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.

Retinoblastoma: From genes to patient care.

Retinoblastoma is the most common paediatric neoplasm of the retina, and one of the earliest model of cancer genetics since the identification of the master tumour suppressor gene RB1. Tumorigenesis has been shown to be driven by pathogenic variants of the RB1 locus, but also genomic and epigenomic alterations outside the locus. The increasing knowledge on this "mutational landscape" is used in current practice for precise genetic testing and counselling. Novel methods provide access to pre-therapeutic tumour DNA, by isolating cell-free DNA from aqueous humour or plasma. This is expected to facilitate assessment of the constitutional status of RB1, to provide an early risk stratification using molecular prognostic markers, to follow the response to the treatment in longitudinal studies, and to predict the response to targeted therapies. The aim of this review is to show how molecular genetics of retinoblastoma drives diagnosis, treatment, monitoring of the disease and surveillance of the patients and relatives. We first recap the current knowledge on retinoblastoma genetics and its use in every-day practice. We then focus on retinoblastoma subgrouping at the era of molecular biology, and the expected input of cell-free DNA in the field.

[Paraneoplastic pemphigus or paraneoplastic autoimmune multiorgan syndrome. Report of 2 cases in children and a review of the literature]. / Pénfigo paraneoplásico/síndrome multiorgánico autoinmune paraneoplásico. Presentación de dos casos en la edad infantil. Revisión de la literatura.

Paraneoplastic pemphigus is an autoimmune blistering disease associated with an occult or previously diagnosed tumor. Its clinical, histological, and immunological features have been clearly defined. It is characterized by the presence of polymorphic skin lesions and by erosions of the oral and genital mucosas that are refractory to conventional treatments. The histology can be variable and includes acantholysis or lichenoid dermatitis. Circulating autoantibodies are a constant feature and confirm the diagnosis. We describe 2 girls with paraneoplastic pemphigus associated with Hodgkin lymphoma in one and Castelman disease in the other. Both children had oral and genital lesions that did not respond to conventional treatments. Biopsy revealed acantholysis in one and a lichenoid reaction in the other, and immunoassays confirmed the diagnosis. Chemotherapeutic treatment of the underlying disease was performed in both cases, together with high-dose corticosteroids for the skin and mucosal lesions. Both patients died due to respiratory failure. We suggest that paraneoplastic pemphigus, although rare in childhood and adolescence, should be included in the differential diagnosis of periorificial erosive dermatitis; this may assist in the detection of an occult neoplasm.

Optimizing the storage of chemotherapeutics for ophthalmic oncology: stability of topotecan solution for intravitreal injection.

BACKGROUND: . Intravitreal administration of topotecan shows activity against tumor vitreous seeding in the conservative treatment of retinoblastoma, a malignant tumor originated in the retina of small children. Adequate storage of the intravitreal topotecan solution would allow immediate availability for patients at health care institutions. The goal of the work was to address the stability of the intravitreal topotecan formulation upon reconstitution. MATERIALS AND METHODS: . Intravitreal topotecan solutions were reconstituted (at a concentration of 0.2 mg topotecan in 1 mL saline solution vehicle, aliquoted in 1 mL plastic syringes) and stored either frozen or at room temperature for different times. Topotecan content was analyzed at time zero and at different conditions using a high performance liquid chromatography method to quantify topotecan lactone (active) and to detect its pH-dependent hydrolysis product, the open carboxylate. RESULTS: . We found that intravitreal topotecan syringes remained stable at room temperature at least for 24 h, at least for 167 days upon stored frozen at -20°C, and up to 8 h after thawing at day 6. The degradation carboxylate product did not appear in the analyzed thawed samples during the whole study. CONCLUSIONS: . This study confirms the stability of frozen intravitreal topotecan syringes and will help optimize the use of this chemotherapy modality at institutions with low resources. Storage of aliquots will also help reduce personnel exposure to chemotherapy at hospital pharmacies.

Phase II window of idarubicin in children with extraocular retinoblastoma.

