS: We used the yeast one-hybrid (Y1H) method to screen for factors that bound to 13 fragments from the lin-39 region: twelve fragments contained sequences conserved between C. elegans and two other nematode species, while one fragment was known to drive reporter gene expression in the early embryo in cells that generate the VPCs. Sixteen transcription factors that bind to eight lin-39 genomic fragments were identified in yeast, and we characterized several factors by verifying their physical interactions in vitro, and showing that reduction of their function leads to alterations in lin-39 levels and lin-39::GFP reporter expression in vivo. Three factors, the orphan nuclear hormone receptor NHR-43, the hypodermal fate regulator LIN-26, and the GATA factor ELT-6 positively regulate lin-39 expression in the embryonic precursors to the VPCs. In particular, ELT-6 interacts with an enhancer that drives GFP expression in the early embryo, and the ELT-6 site we identified is necessary for proper embryonic expression. These three factors, along with the factors ZTF-17, BED-3 and TBX-9, also positively regulate lin-39 expression in the larval VPCs.

CONCLUSIONS: These results significantly expand the number of factors known to directly bind and regulate lin-39 expression, identify the first factors required for lin-39 expression in the embryo, and hint at a positive feedback mechanism involving GATA factors that maintains lin-39 expression in the vulval lineage. This work indicates that, as in other organisms, the regulation of Hox gene expression in C. elegans is complicated, redundant and robust.

Calmodulation meta-analysis: Predicting calmodulin binding via canonical motif clustering

Fri, 06/20/2014 - 2:52pm

The calcium-binding protein calmodulin (CaM) directly binds to membrane transport proteins to modulate their function in response to changes in intracellular calcium concentrations. Because CaM recognizes and binds to a wide variety of target sequences, identifying CaM-binding sites is difficult, requiring intensive sequence gazing and extensive biochemical analysis. Here, we describe a straightforward computational script that rapidly identifies canonical CaM-binding motifs within an amino acid sequence. Analysis of the target sequences from high resolution CaM-peptide structures using this script revealed that CaM often binds to sequences that have multiple overlapping canonical CaM-binding motifs. The addition of a positive charge discriminator to this meta-analysis resulted in a tool that identifies potential CaM-binding domains within a given sequence. To allow users to search for CaM-binding motifs within a protein of interest, perform the meta-analysis, and then compare the results to target peptide-CaM structures deposited in the Protein Data Bank, we created a website and online database. The availability of these tools and analyses will facilitate the design of CaM-related studies of ion channels and membrane transport proteins.

Amyotrophic Lateral Sclerosis Association

Thu, 06/19/2014 - 12:25pm

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, leading to muscular atrophy, progressive loss of muscle control, paralysis, and death. This is a review of the ALS Association web site. The site continues to provide ALS patients and caregivers with current resources for managing life with ALS, and it provides researchers and healthcare professionals with access to evidence-based information on the latest scholarship, and guidelines for the most effective therapies and treatments for ALS. The ALS Association website remains an authoritative resource for anyone seeking quality information about ALS.

The Effects of Vitamin D supplementation on Hepatic Dysfunction, Vitamin D Status, and Glycemic Control in Children and Adolescents with Vitamin D Deficiency and Either Type 1 or Type 2 Diabetes Mellitus

Thu, 06/19/2014 - 10:43am

BACKGROUND: The effects of vitamin D supplementation on mild hepatic dysfunction and glycemic control are unclear in children and adolescents with either type 1 (T1D) or type 2 diabetes (T2D).

HYPOTHESIS: Vitamin D supplementation will improve hepatic dysfunction and glycemic control.

AIM: To determine the effect of vitamin D supplementation on alanine transaminase (ALT), hemoglobin A1c (HbA1c), and serum 25-hydroxyvitamin D [25(OH)D] concentration.

SUBJECTS AND METHODS: A retrospective study of 131 subjects with either T1D (n = 88∶46 females, 42 males), or T2D (n = 43∶26 females, 17 males) of ages 3-18 years between 2007-2013. All subjects had (1) a diagnosis of diabetes for >12 mo, (2) received vitamin D supplementation for the management of vitamin D deficiency (3) had baseline and subsequent simultaneous measurements of HbA1c, ALT, and 25(OH)D. Vitamin D deficiency was defined as 25(OH)D concentration of/L (20 ng/mL).

