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1.  Characteristics of Oral Mucosal Events Related to Bevacizumab Treatment 
The Oncologist  2012;17(2):274-278.
Four case reports are used to provide a detailed clinical description of signs and symptoms limited to the tongue mucosa in patients treated with bevacizumab.
Bevacizumab, a monoclonal antibody targeting a vascular endothelial growth factor (VEGF) protein, has been reported to induce mucosal toxicities. However, the clinical characteristics of these particular toxicities have not been well characterized. We aimed at providing a detailed clinical description of signs and symptoms limited to the tongue mucosa in patients treated with bevacizumab.
A retrospective review of medical records and clinical photographs was performed with specific attention to clinical presentation, evolution, associated symptoms, concomitant medications, and treatment methods.
In total, four patients presented to the dermatology service with clinical findings characterized by multifocal, erythematous circinate and serpiginous erosions on the dorsal tongue surrounded by white hyperkeratotic rims that were temporally related to bevacizumab therapy. Associated increased sensitivity to spicy foods was frequently observed.
These characteristic clinical findings are consistent with geographic tongue. However, large prospective evaluations are necessary to confirm this potential relationship. If bevacizumab is indeed associated with geographic tongue, increased awareness may result in improved reporting and characterization of this particular adverse event.
PMCID: PMC3286177  PMID: 22282905
Bevacizumab; Mucosal toxicity; Adverse event; Geographic tongue
2.  High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma† 
Neuro-Oncology  2010;12(3):297-303.
Recurrent medulloblastoma is highly lethal in previously irradiated patients. Previously irradiated patients with M-0–M-3 recurrences who achieved a minimal disease state prior to protocol enrollment received carboplatin (Calvert formula with area under the curve = 7 mg/mL min, maximum 500 mg/m2/day) on days −8 to −6, and thiotepa (300 mg/m2/day) and etoposide (250 mg/m2/day) on days −5 to −3, followed by autologous stem cell rescue (ASCR) on day 0. Twenty-five patients, aged 7.6–44.7 years (median 13.8 years) at ASCR, were treated. Three (12%) died of treatment-related toxicities within 30 days of ASCR, due to multiorgan system failure (n = 2) and aspergillus infection with veno-occlusive disease (n = 1). Tumor recurred in 16 at a median of 8.5 months (range 2.3–58.5 months). Six are event-free survivors at a median of 151.2 months post-ASCR (range 127.2–201.6 months). The Kaplan–Meier estimate of median overall survival is 26.8 months (95% CI: 11.9–51.1 months) and of event-free survival (EFS) and overall survival are both 24% (95% CI: 9.8%–41.7%) at 10 years post-ASCR. M-0 (vs M-1 + ) recurrence prior to protocol, lack of tissue confirmation of relapse, and initial therapy of radiation therapy (RT) alone (vs RT + chemotherapy) were not significantly associated with better EFS (P = .33, .34, and .27, respectively). Trends toward better EFS were noted in patients (n = 5) who received additional RT as part of their retrieval therapy (P = .07) and whose recurrent disease was demonstrated to be sensitive to reinduction chemotherapy (P = .09). This retrieval strategy provides long-term EFS for some patients with previously irradiated recurrent medulloblastoma. The use of additional RT may be associated with better outcome.
PMCID: PMC2940591  PMID: 20167818
chemotherapy; hematopoietic stem cell transplantation; medulloblastoma
3.  Risk Factors for Severe Neutropenia following Intra-Arterial Chemotherapy for Intra-Ocular Retinoblastoma 
PLoS ONE  2014;9(10):e108692.
Intra-arterial chemotherapy is a promising strategy for intra-ocular retinoblastoma. Neutropenia is the most commonly encountered systemic toxicity and in this study we aimed to determine the risk factors associated with the development of severe (≥grade 3) neutropenia.
Retrospective review of 187 evaluable cycles of melphalan-containing intra-arterial chemotherapy from the first three cycles administered to 106 patients with intra-ocular retinoblastoma from May 2006 to June 2011. Cycles were considered to be evaluable if (1) blood count results were available in the 7 to 14 days post-treatment interval and (2) concurrent intravenous chemotherapy was not administered. Toxicity was assessed via the Common Terminology Criteria for Adverse Events version 4.0.