PURPOSE: The aim of this study was to evaluate in an upfront phase II study the response to idarubicin in children with extraocular retinoblastoma. PATIENTS AND METHODS: The starting dose of idarubicin was 15 mg/m(2)/d (days 1 and 2) weeks 0 and 3. After an interim evaluation, the dose was reduced to 10 mg/m(2)/d (days 1 and 2) weeks 0 and 3 because of hematopoietic toxicity. Response was evaluated at week 6. RESULTS: At the Hospital JP Garrahan (Buenos Aires, Argentina), 10 patients (five bilateral) were entered onto the study from 1995 to 1998. A total of 19 cycles were administered. Extraocular sites included orbit (n = 10), bone marrow (n = 3), bone (n = 1), lymph node (n = 1), and CNS (n = 1). The response rate was 60% (95% confidence interval, 30% to 90%). One complete response was achieved, in addition to five partial responses, two cases of stable disease, and two cases of progressive disease. All patients with bone marrow involvement achieved complete clearance of tumor cells. The patient with CNS disease had progressive disease. All patients had severe hematopoietic toxicity (grade 4 neutropenia and grade 3/4 thrombocytopenia after most cycles). Other toxicities included grade 2 diarrhea in 30%. No echocardiographic changes were detected. CONCLUSION: Idarubicin is active in extraocular retinoblastoma. The activity of this drug should be explored in future phase III studies.

Results of a stage-based protocol for the treatment of retinoblastoma.

PURPOSE: To describe the treatment of retinoblastoma at a single institution using a prospective protocol based on histopathologic staging. PATIENTS AND METHODS: We included 116 consecutive patients (101 eligible, 46 bilateral) from August 1987 to December 1993. Treatment was enucleation or conservative therapy for intraocular disease (stage I patients). Stage II patients (orbital or postlaminar invasion) received vincristine, cyclophosphamide, and doxorubicin for 57 weeks. Patients with orbital mass and extension beyond the cut end of the optic nerve also received orbital radiotherapy (45 Gy). The latter received intrathecal therapy. In those with CNS (stage III) or hematogenous metastasis (stage IV), cisplatin and etoposide were added along with cranial (in patients with a CNS mass and prophylactically in stage IV) or craniospinal (in patients with positive CSF) radiotherapy. RESULTS: The median follow-up time was 39 months (range, 12 to 84). The overall survival rate was 0.84. Survival rates according to stage were as follows: stage I probability of overall survival [pOS] = 0.97) (alive/total), 59 of 60; stage II (pOS = 0.85) including patients with scattered episcleral cells, three of three; orbital mass, one of one; postlaminar invasion up to and beyond the cut end of optic nerve, 10 of 11 and 11 of 14, respectively; of stage III (pOS = 0), zero of six; and stage IV (pOS = 0.50), three of six. Only those patients with preauricular adenopathy as the only metastatic site survived in the latter group. Acute toxicity was mild. CONCLUSION: Chemotherapy is not warranted to prevent systemic metastasis for intraocular disease. Patients with extraocular orbital disease and had a good outcome with this therapy. Patients with metastatic disease fared poorly, except for those with isolated malignant preauricular adenopathy.

Results of treatment with an intensive induction regimen using idarubicin in combination with cytarabine and etoposide in children with acute myeloblastic leukemia.

We report results achieved in our institution with a study opened in July 1990 (similar to the German AML-BFM-87 in which daunorubicin was replaced by idarubicin in the induction phase and cranial preventive radiotherapy was omitted) and closed in December 1994, for the treatment of newly diagnosed acute myeloblastic leukemia (AML), without prior malignancies except for myelodysplasia. This evaluation included 68 patients, whose mean age was 6 years (range: 1 month-16 years). Thirty-nine were boys and 29 were girls. Complete remission rate was 80.9% (55/68), death on induction rate was 14.7% and induction failure rate was 4.4%. At median follow up of 38 months (range: 12-66 months), the 4-year event-free survival (EFS) estimate was 0.428 (S.E.: 0.062), event-free interval (EFI) estimate was 0.529 (S.E.: 0.07) and overall survival (OS) estimate was 0.44 (S.E.: 0.071). We conclude that idarubicin in combination with cytarabine and etoposide is a highly effective regimen for induction in children with AML. Although preventive cranial irradiation was not delivered, we have observed only one combined CNS relapse. Finally, we corroborate that in this setting two definite risk groups may be identified in children with AML.

Children with fever of unknown origin in Argentina: an analysis of 113 cases.