RESULTS: At baseline, vitamin D deficiency occurred in 72.1% of patients with T2D and in 37.5% of T1D patients (p

CONCLUSIONS: Vitamin D supplementation in subjects with T2D was associated with statistically significant decreases in BMI SDS, ALT, and a clinically-significant decrease in HbA1c.

Risk factors for radiation maculopathy and papillopathy after intraocular irradiation

Wed, 06/18/2014 - 11:01am

PURPOSE: To evaluate rates of occurrence and risk factors for radiation maculopathy and radiation papillopathy in patients with choroidal melanoma at high risk for these complications.

DESIGN: Cohort study.

PARTICIPANTS: A total of 558 patients treated with proton irradiation for choroidal melanoma between 1986 and 1996 with small to moderate sized tumors (less than 5 mm in height and 15 mm in diameter) located within 4 disc diameters of the macula or optic nerve and with a median ocular follow-up of 4 years.

METHODS: Annual and cumulative rates of each endpoint were estimated using life table approaches. Prognostic factors were evaluated using the Cox proportional hazards regression.

MAIN OUTCOME MEASURES: Radiation maculopathy, radiation papillopathy, and vision loss to worse than 20/100.

RESULTS: Cumulative 5-year rates for radiation maculopathy, radiation papillopathy, and vision loss were 64%, 35%, and 68%, respectively. Complication rates rose as a function of radiation exposure to the macula (P for trend = 0.04) or optic disc (P for trend < 0.001), although dose-response patterns were nonlinear. History of diabetes was a significant risk factor for maculopathy (P < 0.001) and optic neuropathy (P = 0.009).

CONCLUSIONS: The onset of radiation vasculopathy is determined primarily by the degree of irradiation exposure to the macula and optic disc. Risk may be enhanced among those with underlying vascular disorders.

Patterns of tumor initiation in choroidal melanoma

Wed, 06/18/2014 - 11:01am

This study attempts to document the occurrence of tumors with respect to clock hour location and distance from the macula and to evaluate tumor location in relation to retinal topography and light dose distribution on the retinal sphere. Analysis of patterns of tumor initiation may provide new evidence to clarify the controversy regarding the possible light-related etiology of choroidal melanoma. Incident cases of choroidal and ciliary body melanoma in Massachusetts residents diagnosed between 1984 and 1993 were the basis for analysis. Conventional fundus drawings and photos were used to assess the initiation site of each tumor. The initiation site was defined as the intersect between the largest tumor diameter and the largest perpendicular diameter of the tumor. Initiation sites were recorded using spherical coordinates. The retinal sphere was divided into 61 mutually exclusive sectors defined according to clock hour and anteroposterior distance from the macula. Rates of initiation were computed for each sector, overall, and according to gender and other clinical factors. Results were similar in left and right eyes; therefore, these were combined in analysis. Tumor initiation had a predilection for the macula (P < 0.0001). Overall, no significant clock hour preference was observed (P = 0.63). However, the parafoveal zone showed a strong circular trend (P < 0.01), with highest rates occurring in the temporal region, and the lowest rates occurring in the nasal region. Rates of occurrence in six progressively more anterior concentric zones (designated as the foveal, parafoveal, posterior, peripheral, anterior, and ciliary body zones) were 21.4, 14.2, 12.1, 8.9, 4.5, and 4.3 counts per spherical unit per 1000 eyes, respectively. Concentric zone location did not vary by gender (P = 0.93) or laterality (P = 0.78). However, posterior location was associated with light iris color (P = 0.01). Tumor diameters were largest in the peripheral region of the fundus and smallest in the macular and ciliary body zone (P < 0.001). Clock hour location was not influenced by gender (P = 0.74), laterality (P = 0.53), iris color (P = 0.84), or tumor diameter (P = 0.73). Results suggest that tumor initiation is not uniformly distributed, with rates of occurrence concentrated in the macular area and decreasing monotonically with distance from the macula to the ciliary body. This pattern is consistent with the retinal topography and correlates positively with the dose distribution of solar light on the retinal sphere.

