Publications by authors named "Tanzina Chowdhury"

17 Publications

  • Page 1 of 1

Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30-year SIOP-RTSG experience.

Cancer 2021 Feb 4;127(4):628-638. Epub 2020 Nov 4.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Background: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence.

Methods: Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) registries and the SIOP-RTSG network (1989-2019). Events were defined as relapse, metachronous tumors, or death.

Results: Forty-three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6-44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5-year event-free survival rate was 84.3% (95% confidence interval, 72.4%-98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%-100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1).

Conclusions: Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised.

Lay Summary: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor. In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) and the SIOP-RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur. Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised.
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http://dx.doi.org/10.1002/cncr.33304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894534PMC
February 2021

Embryonal precursors of Wilms tumor.

Science 2019 12;366(6470):1247-1251

Wellcome Sanger Institute, Hinxton CB10 1SA, UK.

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.
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http://dx.doi.org/10.1126/science.aax1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914378PMC
December 2019

Examinations under anaesthesia as a measure of disease burden in unilateral retinoblastoma: the London experience.

Br J Ophthalmol 2020 01 12;104(1):17-22. Epub 2019 Mar 12.

Moorfields Eye Hospital, London, UK.

Background: Early diagnosis strategies and advances in retinoblastoma (Rb) management have resulted in nearly 100% survival. More attention should, therefore, be given to quality of life considerations. We aimed to quantify the number of examinations under anaesthesia (EUAs) in a cohort of patients with Rb, as a measure of disease burden.

Methods: A retrospective analysis of patients with unilateral Rb that presented to the London Rb service from 2006 to 2013, were treated and had long-term follow-up. Correlations of clinical variables to number of EUAs were investigated.

Results: A total of 107 patients with Rb were included that presented at a mean age of 26.51 ± 22.68 months. The International Intraocular Retinoblastoma Classification (IIRC) was group B in 5 (5%), C in 13 (12%), D in 48 (45%) and E in 41 (38%) of the cases. Primary treatment was intravenous chemotherapy in 36 (34%) and enucleation in 71 (66%) of the cases. Mean number of EUAs was 20.67 ± 6.62, 12.52 ± 6.23 and 11.15 ± 6.91 for combined groups B/C, group D and group E patients (p < 0.001), respectively. On analysis, early age atpresentation and conservative treatments were found to significantly correlate with increased number of EUAs (p < 0.001). Mean follow-up time was 74.42 ± 25.16 months and no metastasis or death were reported.

Conclusion: Families should be counselled regarding the number of EUAs associated with the patient's IIRC group, with B/C eyes undergoing twice the number as compared with D/E eyes. For group D cases, where both enucleation and conservative therapy are valid options, treatment choice has a significant impact on the number of EUAs.
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http://dx.doi.org/10.1136/bjophthalmol-2018-313556DOI Listing
January 2020

The diagnostic accuracy and clinical utility of pediatric renal tumor biopsy: Report of the UK experience in the SIOP UK WT 2001 trial.

Pediatr Blood Cancer 2019 06 13;66(6):e27627. Epub 2019 Feb 13.

Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK.

Introduction: The International Society of Paediatric Oncology (SIOP) protocols recommend preoperative chemotherapy appropriate for Wilms tumors (WTs) in children with renal tumors aged ≥6 months, reserving biopsy for "atypical" cases. The Children's Cancer and Leukaemia Group (CCLG) joined the SIOP-WT-2001 study but continued the national practice of biopsy at presentation.

Method: Retrospective study of concordance between locally reported renal tumor biopsies and central pathology review nephrectomy diagnoses of children enrolled by CCLG centers in the SIOP-WT-2001 study.

Results: Biopsy reports were available for 552/787 children with unilateral tumors. 36 of 552 (6.5%) were nondiagnostic: 2 normal tissue, 12 necrotic, 9 insufficient sample, and 13 indeterminate results (disproportionately non-WTs). The sensitivity and specificity of biopsy to identify tumors that did not require SIOP empirical preoperative chemotherapy were 86.0% and 99.6%, respectively. 13 of 548 (2.4%) biopsy results were discordant with nephrectomy; non-WTs other than renal cell carcinoma and clear cell sarcoma of the kidney (CCSK) were poorly recognized. In children aged 6-119 months, 480 of 518 (91.6%) had WT or nephroblastomatosis. 5 of 518 (1%) had benign tumors, and only one diagnosed on biopsy. Biopsy results correctly changed clinical management in 25 of 518 (4.8%), including identifying 19 of 20 CCSKs, but would have led to overtreatment in 5 of 518 (1%) or undertreatment in 4 of 518 (0.8%). In children aged ≥10 years, biopsy correctly changed management in 5 of 19 (26%) cases with no discordance.

Conclusion: Biopsy is less effective at identifying non-WTs than WTs and rarely changes management in younger children. Biopsy should be reserved in SIOP protocols for children ≥10 years and in younger children with clinical or radiological features inconsistent with WT.
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http://dx.doi.org/10.1002/pbc.27627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522371PMC
June 2019

The genetic changes of Wilms tumour.