The aim of this study was to determine the causes of fever of unknown origin, to evaluate new diagnostic tests and to elucidate risk factors for chronic or life-threatening disorders. The medical records of 113 children who had undiagnosed fever for at least 3 weeks were reviewed. Infection (N = 41) was the most frequent cause of fever of unknown origin. Respiratory tract infections were the most common causes in infants and endocarditis and tuberculosis were more frequent in older children. Neoplastic disorders (N = 11) occurred in children older than one year. Juvenile rheumatoid arthritis (N = 9) was the most common collagen-vascular disorder (N = 15). Miscellaneous disorders and factitious fever occurred in 21 and 4 cases, respectively. Twenty-two patients remained undiagnosed. History and physical examination led to a final diagnosis in 81% of cases. Abdominal ultrasonography was performed in 71 patients (61%) and was helpful for diagnosis in 15%. Children with life-threatening or chronic disorders (N = 58) were older than those with self-limiting conditions (N = 55; P = 0.017). Cardiovascular and articular signs and symptoms were more frequent in the former group (P = 0.01).

Atypical skin lesions caused by Curvularia sp. and Pseudallescheria boydii in two patients after allogeneic bone marrow transplantation.

We report two patients who developed atypical skin lesions caused by Curvularia sp. and Pseudallescheria boydii after allogeneic bone marrow transplantation for severe aplastic anemia. The first patient (female, 18-year-old) had multiple hemorrhagic vesicles on day +30 after her second BMT for graft failure. Pseudallescheria boydii was isolated from a skin biopsy. The patient died of respiratory failure probably as a consequence of systemic fungal infection. The second patient (male, 9-year-old) developed an ecthyma gangrenosum-like lesion on his right palm on day +8. Curvularia sp. was isolated from a skin biopsy. Liposomal amphotericin was given to achieve a total dose of 30 mg/kg and followed by oral itraconazole until steroids were discontinued. The infection resolved completely and the patient has remained disease-free. We conclude that emerging fungal organisms such as those described in this report are increasingly recognized in this setting. Early recognition and biopsy of these cutaneous lesions will allow prompt initiation of therapy to prevent systemic infection.

Circulating retinoblastoma cells in a patient with metastatic disease.

We report an unusual case of a two-year-old girl with metastatic retinoblastoma and massive bone marrow involvement who showed the overt presence of circulating retinoblastoma cells in peripheral blood smears a few days before death. This extended disease developed after an early relapse that followed abandoned primary chemotherapy. To the best of our knowledge, there are no previous reports about the presence of circulating retinoblastoma cells in peripheral blood films. We conclude that the search for bone marrow invasion in patients with disseminated retinoblastoma should be exhaustive to achieve an accurate staging assessment. Peripheral blood smears should be examined cautiously to detect occasional circulating retinoblastoma cells when the bone marrow is massively involved.

Retinoblastoma with low risk for extraocular relapse.

OBJECTIVE: To define a subgroup of patients with retino-blastoma and low risk of extraocular relapse through histopathological and clinical variables. PATIENTS AND METHODS: Inclusion criteria consisted of stage I (intraocular disease), stage IIb1 (without concomitant choroid and/or scleral invasion), and nonenucleated patients (according to the Grabowski-Abramson classification). A total of 112 consecutive patients admitted to Hospital JP Garrahan from 1987 to 1997 were evaluable. Treatment included enucleation or local therapy and no chemotherapy. RESULTS: Forty-one patients had stage Ia (intraretinal), 8 stage Ib (prelaminar optic nerve invasion), 40 stage Ic (uveal invasion), and 12 stage IIb1 (postlaminar optic nerve invasion and cut end free of tumor). Eleven patients had neither eye enucleated. Median follow-up was 60 months. Only two events occurred: one patient had progressive disease in the contralateral globe and died of CNS metastasis and another had an orbital relapse that was successfully treated. Both had choroidal invasion. Five-year pEFS and pOS were 0.97 and 0.98, respectively. Neither length of the optic nerve stump, tumor size, anterior chamber invasion, degree of differentiation, nor degree of ocular coat invasion correlated with increased risk of metastasis. CONCLUSIONS: A subset of patients with retinoblastoma with low risk of relapse can be determined using histopathological evaluation of the invasion of ocular coats. Adjuvant chemotherapy is not warranted for patients with intraretinal extension and prelaminar optic nerve invasion. It is also probable that those patients with isolated choroidal invasion and those with postlaminar optic nerve extension with surgical margins clear of tumor do not need chemotherapy.