Metastatic melanoma death rates by anatomic site after proton beam irradiation for uveal melanoma

Wed, 06/18/2014 - 11:01am

BACKGROUND: Ciliary body location is an established prognostic factor for metastasis-related death from uveal melanoma. We evaluated alternative approaches for classifying this covariate when constructing predictive models of patient survival.

METHODS AND DESIGN: The analyses were based on a consecutive series of 1848 primary choroidal and/or ciliary body melanoma patients treated with proton beam irradiation (70 cobalt gray equivalent in 5 fractions) at the Harvard Cyclotron Laboratory, Boston, Mass, between July 1975 and December 1995. For each patient, the anatomic site of the tumor was classified according to an estimate of the proportion of the tumor base lying anterior to the ora serrata. Using proportional hazards regression, we estimated relative risk ratios and death rates from melanoma metastasis according to the extent of ciliary body involvement. All estimates were adjusted for other established prognostic factors.

RESULTS: Patients were followed up through April 30, 1998; none were lost to follow-up. Of 1848 patients analyzed, 378 died of melanoma metastasis. The median follow-up period among survivors was 9.5 years. Ciliary body origin (>50% of tumor base anterior to the ora serrata) was positively associated with tumor pigmentation (P<.001), tumor height (P<.001), and extrascleral extension of the tumor (P<.001). Compared with tumors involving only the choroid, melanoma-associated death rates increased with the proportion of the tumor base lying within the ciliary body (P =. 006); the multivariate-adjusted relative risk ratio for greater than 75% involvement was 2.30 (95% confidence interval [CI], 1.26-4.23). The covariate-adjusted 5-year death rates for ciliary body origin and choroidal origin were 15.9% (95% CI, 11.3%-21.2%) and 9.8% (95% CI, 8.3%-11.7%), respectively.

CONCLUSION: Patients with melanomas of presumed ciliary body origin seem to be subject to a higher risk of death resulting from melanoma metastasis. Arch Ophthalmol. 2000;118:1066-1070

Adaptational process of parents of pediatric oncology patients

Wed, 06/18/2014 - 11:01am

This study, based on grounded theory, explores the adaptational process of parents of pediatric oncology patients. Thirty-two Taiwanese parents (26 mothers and 6 fathers) were interviewed. Data were collected through individual in-depth and focus group interviews, observations, medical chart review, nurses' note, and researchers' reflexive journals. The findings suggest that parents adapt to their children's cancer by a dynamic process; i.e., they modify their coping tasks and related strategies as clinical events (e.g., diagnosis, side effects, relapses, or death) occur. This adaptational process consisted of five components: confronting treatment, maintaining family integrity, establishing support, maintaining emotional well-being, and searching for spiritual meaning. Related factors such as coping tasks are described.

Use of alternative therapy among pediatric oncology patients in Taiwan

Wed, 06/18/2014 - 11:01am

Both alternative medicine and western medicine have been commonly used to treat pediatric cancer patients in Taiwan. Each has its own intrinsic strengths and weaknesses and they can be complementary. Little is known about medical help-seeking behaviors of parents of pediatric cancer patients, especially those related to alternative therapies. This study investigated the extent and parental expectations on use of alternative therapies. All primary caregivers of 63 eligible patients were interviewed. Use of alternative therapies, regardless of education level or social status of their families, is prevalent (n = 46, 73%) in Taiwan. Commonly used alternative therapies included, in order of popularity, formulated functional food (n = 22, 48%), temple worship/shamanism (n = 19, 40%), traditional Chinese medicine (n = 9, 20%), secret recipes/herbs (n = 13, 28%), and diet supplements (n = 9, 19%). Such practices generally occur without medical guidance from oncologists, largely because of poor interactions between parents and oncologists. Future efforts should be made to encourage both parents and oncologists to discuss this issue. Nurses may serve as mediators by developing mutual trust and a sharing relationship between these groups.