54 cycles (29%) were associated with grade 3 (n = 43) or grade 4 (n = 11) neutropenia. Multivariate stepwise logistic regression revealed that a higher melphalan dose (>0.40 mg/kg) was significantly associated with severe neutropenia during all 3 cycles (odds ratio during cycle one 4.11, 95% confidence interval 1.33–12.73, p = 0.01), but the addition of topotecan and/or carboplatin were not. Prior treatment with systemic chemotherapy was not associated with severe neutropenia risk in any analysis.
Intra-arterial melphalan-based chemotherapy can cause severe neutropenia, especially when a dose of greater than 0.40 mg/kg is administered. Further study with a larger sample may be warranted.
PMCID: PMC4193762  PMID: 25303673
4.  Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: a pilot study 
Pediatric blood & cancer  2013;61(8):1440-1444.
Individuals with hereditary retinoblastoma (RB) are at very high risk of developing subsequent malignant neoplasms (SMN) of which osteosarcoma (OS) is one of the most common. We hypothesized that annual surveillance using whole-body magnetic resonance imaging (WB-MRI) in asymptomatic survivors of hereditary RB would detect SMN of the bone and soft tissues at an early stage.
Retrospective review of the results of a WB-MRI screening program in hereditary RB survivors from February 2008 – August 2012. The primary outcome was to determine the sensitivity and specificity of WB-MRI in detecting SMNs.
Twenty-five patients had at least one WB-MRI performed (range: 1 – 5). First WB- MRI was performed at a median age of 16 years (range: 8 – 25 years). WB-MRI detected new osseous abnormalities suspicious for malignancy in 5 patients: 2 were diagnosed with localized high-grade OS of the extremity and 3 were found to have benign osseous abnormalities after dedicated imaging (n=5/5) and/or biopsy (n=3/5). One patient was diagnosed with secondary OS three months after a normal screening WB- MRI exam. Among a total of 41 WB-MRI screening tests performed in survivors of hereditary RB, the sensitivity of detecting SMN was 66.7% and the specificity was 92.1%.
Preliminary results suggest that annual WB-MRI surveillance detects SMN in survivors of hereditary RB, but with modest sensitivity. Further study is needed to assess the performance of annual surveillance WB-MRIs and whether this modality decreases SMN-related mortality in RB survivors.
PMCID: PMC4007376  PMID: 24402721
Retinoblastoma; survivors; screening; whole-body MRI; pediatric oncology
5.  In Reply 
The Oncologist  2013;18(4):e18.
This reply to the letter by Hubiche et al. further discusses the hypothesis that geographic tongue is a novel entity related to bevacizumab therapy.
PMCID: PMC3639540  PMID: 23576479
6.  Electroretinogram Monitoring of Dose-Dependent Toxicity after Ophthalmic Artery Chemosurgery in Retinoblastoma Eyes: Six Year Review 
PLoS ONE  2014;9(1):e84247.
To report electroretinogram responses of retinoblastoma children under anesthesia before and after treatment with chemotherapeutic drugs (melphalan, topotecan, carboplatin) delivery by ophthalmic artery chemosurgery (OAC).
A cohort study of 81 patients with retinoblastoma treated with OAC. All patients treated with OAC at our center through May 2012 for whom the requisite ERG data were available are included in the analysis. This study recorded the ERG 30 Hz flicker amplitude response changes from baseline, at 3 and 12 months following OAC treatment completion. Both univariate and multivariate linear regression models were evaluated, with generalized estimating equations to correct for correlations within patients. Independent numerical variables included maximum doses and cumulative doses of melphalan, topotecan and carboplatin.
By univariate analysis, both melphalan and topotecan appear to be associated with changes in ERG amplitude at both 3 and 12 months; but for the most part, these changes are minimal and likely clinically insignificant. By multivariate analysis, maximum and cumulative melphalan have a modest, temporary effect on the ERG amplitude change, which is apparent at 3 months but no longer evident at 12 months after completing treatment. By multivariate analysis, topotecan and carboplatin do not appear to adversely effect the change in ERG response.
Melphalan has the strongest, and carboplatin the weakest association with reduction in ERG response amplitudes; but for the most part, these changes are minimal and likely clinically insignificant. These conclusions apply only over the dose ranges used here, and should be applied with caution.
PMCID: PMC3896342  PMID: 24465398
7.  Sinonasal Adenocarcinoma: A rare second malignancy in long term retinoblastoma survivors 
Pediatric blood & cancer  2011;57(4):10.1002/pbc.23161.
