Ocular and systemic toxicity of high-dose intravitreal topotecan in rabbits: Implications for retinoblastoma treatment.

Although many more eyes of children with retinoblastoma are salvaged now compared to just 10 years ago, the control of vitreous seeding remains a challenge. The introduction of intravitreal injection of melphalan has enabled more eyes to be salvaged safely but with definite retinal toxicity. Intensive treatment with high-dose intravitreal topotecan may be a strategy to control tumor burden because of its cell cycle-dependent cytotoxicity and the proven safety in humans. Therefore, we evaluated the ocular and systemic safety of repeated high-dose intravitreal injections of topotecan in rabbits. Systemic and ocular toxicity was assessed in non-tumor-bearing rabbits after four weekly injections of three doses of topotecan (10 µg, 25 µg, and 50 µg) or vehicle alone. Animals were evaluated weekly for general and ophthalmic clinical status. One week after the last injection, vitreous and plasma samples were collected for drug quantification and the enucleated eyes were subjected to histological assessment. Weight, hair loss, or changes in hematologic values were absent during the study period across all animal groups. Eyes injected with all topotecan doses or vehicle showed no signs of anterior segment inflammation, clinical or histologic evidence of damage to the retina, and ERG parameters remained unaltered throughout the study. Vitreous and plasma topotecan lactone concentrations were undetectable. Four weekly intravitreal injections of topotecan up to 50 µg in the animal model or a 100 µg human equivalent dose were not toxic for the rabbit eye. High doses of topotecan may show promising translation to the clinic for the management of difficult-to-treat retinoblastoma vitreous seeds.

Emerging therapy in arthritis: Modulation of markers of the inflammatory process.

The induction of tolerance has been proposed as a therapeutic strategy for arthritis aiming to decrease progression of the pathology, probably by promoting suppressor mechanisms of the autoimmune response. This work aimed to confirm whether the treatment with vitamin D3 could synergize oral tolerance induced by hydrolyzed collagen peptides, in our experimental model of antigen induced arthritis in New Zealand rabbits. Clinical observation of the phenomenon indicates that simultaneous treatment with hydrolyzed collagen peptides and vitamin D3 was beneficial when compared with no treatment, for arthritic animals, and for arthritic animals that received treatment with only hydrolyzed collagen peptides or vitamin D3. Treatment with hydrolyzed collagen peptides caused diminished proinflammatory cytokine levels, an effect synergized significantly by the simultaneous treatment with vitamin D3. The anatomical-pathological studies of the animals that received both treatments simultaneously showed synovial tissues without lymphocytic and plasma cell infiltrates, and without vascular proliferation. Some of the synovial tissue of the animals of these groups showed a slight decrease in Galectin-3 expression. We propose that simultaneous oral treatment with vitamin D3 and hydrolyzed collagen peptides could increase the immunoregulatory effect on the process of previously triggered arthritis. We used articular cartilage hydrolysate and not collagen II because peptides best expose antigenic determinants that could induce oral tolerance. Oral tolerance may be considered in the design of novel alternative therapies for autoimmune disease and we have herein presented novel evidence that the simultaneous treatment with vitamin D3 may synergize this beneficial effect.

Breast cancer risk after radiotherapy for heritable and non-heritable retinoblastoma: a US-UK study.

BACKGROUND: Retinoblastoma is a rare childhood eye cancer caused by germline or somatic mutations in the RB1 gene. Previous studies observed elevated breast cancer risk among retinoblastoma survivors. However, there has been no research on breast cancer risk in relation to radiation (primarily scatter radiation from the primary treatment) and genetic susceptibility of retinoblastoma survivors. METHODS: Two groups of retinoblastoma survivors from the US and UK were selected, and breast cancer risk analysed using a case-control methodology, nesting within the respective cohorts, matching on heritability (that is to say, having bilateral retinoblastoma or being unilateral cases with at least one relative with retinoblastoma), and using exact statistical methods. There were a total of 31 cases and 77 controls. RESULTS: Overall there was no significant variation of breast cancer risk with dose (P>0.5). However, there was a pronounced and significant (P=0.047) increase in the risk of breast cancer with increasing radiation dose for non-heritable retinoblastoma patients and a slight and borderline significant (P=0.072) decrease in risk of breast cancer with increasing radiation dose for heritable retinoblastoma patients, implying significant (P=0.024) heterogeneity in radiation risk between the heritable and non-heritable retinoblastoma groups; this was unaffected by the blindness status. There was no significant effect of any type of alkylating-agent chemotherapy on breast cancer risk (P>0.5). CONCLUSIONS: There is significant radiation-related risk of breast cancer for non-heritable retinoblastoma survivors but no excess risk for heritable retinoblastoma survivors, and no significant risk overall. However, these results are based on very small numbers of cases; therefore, they must be interpreted with caution.