A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma

Wed, 06/18/2014 - 11:01am

OBJECTIVE: To determine if a reduction in proton radiation dose from the standard dose of 70 cobalt gray equivalents (CGE) to 50 CGE would decrease radiation-induced complications, thereby improving visual prognosis, without compromising local tumor control for patients with uveal melanoma at high risk of these complications.

DESIGN: Randomized, double-masked clinical trial.

PARTICIPANTS: A total of 188 patients with small or medium-sized choroidal melanomas (height) near the optic disc or macula (within 4 disc diameters of either structure).

METHODS: Patients were treated with proton beam therapy at doses of either 50 CGE or 70 CGE between October 1989 and July 1994, and followed up biannually through April 1998. Outcomes included visual acuity, radiation complications, melanoma recurrence, and metastasis.

RESULTS: Proportions of patients retaining visual acuity of at least 20/200 were similar in the 2 dose groups at 5 years after radiation (approximately 55%). Similar numbers of patients in each group experienced tumor regrowth (2 patients at 50 CGE vs 3 patients at 70 CGE; P>.99) and metastasis (7 patients at 50 CGE vs 8 patients at 70 CGE;P=.79). Five-year rates of radiation maculopathy also were similar (for both groups, approximately 75% for tumors within 1 disc diameter and 40% for tumors >1 disc diameter from the macula). Rates of radiation papillopathy were nonsignificantly decreased in the 50-CGE treatment group when tumors were located 1 disc diameter or less from the optic disc (P=.20). Patients treated with the lower dose also experienced significantly less visual field loss.

CONCLUSIONS: This level of dose reduction did not result in a lesser degree of visual acuity loss. The lower-dose group did experience significantly less visual field loss. Local tumor recurrence and metastatic death rates were similar in both dose groups.

The Chinese version of the Parenting Stress Index: a psychometric study

Wed, 06/18/2014 - 11:01am

This study examined the psychometric properties of a Chinese version of the Parenting Stress Index/Short Form (PSI/SF). A 15-item simplified PSI/SF (S-PSI/SF) was subsequently developed which maintained a level of reliability and validity similar to the full version. The Chinese PSI/SF was tested on 149 parents (100 mothers, 49 fathers) of pediatric cancer patients in Taiwan. Psychometric testing was conducted using item analysis, Cronbach's alpha and confirmatory factor analysis. The S-PSI/SF was constructed based on the item analysis of the PSI/SF. Both the PSI/SF and S-PSI/SF produced good reliability coefficients. Confirmatory factor analyses indicated that both PSI/SF and S-PSI/SF met all criteria for goodness of fit. Compared with the PSI/SF, the S-PSI/SF demonstrated better internal consistency and overall fit at the one-subscale level, and satisfactory overall fit at two- and three-subscale levels. Despite the limited number of items included, the S-PSI/SF had a very good factor structure. No gender difference in parenting distress index was observed between mothers and fathers of pediatric cancer patients. Conclusion: The 15-item S-PSI/SF is a brief, easily administered instrument that has evidence of reliability and validity in Taiwanese parents of children with cancer. It could serve as a valuable assessment tool in clinical practice to identify parenting stress with a need for intervention.

Pediatric violence-related injuries in Boston: results of a city-wide emergency department surveillance program

Wed, 06/18/2014 - 11:01am

CONTEXT: Violence-related injuries among children are common, but age-based incidence data are not easily available.

OBJECTIVES: To describe injuries due to violence in a population-based case series of children and to estimate injury incidence.

DESIGN: Prospective surveillance of children residing in Boston, Mass, who received pediatric emergency department treatment for violence-related injury during a 4-year period beginning April 15, 1995.

SETTING: Pediatric emergency departments in Boston.

PATIENTS: Children aged 3 through 18 years who came to a hospital emergency department between April 1995 and April 1999. Violence-related injuries were defined as those resulting from a situation of conflict involving 2 or more persons with intent to harm, as assessed by health care personnel caring for the patients. Self-inflicted injuries and injuries caused by child abuse (including any injury resulting from a conflict with a parent or guardian) were excluded. Homicides of Boston children aged 3 through 18 years who were killed during the study period were included based on police data.