Retinoblastoma is the most common primary cancer of the eye in children. The incidence of second tumors in survivors of bilateral retinoblastoma and in survivors of unilateral retinoblastoma who presumably carry a germline RB1 mutation is documented. This paper describes the previously unrecognized association of sinonasal adenocarcinoma as a second malignancy in retinoblastoma survivors. We present three cases who received radiation therapy as a part of their treatment and developed sinonasal adenocarcinoma as a second malignancy. Sinonasal adenocarcinoma should be considered as a second malignancy in retinoblastoma survivors who present with vague sinus symptoms.
PMCID: PMC3867788  PMID: 21548012
Retinoblastoma; Sinonasal adenocarcinoma; second malignancy
8.  Carboplatin +/− Topotecan Ophthalmic Artery Chemosurgery for Intraocular Retinoblastoma 
PLoS ONE  2013;8(8):e72441.
Carboplatin administered systemically or periocularly can result in dramatic and prompt regression of retinoblastoma. However, both routes are rarely curative alone and have undesirable side effects. We aimed to assess the efficacy and toxicity of carboplatin +/− topotecan delivered by ophthalmic artery chemosurgery whereby chemotherapy is infused into the eye via the ophthalmic artery.
This retrospective, IRB-approved study investigated retinoblastoma patients whom received carboplatin +/− topotecan ophthalmic artery chemosurgery. Patient survival, ocular survival, hematologic toxicity, ocular toxicity, second cancer development and electroretinogram response were all evaluated.
57 carboplatin +/− topotecan infusions (of 111 total) were performed in 31 eyes of 24 patients. The remaining infusions were melphalan-containing. All patients were alive and no patient developed a second malignancy at a median follow up of 25 months. The Kaplan-Meier estimate of ocular survival at two years was 89.9% (95% confidence interval [CI], 82.1–97.9%) for all eyes. Grade 3 or 4 neutropenia developed in two patients and one patient developed metastatic disease. By univariate analysis, neither increasing maximum carboplatin/topotecan dose nor cumulative carboplatin/topotecan dose was associated with statistically significant reduction in the electroretinogram responses.
Carboplatin +/− topotecan infusions are effective for ophthalmic artery chemosurgery in retinoblastoma: they demonstrate low hematologic and ocular toxicity and no statistically significant influence on electroretinogram responses, and used in conjunction with melphalan-containing OAC, demonstrate excellent patient survival and satisfactory ocular survival.
PMCID: PMC3749169  PMID: 23991112
9.  Combined, Sequential Intravenous and Intra-Arterial Chemotherapy (Bridge Chemotherapy) for Young Infants with Retinoblastoma 
PLoS ONE  2012;7(9):e44322.
Intra-arterial (IA) chemotherapy has more risks of procedural complications in neonates and young infants. For these reasons, we have developed a strategy of bridge intravenous single agent chemotherapy to postpone IA chemotherapy in these children
Neonates and young infants with retinoblastoma who required chemotherapy were treated with systemic carboplatin chemotherapy (18.7 mg/kg IV every 3–4 weeks) until they reached the age of 3 months and a weight of 6 Kg. If necessary, IA chemotherapy was subsequently performed at 4 weeks intervals. Efficacy was judged by tumor regression on ophthalmological examination. Retinal toxicity was judged by electroretinography.
Eleven children (19 eyes) were treated. All patients are alive and no patient has developed metastatic disease or second malignancies (mean follow-up 27 months, range 9–46 months). Intravenous carboplatin (median 2 cycles, range 1–5) combined with cryotherapy and laser was given to all children. This was effective for five eyes, which did not require IA chemotherapy. IA chemotherapy was administered to 14 eyes (median 3.5 cycles per eye, range 1 to 6). No radiation therapy was required. The Kaplan Meier estimate of ocular radiation-free survival was 94.7% at one year (95% confidence interval 68.1–99.2%). One eye was enucleated due to tumor progression. ERG showed no deterioration of retinal function.
Bridge IV-IA chemotherapy was feasible and safe, and is a promising strategy to treat retinoblastoma in neonates and young infants.
PMCID: PMC3445577  PMID: 23028521
10.  Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1 mutation 
Although ionizing radiation induces germline mutations in animals, human studies of radiation-exposed populations have not detected an effect. We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their child's conception. Parents of 206 cases from 9 North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower GI series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child (matched odds ratio (OR)=3.6, 95% confidence interval (CI) 1.2, 11.2, 2-sided P=0.02), as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI 1.2, 14.4, P =0.02). Maternal history of lower GI series was also associated with increased risk (OR=7.6, 95% CI 2.8, 20.7, P <0.001) as was estimated total dose (OR for highest dose=3.0, 95% CI 1.4, 7.0, P =0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.