Intra-arterial chemotherapy as a treatment for intraocular retinoblastoma: alternatives to direct ophthalmic artery catheterization.

BACKGROUND AND PURPOSE: Intra-arterial chemotherapy is a very effective treatment option for intraocular retinoblastoma. However, direct catheterization of the OA is not always possible. The purpose of this work was to report our initial results with intra-arterial chemotherapy for intraocular retinoblastoma when delivery of the drug was not via direct catheterization of the OA. MATERIALS AND METHODS: Retrospective review of 110 eyes (89 patients) undergoing a total of 351 intra-arterial treatments at our institution between 2006 and 2010 identified 18 eyes (14 patients) that received at least 1 infusion via a vascular route other than direct OA catheterization. Alternatives included catheterization of the orbital branch of the MMA and temporary balloon occlusion of the ICA. RESULTS: Tumor control was observed in 17 of 18 eyes at a mean follow-up of 18.9 months (median, 17.5 months; range, 8-36 months). The mean number of intra-arterial infusions was 3.7 per eye (median, 3; range, 2-9). Treatment routes included the following: MMA only, 3 eyes; MMA + OA, 4 eyes; MMA + balloon, 2 eyes; balloon only, 1 eye; balloon + OA, 7 eyes; balloon + OA + MMA, 1 eye. Intra-arterial chemotherapies included melphalan, topotecan, and carboplatin. Complications were all transient. ERG readings were the following: stable, 10 eyes; improved, 3 eyes; reduced, 5 eyes. One patient died from a second malignancy (pinealoblastoma). CONCLUSIONS: This initial experience shows that when direct OA catheterization is not possible, using alternative routes of intra-arterial chemotherapy saves eyes and preserves vision with acceptable side effects.

Survival of retinoblastoma in less-developed countries impact of socioeconomic and health-related indicators.

BACKGROUND: The survival of retinoblastoma in less-developed countries (LDCs) and the impact of socioeconomic variables on survival are not widely available in the literature. METHODS: A systematic review of publications from LDCs was performed. Articles were from multiple databases and written in seven languages. Results were correlated with socioeconomic indicators. Lower-income countries (LICs) and middle-income countries (MICs) were included in our analyses. RESULTS: An analysis of 164 publications including 14,800 patients from 48 LDCs was performed. Twenty-six per cent of the papers were written in languages other than English. Estimated survival in LICs was 40% (range, 23-70%); in lower MICs, 77% (range, 60-92%) and in upper MICs, 79% (range, 54-93%; p = 0.001).Significant differences were also found in the occurrence of metastasis: in LICs, 32% (range, 12-45); in lower MICs, 12% (range, 3-31) and in upper MICs, 9.5% (range, 3-24; p = 0.04). On multivariate analysis, physician density and human development index were significantly associated with survival and metastasis. Maternal mortality rate and per capita health expenditure were significantly associated with treatment refusal. CONCLUSIONS: Important information from LDCs is not always available in English or in major databases. Indicators of socioeconomic development and maternal and infant health were related with outcome.

Orbital recurrence of retinoblastoma following enucleation.

BACKGROUND/AIMS: To determine the incidence, clinical presentation and histopathological profile of patients developing orbital recurrence following enucleation for retinoblastoma. METHODS: A cohort of 1674 consecutive patients undergoing enucleations between 1914 and 2006 was retrospectively reviewed to identify cases of orbital recurrence. A detailed chart review of all identified patients with orbital recurrence following enucleation was performed. The main outcome measures were histopathological features of the enucleated globe, clinical presentation, status of metastatic disease and clinical outcomes of treatment at last follow-up. RESULTS: There were 71 cases of orbital recurrence identified in the study, for an incidence of 4.2% (71 of 1674 cases). The diagnosis of orbital recurrence was made between 1 and 24 months after enucleation (mean 6 months), with 69 of the 71 patients (97%) being diagnosed within the first 12 months. Over a follow-up period of 3-208 months (mean 34.8 months), 60 of 71 patients developed metastatic disease (85%), and 53 of 71 patients died from metastatic retinoblastoma (75%). For the subgroup of cases diagnosed as having orbital recurrences after 1984, 10 of 11 patients (91%) are alive and well. CONCLUSIONS: All patients undergoing enucleation for retinoblastoma need to be followed carefully for the first 2 years after surgery for the possibility of orbital relapse. The majority of retinoblastoma patients with orbital tumour recurrence develop systemic metastatic disease, although mortalities appear to be improving in the modern era.