MAIN OUTCOME MEASURE: Population-based violence-related injury rates.

RESULTS: There were 2035 injury-related visits caused by violence, which reflects a rate of 52.7 (95% confidence interval, 50.5-54.9) per 10 000 person-years. Most injuries were relatively minor; 6.4% of visits resulted in admission. The youth violence-related injury rate in Boston declined at an average rate of 12% annually during the period studied.

CONCLUSION: Pediatric emergency department monitoring of violence-related injury in Boston suggests that childhood injuries due to violence declined during the late 1990s.

Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment

Wed, 06/18/2014 - 11:01am

OBJECTIVE: To evaluate the safety and efficacy of intravitreal injections of an antigen-binding fragment of a recombinant humanized monoclonal antibody directed toward vascular endothelial growth factor (rhuFab VEGF) in a monkey model of choroidal neovascularization (CNV).

METHODS: In phase 1 of the study, each animal received intravitreal injections, 500 microg per eye, of rhuFab VEGF in one eye (prevention eye), while the contralateral eye received rhuFab VEGF vehicle (control eye) at 2-week intervals. On day 21, laser photocoagulation was performed to induce CNV. In phase 2, the vehicle-treated eye was crossed over and both eyes received 500 microg of rhuFab VEGF beginning 21 days following laser-induced injury at days 42 and 56. The eyes were monitored by ophthalmic examinations, color photographs, and fluorescein angiography.

RESULTS: rhuFab VEGF did not cause any ocular hemorrhages. All eyes treated with rhuFab VEGF developed acute anterior chamber inflammation within 24 hours of the first injection that resolved within 1 week, and this inflammation was less severe with subsequent injections. The incidence of CNV, defined angiographically, was significantly lower in the prevention eyes than the control eyes (P<.001). Subsequent treatments were associated with less leakage in eyes with established CNV that were crossed over from the control eyes to the treatment eyes (P =.001).

CONCLUSIONS: Intravitreal rhuFab VEGF injections prevented formation of clinically significant CNV in cynomolgus monkeys and decreased leakage of already formed CNV with no significant toxic effects.

CLINICAL RELEVANCE: This study provides the nonclinical proof of principle for ongoing clinical studies of intravitreally injected rhuFab VEGF in patients with neovascular age-related macular degeneration.

Prescription drug coverage and seniors: how well are states closing the gap

Wed, 06/18/2014 - 11:01am

As policymakers debate adding a drug benefit to Medicare, many states are attempting to provide drug coverage for low-income seniors through Medicaid and state-funded pharmacy assistance programs. This 2001 survey of seniors in eight states finds marked differences among states in the percentage of seniors with coverage and in the sources providing coverage. Among low-income seniors, a range of 20 percent (New York and California) to 38 percent (Michigan and Texas) lacked drug coverage. In all states Medicaid was an important source of coverage for the poor, but the depth of Medicaid drug coverage varied widely across states. Even states with pharmacy assistance programs fell far short of closing the prescription coverage gap for low-income seniors. Finally, the study finds that classifying beneficiaries as either having coverage or not misses major differences in depth of coverage, with some sources of coverage appearing only marginally better than no coverage at all. With erosion of state and private sources of prescription benefits expected, the findings speak to the need for a national policy solution.

Long-term risk of local failure after proton therapy for choroidal/ciliary body melanoma

Wed, 06/18/2014 - 11:01am

PURPOSE: To quantitate long-term risk of local treatment failure after proton irradiation of choroidal/ciliary body melanomas and to evaluate risk of metastasis-related deaths after local failure.

METHODS: We followed prospectively 1,922 patients treated at the Harvard Cyclotron between January 1975 and December 1996 for local recurrences of their tumors. Mortality surveillance was completed through June 1999. For analysis, patient follow-up continued until tumor regrowth was detected or, in patients without recurrence, until the date of the last dilated examination prior to April 1998. Actuarial methods were used to calculate rates of recurrence and metastatic deaths. Cox regression models were constructed to evaluate risk factors for these outcomes.