PMCID: PMC3124307  PMID: 20648557
germline mutation; ionizing radiation; retinoblastoma; case-control studies; pediatric cancer
11.  Intraocular Hemorrhage After Intra-Arterial Chemotherapy for Retinoblastoma in Sickle Cell Trait 
Massive intraocular hemorrhage developed in a child with advanced unilateral retinoblastoma after intrarterial treatment with Melphalan and Topotecan. The child tested positive for sickle cell trait. Sickle cell trait may predispose such children to slower vascular transit time, hypoxia, sickling and vascular occlusion caused by catheter induced decreased flow. Enucleation confirmed the ultrasound and selective angiogram findings in addition to a completely calcified tumor. Clinicians should be on the lookout for the association of sickle-cell disease/trait and intraocular hemorrhages after intraarterial chemotherapy to fully understand its clinical significance.
PMCID: PMC3267092  PMID: 22291865
Retinoblastoma; sickle cell; intra-arterial chemotherapy; enucleation.
12.  Secondary Skull Base Malignancies in Survivors of Retinoblastoma: The Memorial Sloan Kettering Cancer Center Experience 
Skull Base  2011;21(2):103-108.
We report the pathology and outcome of secondary skull base tumors in patients previously treated with external beam radiation for retinoblastoma (Rb). Rb patients are at increased risk of second head and neck primary malignancies due to early radiation exposure during treatment and loss of RB1 protein in genetic carriers. An institutional database was reviewed for patients with retinoblastoma who had previously received radiation therapy and subsequently developed skull base tumors. Seventeen patients met the selection criteria. The median age of Rb diagnosis was 12 months. Thirteen cases underwent enucleation in addition to radiation therapy as part of initial Rb treatment. A median of 19 years elapsed between the diagnosis of Rb and diagnosis of skull base malignancy. The most common tumors were osteogenic sarcoma (39%) and leiomyosarcoma (22%). Eleven (71%) patients received postoperative chemotherapy, and 7 (41%) received postoperative radiotherapy. Three (24%) patients underwent salvage surgery for recurrent disease. Five-year survival was 68%, and 10-year survival was 51% by Kaplan-Meier analysis. Secondary malignancy in Rb patients is a well-defined event. The use of surgery with appropriate adjuvant therapy was associated with a 51% 10-year survival in this study population.
PMCID: PMC3312595  PMID: 22451810
Skull base neoplasms; retinoblastoma; neoplasms; second primary; radiotherapy
13.  Histopathologic Findings of Eyes Enucleated After Treatment with Chemosurgery for Retinoblastoma 
Intra-arterial chemotherapy (chemosurgery) for the treatment of retinoblastoma has been performed more than 1600 times (more than 1400 times in Japan and 200 times in New York) over the past 20 years.Despite this treatment’s success some eyes cannot be saved and require enucleation. Here we report the histopathologic findings of the remaining intraocular tumor of eyes that were enucleated following treatment that included chemosurgery in New York City.
Materials and Methodology:
Independent histopathologic review of the enucleated eyes was correlated with the clinical findings that prompted enucleation.
Between May 1, 2006 and April 30, 2009, 56 eyes received chemosurgery at our institution, and 10 of these were enucleated subsequently. All were Reese Ellsworth Group 5 at enucleation. Of the 21 eyes that were treated with chemosurgery as the primary treatment, 1 (5%) was enucleated subsequently; its histopathology revealed residual non-necrotic, non-calcified tumor. Of the 34 eyes treated with chemosurgery after other treatments, 9 (24%) were enucleated, and 5 of these eyes contained non-calcified, non-necrotic tumor. None was enucleated for complications of chemosurgery. All patients were alive and free of metastatic disease as of September 2009.
A significant number of eyes with advanced intraocular retinoblastoma avoided enucleation as a result of chemosurgery. The rate of eyes that were enucleated was higher when chemosurgery was the secondary rather than the primary treatment. Of the eight eyes enucleated for progressive disease six had non-necrotic, non-calcified tumor cells.
PMCID: PMC3052645  PMID: 21399766
Retinoblastoma; histopathology; chemosurgery.