Production of patulin and citrinin by Penicillium expansum from British Columbia (Canada) apples.

Twenty-four isolates of Penicillium expansum Link from British Columbia (Canada) apples were cultured in yeast-extract sucrose (YES) at 25°C for 28 days to investigate production of patulin and citrinin. These isolates proved to be potent producers of citrinin, patulin, or in most cases, both mycotoxins. In every isolate, citrinin, patulin, or both compounds were produced at levels as high as 565 µg/mL (mean 269 µg/mL) and 100 µg/mL (mean 31 µg/mL), respectively. Of the 24 isolates, 4 produced citrinin only, and 2 produced patulin only. Overall, 83% of the isolates formed patulin and 91% formed citrinin. YES broth proved to be an effective medium for patulin and citrinin production. Other workers have noted that production of these mycotoxins in culture often presages production in fruits, so these results might help Canadian fruit processors evaluate and minimize mycotoxin levels in their products.

Niveles de topotecan en el vitreo luego de la administración periocular en conejos / Vitreous topotecan levels after periocular administration in rabbits

Estudiar los niveles de topotecan total y lactona en el vitreo luego de la administración periocular en un modelo animal. Material y métodos: Se administró 1 mg de topotecan periocular en ambos ojos a 9 conejos sin retinoblastoma y se midieron niveles en el vitreo a las 0.25, 0.5, 1, 2, 4 y 24 horas. Se midieron niveles plasmáticos en 2 animales a las 2 horas. Se midió topotecan total y lactona por HPLC. Todos los animales fueron enucleados al completar el experimento y los ojos fueron examinados patológicamente para evalur toxicidad. Resultados: Tanto el topotecan total como la lactona alcanzaron niveles en el vitreo, mostrando un pico a los 30 minutos de la administración periocular. Los niveles medios en el pico fueron de 158 ng/ml para el topotecan total y 122 ng/ml para el topotecan lactona decayendo con una vida media de 2.44 hs. y 2.8 hs. para el topotecan total y lactona respectivamente. Se encontraron bajos niveles plasmáticos en los 2 animales estudiados a las 2 hs. de la administración de topotecan periocular ((32.0 ng7ml). No se evidencio toxicidad significativa. Conclusiones: En este estudio preliminar, el topotecan mostro lograr pernetrar al vitreo luego de la administración periocular a concentraciones potencialmente tumoricidas. Nuestro grupo proseguirá con estudios más detallados para evaluar su comportamiento famacocinético con el fin de utilizarlo potencialmente en paciente con retinoblastoma.

Assessment of ochratoxin A and tenuazonic acid in Canadian ice-wines.

Twenty-six samples of commercial ice-wine made from late-harvested grapes were assayed for the mycotoxins ochratoxin A and tenuazonic acid. Canadian wines originated in British Columbia (18) and Ontario (8). For comparison two German wines from Hesse were also studied. Four additional samples of research ice-wine originating in were also studied. In all wine samples, assays using immuno-affinity chromatography and fluorescence liquid chromatography indicated ochratoxin A below 0.15 µg/L, the limit of determination of the method. Tenuazonic acid was determined by solidphase micro-extraction and liquid chromatography and was below the limit of determination (70 µg/L) in all samples. The European Union food tolerance limit for ochratoxin A in wine is 2 µg/L. A tolerance for tenuazonic acid has not yet been established.

Systemic carboplatin for retinoblastoma: change in tumour size over time.

BACKGROUND/AIM: Chemotherapy for intraocular retinoblastoma is used to shrink individual retinal tumours to a size amenable to focal treatments. Quantitative data regarding retinal tumour response following treatment with primary systemic carboplatin are reported. METHODS: Changes in area and largest basal diameter of tumours that were exposed to carboplatin, had no concomitant focal treatment, and had digital funduscopic photography performed before and after treatment, were measured. Response was evaluated. RESULTS: 36 tumours were measured following one treatment: 34/36 (94.4%) responded, with a 37.1% mean decrease in area (median = 37.0%; range 4.0%-76.7%). Mean reduction in basal diameter was 21.3% (med = 21.0%; -7.9%-52.5%). 20 tumours were treated with a second cycle: 15/20 (75.0%) responded. Mean decrease in area was 17.8% (med = 15.3%; -7.0%-49.7%). The mean cumulative decrease in area after two treatments was 55.1% (med = 56.2%; 33.0%-74.5%). Mean cumulative reduction in basal diameter was 33.6% (med = 33.6%; 10.9%-53.2%). 12 tumours were treated with a third cycle: 3/12 (25.0%) responded, 8/12 were stable, and one progressed. Mean decrease in area was 5.4% (med = 7.2%; -17.7%-20.6%). Cumulative decrease in area after three treatments was 58.1% (med = 57.3%; 34.8%-77.2%). Mean cumulative reduction in basal diameter was 38.8% (med = 38.2%; 19.1%-54.1%). CONCLUSIONS: Carboplatin caused measurable shrinkage of retinoblastoma tumours. Response was greatest following the initial treatment and decreased with subsequent treatments.

Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy?

AIMS: To describe the outcome of patients with non-metastatic unilateral retinoblastoma with high risk histopathological features after primary enucleation, and to clarify the need and results of adjuvant therapy. PATIENTS AND METHODS: From 1980 to 2001 adjuvant therapy was recommended only to patients with scleral involvement, post-laminar optic nerve involvement (PLONI) with either a positive margin or associated choroidal involvement, or (before 1994) isolated PLONI. RESULTS: 108 of 224 patients had at least one high risk feature (choroidal, scleral, anterior chamber, and/or PLONI). Patients with isolated choroidal (n = 55) or anterior chamber (n = 2) invasion, and most with PLONI without other risk factors (n = 21) were not treated; three relapsed but are long term survivors after intensive therapy. Four with isolated PLONI received adjuvant chemotherapy and none relapsed. Three of 11 with PLONI and concomitant choroidal or scleral involvement who received adjuvant therapy relapsed, versus two of four not treated. Two of five with scleral disease relapsed. All 12 with cut end involvement received adjuvant treatment and none relapsed. In the total group, all four patients who relapsed after adjuvant therapy died. CONCLUSIONS: Relapsing patients can be rescued with intensive therapy. Those with isolated choroidal or PLONI have a good prognosis without adjuvant therapy. Patients with PLONI with a positive margin have a good prognosis if treated with combined therapy. Those with scleral involvement or PLONI with concomitant choroid disease may benefit from adjuvant therapy.

Moniliformin in barley inoculated with Fusarium avenaceum.

To assess production of the mycotoxin moniliformin, inoculation trials with four barley cultivars and local isolates of Fusarium avenaceum were performed at two different experimental farms in southern Manitoba, Canada, during 1997-99. In the 1997 study, moniliformin was detected in 11 of 16 barley rows at levels between 0.19 and 1.62 mg g(-1), and F. avenaceum infection ranged from 10 to 57% in rows where the toxin was detected. In the 1998 study, moniliformin was detected in only three of 16 barley rows, with levels between 0.06 and 0.43 micro g g(-1), and F. avenaceum infection between 16 and 39%. In the 1999 study, moniliformin was detected in 11 of 16 barley rows with levels between 0.09 and 0.42 micro g g(-1), and F. avenaceum infection between 37 and 76%. In the 1997 trial, moniliformin was found in a single water-inoculated control row at 0.15 micro g g(-1). The data suggest that in years of high rainfall and F. avenaceum infection, moniliformin is likely to be found in Manitoba barley.

The impact of ancillary HIV services on engagement in medical care in New York City.

The advent of antiretroviral therapies in 1996 prompted an interest in the role played by ancillary services in improving access to and retention in medical care, particularly since the success of the new therapies is often contingent upon ongoing and appropriate primary medical care. Using self-reported survey data from a longitudinal representative sample of 577 HIV-positive adults in New York City, this paper explores the impact of such supportive services as drug treatment, case management, housing assistance, mental health treatment and transportation on engagement with medical care. The study's principal finding was that specific ancillary services were significantly associated with an increase in an individual's likelihood of entering medical care and maintaining appropriate medical care services for HIV, particularly when the services addressed a corresponding need.

Comparison of Canadian Fusarium graminearum isolates for aggressiveness, vegetative compatibility, and production of ergosterol and mycotoxins.

Fusarium graminearum is the predominant pathogen causing fusarium head blight of cereals in North America. Fifteen Canadian isolates of Fusarium graminearum were highly diverse in terms of vegetative compatibility grouping (VCG) and varied for production of ergosterol and mycotoxin production in rice culture. Aggressiveness was assessed by scoring the disease severity incited in wheat spikes by each isolate. Two inoculation methods, single-floret injection and spray of entire spikes, were used to screen 4 wheat varieties for reaction to the F. graminearum isolates. All isolates were of broadly similar aggressiveness, with disease severity ranging from 17.2 to 39.1 for single floret injection, and 39.1 to 69.0 for spray inoculation. Disease severity, ergosterol production, and mycotoxin development were not correlated. Using nitrate non-utilizing mutants the 15 isolates were grouped into 14 VCGs. Deoxynivalenol (DON) was produced by all isolates in rice culture, at levels between 0.2 and 249 ppm. 15-acetyldeoxynivalenol was produced by 14 of the 15 isolates at levels between 0.4 and 44.6 ppm. These results reveal a high level of diversity for several characteristics among F. graminearum isolates from Canada.