Intraocular carboplatin concentrations following intravenous administration for human intraocular retinoblastoma.

Previous studies of the penetration of carboplatin into the vitreous have depended on unaffected animals or on animal models for other cancers. The objective of this study was to determine the intraocular levels of carboplatin following intravenous administration of carboplatin in the treatment of human intraocular retinoblastoma. Eight patients with bilateral intraocular retinoblastoma were treated in a consistent fashion with intravenous carboplatin. One additional patient was similarly treated, but enucleated one month later. Samples were taken from those nine eyes after enucleation one to two hours after the administration of 18.7 mg/kg (560 mg/m( 2) for patients more than 12 kg) of intravenous carboplatin, and carboplatin concentrations in the aqueous and vitreous were then measured by atomic absorption spectrometry. The mean concentration measured in the aqueous was 5.13 microg/ml and in the vitreous 4.05 microg/ml, and vitreal concentrations were an average of 80% of aqueous concentrations. In one patient, a vitreous concentration of carboplatin was detected after an interval of one month that was 10% of the levels found in the samples enucleated one hour post-administration. These concentrations are much higher than previous animal studies would predict, and are similar to levels measured in unaffected animals when the drug is given after the use of cryotherapy. The concentration also approaches levels previously shown to be toxic to the retina. This elevation in carboplatin concentration may be due to disruption of the blood-vitreous barrier by active tumor.

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.

Successful treatment of metastatic retinoblastoma with high-dose chemotherapy and autologous stem cell rescue in South America.

High-dose chemotherapy (HDC) followed by autologous stem cell rescue (ASCR) is the only curative treatment for metastatic retinoblastoma, but its feasibility in developing countries is unknown. We report 11 consecutive children (six unilateral) treated in three South-American middle-income countries with HDC-ASCR. One patient had metastatic retinoblastoma at diagnosis and the remaining ones had a metastatic relapse. Metastatic sites included BM=6, bone=4, orbit=5 and central nervous system (CNS)=4. All patients received induction with conventional chemotherapy achieving CR at a median of 5.7 months from the diagnosis of metastasis. Conditioning regimens included carboplatin and etoposide with thiotepa in six or with CY in four or melphalan in one patient. All patients engrafted after G-CSF-mobilized peripheral blood ASCR and no toxic deaths occurred. Two children received post-ASCR CNS radiotherapy. Seven children have disease-free survival (median follow-up 39 months). CNS relapse, isolated (n=3) or with systemic relapse (n=1), occurring at a median of 7 months after ASCT was the most common event. In the same period, five children with metastatic retinoblastoma did not qualify for HDC-ASCR and died. We conclude that HDC-ASCR is a feasible and effective treatment for children with metastatic retinoblastoma in middle-income countries.

Immune response to racotumomab in a child with relapsed neuroblastoma.

Immunotherapy targeting ganglioside antigens is a powerful tool for the treatment of high risk neuroblastoma. However, only treatment with anti-GD2 antibodies has been used in clinical practice and other options may be pursued. We report the use of racotumomab, an anti-idiotype vaccine against N-glycolyl neuraminic acid (NeuGc)- containing gangliosides, eliciting an immune response in a child with relapsed neuroblastoma expressing the NeuGcGM3 ganglioside.

Evaluación de secuelas visuales y cosméticas del tratamiento conservador con terapia radiante externa en pacientes con retinoblastoma bilateral en el Hospital de Pediatría Garrahan / Assessment of visual and cosmetic sequelae of conservative treatment of external beam radiation of patients with bilateral retinoblastoma at the Pediatric Hospital Garrahan