14.  Spontaneously Resolving Periocular Erythema and Ciliary Madarosis Following Intra-arterial Chemotherapy for Retinoblastoma 
Purpose and Design:
To describe an unusual clinical finding seen in children undergoing intra-arterial chemotherapy for retinoblastoma.
Materials and Methods:
A retrospective review of 69 eyes of 63 patients receiving intra-arterial chemotherapy over a 3-year period. Charts and photographs of 69 consecutive cases were reviewed, and data were collected on patients with clinical evidence of a hyperemic cutaneous periocular abnormality following the procedure.
A blanching erythematous and edematous patch was noted in the periocular region in 16% (11 of 69) of the children who received intraarterial chemotherapy. The plaque extended into the region of the supertrochlear and medial marginal artery distribution on the ipsilateral side of the intra-arterial chemotherapy. All patches of erythema spontaneously resolved within 3 months following completion of the intra-arterial chemotherapy.
Periocular erythema and swelling is a self-limited clinical finding associated with intra-arterial chemotherapy in a small number of patients.
PMCID: PMC2934711  PMID: 20844675
Cancer; Eye; Intra-Arterial Chemotherapy; Melphalan; Retinoblastoma; Skin; Topotican
15.  Myeloablative Chemotherapy with Autologous Bone Marrow Rescue in Children and Adolescents with Recurrent Malignant Astrocytoma: Outcome Compared with Conventional Chemotherapy: A Report from the Children’s Oncology Group 
Pediatric blood & cancer  2008;51(6):806-811.
Children and adolescents with malignant astrocytomas recurring after initial treatment have a dismal prognosis, with only rare patients surviving one year beyond recurrence. The purpose of this study was to attempt to improve their survival.
Twenty-seven children and adolescents with malignant astrocytomas (17 glioblastoma multiforme and 10 anaplastic astrocytoma) following initial tumor progression, received myeloablative chemotherapy followed by autologous marrow rescue with one of three thiotepa and etoposide-based chemotherapy regimens, administered alone (n=11) or combined with carmustine (n=5) or carboplatin (n=11). Time to progression and death following myeloablative chemotherapy for these patients was compared non-randomly with outcome of a contemporaneously treated cohort of similar patients who received only conventional chemotherapy following initial tumor progression. The two cohorts were compared for age, histology, prior therapies, extent of surgical resection at progression and time from initial diagnosis to progression.
Five of 27 children (two with glioblastoma multiforme and three with anaplastic astrocytoma) survive event-free from 8.3 to 13.3 years (median of 11.1 years) following myeloablative chemotherapy. Of 56 children with recurrent malignant astrocytoma who received conventional chemotherapy following initial progression, no patient survives. Differences in distributions of survival were not significant when stratified by surgical debulking (p=0.39). However, for patients who were surgically debulked, the survival distributions are significantly different (p=0.017).
Myeloablative chemotherapy with autologous marrow rescue can produce durable remissions in children and young adults with recurrent malignant gliomas, in the setting of minimal residual tumor burden achieved surgically.
PMCID: PMC2844080  PMID: 18802947
Myeloablative chemotherapy; autologous bone marrow rescue; recurrent malignant astrocytoma
16.  The Location and Appearance of Second Malignancies in Patients With Bilateral Retinoblastoma 
Sarcoma  1997;1(2):89-93.
Purpose. This paper describes the clinical history and radiographic appearance of second malignancies in patients with bilateral retinoblastoma.
Subjects/methods. The imaging studies and clinical data of 14 patients with a history of bilateral retinoblastoma who were treated for second malignancies were reviewed.
Results. A total of 17 tumors were identified in 14 patients during the period 1978–1996. The median age of occurrence of the second malignancy was 17 years (range 10–32 years). Fourteen of the 17 malignancies occurred in the facial structures and three developed in the lower extremities. The histologies included osteosarcoma (n = 5), malignant fibrous histiocytoma (n = 3), high-grade spindle cell sarcoma (n = 3), malignant mesenchymoma (n = 1), leiomyosarcoma (n = 4) and angiosarcoma (n = 1). The tumors were locally aggressive and had a similar appearance to those found in nonretinoblastoma patients. Six of the 14 patients are alive and disease free.
Discussion. Most of the adolescent and young adult retinoblastoma survivors developed second malignancies in the irradiated facial structures but some occurred in distal sites. Radiologically, these tumors do not differ in appearance from those seen in non-retinoblastoma patients with the exception of their location.
PMCID: PMC2395350  PMID: 18521207

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