Nat Rev Nephrol 2019 04;15(4):240-251

Wellcome Sanger Institute, Cambridge, UK.

Wilms tumour is the most common renal malignancy of childhood. The disease is curable in the majority of cases, albeit at considerable cost in terms of late treatment-related effects in some children. However, one in ten children with Wilms tumour will die of their disease despite modern treatment approaches. The genetic changes that underpin Wilms tumour have been defined by studies of familial cases and by unbiased DNA sequencing of tumour genomes. Together, these approaches have defined the landscape of cancer genes that are operative in Wilms tumour, many of which are intricately linked to the control of fetal nephrogenesis. Advances in our understanding of the germline and somatic genetic changes that underlie Wilms tumour may translate into better patient outcomes. Improvements in risk stratification have already been seen through the introduction of molecular biomarkers into clinical practice. A host of additional biomarkers are due to undergo clinical validation. Identifying actionable mutations has led to potential new targets, with some novel compounds undergoing testing in early phase trials. Avenues that warrant further exploration include targeting Wilms tumour cancer genes with a non-redundant role in nephrogenesis and targeting the fetal renal transcriptome.
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http://dx.doi.org/10.1038/s41581-019-0112-0DOI Listing
April 2019

Strabismus in retinoblastoma survivors with long-term follow-up.

J AAPOS 2018 08 1;22(4):276.e1-276.e7. Epub 2018 Aug 1.

Retinoblastoma Service, Royal London Hospital, London, United Kingdom.

Purpose: To report the long-term strabismus rate in salvaged retinoblastoma (Rb) patients and investigate possible risk factors leading to strabismus.

Methods: The medical records of patients with Rb presenting at a single institution over a 9-year period were reviewed retrospectively with regard to ocular alignment outcomes after long-term follow-up.

Results: A total of 64 eyes of 42 patients (22 bilateral cases [52%]) were included, presenting with International Intraocular Retinoblastoma Classification (IIRC) in the worse eye as follows: group A (n = 1), B (n = 16), C (n = 12), D (n = 11), no Rb (n = 2). Fifteen patients (36%) were initially referred because of family history of Rb. Mean age at presentation was 8.2 months (range, 0.3-58.3 months). Overall treatments included intravenous chemotherapy (62 eyes), intraophthalmic artery chemotherapy (10 eyes), brachytherapy (11 eyes), transpupillary thermotherapy (22 eyes), cryotherapy (47 eyes), and external beam radiotherapy (4 eyes). At final follow-up (mean, 93.7 months), 69% of patients had strabismus, with exotropia being the most common type (n = 18), followed by esotropia (n = 8), and alternate exotropia/esotropia (n = 3). On univariate analysis, the worse eye group IIRC and cTNMH, sporadic cases, strabismus, and foveal tumor at presentation were found to be significantly associated with strabismus at final follow-up (P ≤ 0.043). On multivariate analysis, only foveal involvement was found to be significant (P < 0.001).

Conclusions: Strabismus, exotropia in particular, is a common adverse sequela following successful conservative treatment for Rb, with 69% of the present cohort having some type of deviation after long-term follow-up, for which foveal tumor at presentation was found to be a significant risk factor.
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http://dx.doi.org/10.1016/j.jaapos.2018.03.007DOI Listing
August 2018

The management of retinoblastoma.

Oncogene 2018 03 11;37(12):1551-1560. Epub 2018 Jan 11.

Moorfields Eye Hospital, London, UK.

Retinoblastoma (Rb) is the most common primary intraocular malignancy of childhood, but an uncommon paediatric cancer, with a constant incidence worldwide of 1:15,000-1:20,000 live births. Despite its rarity, Rb has served as a cornerstone in the field of oncology in many of the aspects that comprise cancer management, including classification schemes, treatment modalities, genetic testing and screening. Until just over half a century ago, the major treatment for Rb was eye removal, and prognosis was poor with outcome fatal for most children. The dramatic evolution, in a short period of time across all fields of Rb management, as well as the development of specialized centres, better infrastructure and introduction of awareness campaigns, has resulted in nearly 100% survival in developed countries and allowed eye salvage in many of the cases. External beam radiotherapy was used as the main treatment choice for four decades, but replaced by chemotherapy at the turn of the century. Initially, and still in many centres, chemotherapy is administered intravenously, but recently is targeted directly into the eye by means of intra-ophthalmic artery and intravitreal chemotherapy. To date, a range of treatments is available to the Rb expert, including enucleation, but there is lack of consensus in a number of scenarios as to what to use and when. In such a rare cancer, treatment outcomes are reported usually via retrospective analyses, with few prospective randomized controlled trials. Classification schemes have also evolved following the introduction of new treatment modalities, but discrepancies exist among centres with respect to the preferred schema and its interpretation. Retinoblastoma management is a remarkable success story, but the future will require a collaborative effort in the form of multicentre randomized controlled trials in order to further improve the quality of care for this subset of young children with ocular cancer.
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http://dx.doi.org/10.1038/s41388-017-0050-xDOI Listing
March 2018

Primary enucleation for group D retinoblastoma in the era of systemic and targeted chemotherapy: the price of retaining an eye.