RESULTS: Median ocular follow-up after irradiation was 5.2 years. Local recurrence was documented in 45 patients by ultrasound and/or sequential fundus photographs; in 17 more patients, the eye was enucleated due to suspected but unconfirmed tumor growth. Recurrences were documented between 2 months and 11.3 years after irradiation. The 5- and 10-year rates of regrowth, including suspected cases, were 3.2% (95% confidence interval [CI], 2.5%-4.2%), and 4.3% (95% CI, 3.3%-5.6%). Among the 45 documented recurrences, about one half (21) occurred at the margin, presumably due to treatment planning errors. The remaining cases represented extrascleral extensions (nine cases), ring melanomas (six cases), or uncontrolled tumor (nine cases). Recurrence of the tumor was independently related to risk of tumor-related death.

CONCLUSION: These data, based on relatively long-term follow-up, demonstrate that excellent local control is maintained after proton therapy and that patients with recurrences experience poorer survival.

Evidence-based estimates of outcome in patients irradiated for intraocular melanoma

Wed, 06/18/2014 - 11:01am

BACKGROUND: Melanoma of the eye is the only potentially fatal ocular malignancy in adults. Until radiation therapy gained wide acceptance in the 1980s, enucleation was the standard treatment for the tumor. Long-term results after proton beam irradiation are now available.

METHODS: We developed risk score equations to estimate probabilities of the 4 principal treatment outcomes-local tumor recurrence, death from metastasis, retention of the treated eye, and vision loss-based on an analysis of 2069 patients treated with proton beam radiation for intraocular melanoma between July 10, 1975, and December 31, 1997. Median follow-up in surviving patients was 9.4 years.

RESULTS: Tumor regrowth occurred in 60 patients, and 95% of tumors (95% confidence interval, 93%-96%) were controlled locally at 15 years. Risk scores were developed for the other 3 outcomes studied. Overall, the treated eye was retained by 84% of patients (95% confidence interval, 80%-87%) at 15 years. The probabilities for vision loss (visual acuity worse than 20/200) ranged from 100% to 20% at 10 years and for death from tumor metastases from 95% to 35% at 15 years, depending on the risk group.

CONCLUSIONS: High-dose radiation treatment was highly effective in achieving local control of intraocular melanomas. In most cases, the eye was salvaged, and functional vision was retained in many patients. The mortality rate was high in an identifiable subset of patients who may benefit from adjuvant therapies directed at microscopic liver metastases.

Tumor basal area and metastatic death after proton beam irradiation for choroidal melanoma

Wed, 06/18/2014 - 11:01am

BACKGROUND: Tumor dimension is an established prognostic factor for metastasis-related death after radiotherapy for uveal melanoma.

OBJECTIVE: To compare various methods of modeling the relationship between tumor dimension and metastatic death.

PATIENTS AND METHODS: The analyses were based on a consecutive series of 1204 patients with primary choroidal melanoma treated with proton beam irradiation (70 cobalt-gray equivalent in 5 fractions) at the Harvard Cyclotron Laboratory, Boston, Mass, between January 1985 and December 1998. Largest basal diameter and largest perpendicular basal diameter were recorded at the time of surgical placement of tantalum rings used for tumor localization during proton treatment. The height of the tumor and the axial diameter of the eye were measured by ultrasonography prior to treatment. Using proportional hazards regression, we compared the prognostic influence of different indices of tumor size with estimated risk ratios and death rates according to tumor basal area and largest basal diameter. All estimates were adjusted for other established prognostic factors.

RESULTS: Patients were followed up annually through June 30, 2000. Of the 1204 patients analyzed, 193 died of melanoma metastasis. The median follow-up among survivors was 7.9 years. The 5- and 10-year metastatic death rates were 12.8% and 20.7%, respectively. Among various approaches for modeling tumor dimension, the logarithm of tumor basal area had the highest log-likelihood and performed better than other approaches in 85% of the simulations. Based on this model, the covariate-adjusted rate ratio for any doubling in tumor basal area was 1.92 (95% confidence interval, 1.62-2.28).

CONCLUSION: Tumor basal area is a better prognostic indicator than largest tumor diameter and tumor volume in the prediction of metastatic death after proton beam irradiation for uveal melanoma.