Third (fourth and fifth) nonocular tumors in survivors of retinoblastoma.

OBJECTIVE: This study aimed to investigate the incidence, timing, pattern, and distribution of, as well as survival as a result of, third, fourth, and fifth primary tumors in survivors of retinoblastoma. DESIGN: This study was a retrospective case series of patients diagnosed with retinoblastoma and a second malignant neoplasm. Records were examined for demographic, prior treatment, and second tumor information, as well as any evidence of the development of a third, fourth, or fifth nonocular tumor. When possible, telephone inquiries were conducted for follow-up. PARTICIPANTS: The study included 1506 patients followed in the Ophthalmic Oncology Center at New York-Presbyterian Hospital, New York Weill Cornell Medical Center, 211 of whom developed a second tumor and had sufficient treatment data to be useful for analysis. MAIN OUTCOME MEASURES: The development of third and additional nonocular tumors and survival from these tumors were the primary outcome measures. RESULTS: Of 211 second-tumor patients, 142 died before an additional malignancy developed (median survival time, 1.8 +/- 0.3 years) and in 28, third tumors developed (5-year incidence rate, 11%; 10-year incidence rate, 22%; median time to third tumor development, 5.8 +/- 8.3 years). The 5- and 10-year survival rates for this group were 41% and 30%, respectively (median survival time, 4.1 +/- 1.0 years). Of 28 patients in whom third tumors developed, 27 (96%) had received radiation therapy for their retinoblastoma. The most common sites for third tumors were soft tissues of the head (36% of all third tumors) and skin (36% of all third tumors). In six patients, a fourth tumor developed, and in two patients a fifth tumor developed. All fourth and fifth tumors were found in the soft tissues of the head, the skin, or the bones. CONCLUSIONS: Survivors of retinoblastoma in whom second malignant neoplasms develop are at a higher risk for the development of additional tumors than they were for the development of a second tumor. The locations and expected ages at which additional tumors develop are consistent with the patterns we have seen in second tumors.

The measurement of three dimensional dose distribution of a ruthenium-106 ophthalmological applicator using magnetic resonance imaging of BANG polymer gels.

The BANG (MGS Research Inc., Guilford, CT) polymer gel has been used as a dosimeter to determine the three-dimensional (3D) dose distribution of a ruthenium-106 (Ru-106) ophthalmologic applicator. An eye phantom made of the BANG gel was irradiated with the Ru-106 source for up to 1 h. The phantom and a set of calibration vials were scanned simultaneously in a GE 1.5 T MR imager using the Hahn spin-echo pulse sequence with a TR of 2000 ms and two TEs of 20 ms and 100 ms. The T(2) values were evaluated on a pixel-by-pixel basis using custom-built software on a DEC alpha workstation and converted to dose using calibration data. Depth doses and isodose lines of the Ru-106 eye-plaque were generated. It is concluded that the BANG gel dosimetry offers the potential for measuring the 3D dose distributions of an ophthalmologic applicator, with high spatial resolution and relatively good accuracy.

Trichothecene and moniliformin production by Fusarium species from western Canadian wheat.

Fusarium graminearum, Fusarium culmorum, and Fusarium avenaceum, isolated from Fusarium-damaged wheat harvested in western Canada, were cultured and evaluated for mycotoxin production. Extracts of the culture media were assayed for trichothecenes by gas chromatography-mass spectrometry and for moniliformin by liquid chromatography. Deoxynivalenol (DON) was found in 28 of 42 isolates of F. graminearum and 42 of 42 isolates of F. culmorum at levels ranging from 0.5 to 25.0 microg/g. 15-AcetylDON was found in 28 of 42 isolates of F. graminearum at levels ranging from 1.0 to 7.1 microg/g. 3-AcetylDON was found in 41 of 42 isolates of F. culmorum at levels ranging from 0.8 to 13.0 microg/g. Several other trichothecenes were assayed but not detected in the culture medium. Moniliformin was present in 40 of 42 isolates of F. avenaceum at levels ranging from 1.3 to 138.1 microg/g, but was not present in any of the isolates of F. graminearum or F. culmorum.