El Retinoblastoma es la neoplasia ocular más frecuente en pediatría. La Terapia radiante externa fue hasta hace una década el tratamiento conservador de elección. Luego se incluyó la quimio reducción; en un intento de evitar la radioterapia externa y sus complicaciones. En este estudio retrospectivo evaluamos los resultados del tratamiento conservador con terapia radiante externa o con quimio reducción en el servicio de oftalmología del Hospital Nacional de Pediatría Juan P. Garrahan, desde 1987 a 2009. De un total de 571 pacientes con diagnóstico de Retinoblastoma, 341 fueron unilaterales y 217 bilaterales. De estos últimos se analizaron 166 pacientes cuya edad media al diagnostico fue de 12 meses. Se trataron 332 ojos de 166 pacientes con Retinoblastoma bilateral, 157 ojos (47,3%) recibieron quimioreducción como tratamiento inicial, 115 ojos (34,6%) fueron enucleados al inicio, 45 ojos (13,6%) recibieron radioterapia externa como único tratamiento y 15 ojos (4,5%) recibieron tratamiento local solo (laser o crioterapia) como primera elección. Se analizaron los datos con el programa estadístico STATA 12.0 stataCorp Texas.USA. La agudeza visual final fue superior a 20/70 en el 51,5% de los pacientes e inferior en el 48,5%. Se encontró una relación significativa (p=0,005) entre el estadio al diagnóstico y la agudeza visual final; los pacientes con discapacidad visual se presentaron con estadios avanzados. Se evaluaron todas las orbitas enucleadas (157); de ellas el 74,5% recibieron radioterapia externa antes o después de la enucleación. El 24,8% de las orbitas irradiadas presentaron deformidad de la cavidad, con mala adaptación de prótesis y retracción orbitaria, el 70,1% presentaron cambios que permitían una adaptación de prótesis aceptable con alguna limitación de movilidad y solo 6 orbitas (5,12%) presentaban una muy buena cavidad para adaptación cosmética. Cuarenta de 157 orbitas enucleadas no recibieron radioterapia en ningún momento (25,5%), el 92,5% de ellas presentaron buena adaptación y solo el 7,5% tuvieron problemas de adaptación debido a complicaciones postoperatorias. El diagnóstico precoz, el tratamiento oportuno, y el uso de quimio reducción como terapia inicial en Retinoblastoma intraocular, permiten aumentar la tasa de preservación del globo ocular y reducen o eliminan la necesidad de recibir Terapia radiante externa, evitando sus secuelas (AU)

Retinoblastoma is the most common ocular neoplasia in childhood. External beam radiation therapy was the conservative treatment of choice until a decade ago. Subsequently, chemoreduction was added trying to avoid external beam radiation therapy and its complications. In this retrospective study we assess the results of conservative therapy with external beam radiation therapy or with chemoreduction at the Department of Ophthalmology at the Pediatric Hospital Juan P. Garrahan between 1987 and 2009. Of a total of 571 patients with a diagnosis of retinoblastoma, 341 had unilateral and 217 bilateral retinoblastoma. Of the latter patients, 166 patients were analyzed with a mean age at diagnosis of 12 months. Overall, 332 eyes of 166 patients with bilateral retinoblastoma were treated; at initial treatment 157 eyes (47.3%) underwent chemoreduction, 115 eyes (34.6%) were enucleated, 45 eyes (13.6%) underwent external beam radiation therapy as the only treatment, and 15 eyes (4.5%) only received local treatment (laser or cryotherapy) as a first choice. Data were analyzed using STATA 12.0 stataCorp Texas.USA. Final visual acuity was more than 20/70 in 51.5% and less in 48.5% of the patients. A significant relationship (p=0.005) between stage at diagnosis and final visual acuity was found; patients with visual impairment presented with advanced stages. All enucleated orbits were assessed (157); 74.5% underwent external beam therapy before or after enucleation. Of all irradiated orbits, 24.8% presented with cavity deformity, poor prosthesis fit, or contraction of the socket. Of all patients, 70.1% presented with changes that allowed acceptable fitting of the prosthesis with slight movement limitation and only 6 orbits (5.12%) had a good cavity for cosmetic appearance. Forty of 157 enucleated orbits did not receive radiation therapy at any moment (25.5%); 92.5% of them had a good fitting and in only 7.5% fitting problems due to postoperative complications were found. Early diagnosis, adequate treatment, and use of chemoreduction as initial therapy of intraocular retinoblastoma allow for an increased rate of preservation of the eye and reduce or eliminate the need for external beam therapy and its sequelae (AU)

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.