Br J Ophthalmol 2018 02 28;102(2):265-271. Epub 2017 Jun 28.

Ocular Oncology Service, Moorfields Eye Hospital, London, UK.

Background: Chemotherapy is increasingly used as primary treatment for group D retinoblastoma, whereas primary enucleation is considered to have a diminishing role. This study aimed to compare the management course, including number of examinations under anaesthesia (EUAs), of group D patients treated by enucleation versus chemotherapy.

Methods: A retrospective analysis of 92 group D patients, of which 40 (37 unilateral) underwent primary enucleation and 52 (17 unilateral) were treated with intravenous chemotherapy. Number of EUAs was compared between the treatment groups with respect to the whole cohort, using univariate and multivariate analysis, and to unilateral cases only.

Results: Patients were followed up for a median of 61 months (mean: 66, range: 14-156), in which time primary enucleated patients had on average seven EUAs and chemotherapy-treated patients 21 EUAs (p<0.001). Chemotherapy, young age, bilateral disease, multifocal tumours, familial and germline retinoblastoma were found on univariate analysis to correlate with increased number of EUAs (p≤0.019). On multivariate analysis, however, only treatment type and presentation age were found significant (p≤0.001). On subanalysis of the unilateral cases, patients undergoing primary enucleation had in average seven EUAs, as compared with 16 in the chemotherapy group (p<0.001). Of the 55 unilateral-presenting patients, a new tumour developed in the fellow eye only in a single familial case.

Conclusion: Group D patients' families should be counselled regarding the significant difference in number of EUAs following primary enucleation versus chemotherapy when deciding on a treatment strategy. In this regard, primary enucleation would be most beneficial for older patients with unilateral disease.
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http://dx.doi.org/10.1136/bjophthalmol-2017-310624DOI Listing
February 2018

Reagent-Free Quantification of Aqueous Free Chlorine via Electrical Readout of Colorimetrically Functionalized Pencil Lines.

ACS Appl Mater Interfaces 2017 Jun 7;9(24):20748-20761. Epub 2017 Jun 7.

Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.

Colorimetric methods are commonly used to quantify free chlorine in drinking water. However, these methods are not suitable for reagent-free, continuous, and autonomous applications. Here, we demonstrate how functionalization of a pencil-drawn film with phenyl-capped aniline tetramer (PCAT) can be used for quantitative electric readout of free chlorine concentrations. The functionalized film can be implemented in a simple fluidic device for continuous sensing of aqueous free chlorine concentrations. The sensor is selective to free chlorine and can undergo a reagent-free reset for further measurements. Our sensor is superior to electrochemical methods in that it does not require a reference electrode. It is capable of quantification of free chlorine in the range of 0.1-12 ppm with higher precision than colorimetric (absorptivity) methods. The interactions of PCAT with the pencil-drawn film upon exposure to hypochlorite were characterized spectroscopically. A previously reported detection mechanism relied on the measurement of a baseline shift to quantify free chlorine concentrations. The new method demonstrated here measures initial spike size upon exposure to free chlorine. It relies on a fast charge built up on the sensor film due to intermittent PCAT salt formation. It has the advantage of being significantly faster than the measurement of baseline shift, but it cannot be used to detect gradual changes in free chlorine concentration without the use of frequent reset pulses. The stability of PCAT was examined in the presence of free chlorine as a function of pH. While most ions commonly present in drinking water do not interfere with the free chlorine detection, other oxidants may contribute to the signal. Our sensor is easy to fabricate and robust, operates reagent-free, and has very low power requirements and is thus suitable for remote deployment.
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http://dx.doi.org/10.1021/acsami.7b03968DOI Listing
June 2017

Long-term Visual Acuity, Strabismus, and Nystagmus Outcomes Following Multimodality Treatment in Group D Retinoblastoma Eyes.

Am J Ophthalmol 2017 Jul 10;179:137-144. Epub 2017 May 10.

Moorfields Eye Hospital, London, United Kingdom; Retinoblastoma Service, Royal London Hospital, London, United Kingdom; National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom.

Purpose: To analyze the long-term visual acuity, strabismus, and nystagmus outcomes in Group D retinoblastoma following multimodality treatments in a national retinoblastoma referral center.

Design: Retrospective interventional case series.

Methods: A 13-year retrospective chart review of Group D eyes treated initially with intravenous chemotherapy (IVC) and followed up for at least 1 year from last treatment. Risk factors for final visual acuity (VA) were analyzed, and rate of strabismus and nystagmus at last follow-up visit were calculated.

Results: One hundred and four Group D eyes (92 patients) presented to our center during the study period, of which 32 (27 patients) met the inclusion criteria. Following IVC (vincristine, etoposide, and carboplatin), adjuvant treatments included intraophthalmic artery chemotherapy in 5 (16%) eyes, plaque brachytherapy in 5 (16%), transpupillary thermotherapy (TTT) in 18 (56%), and cryotherapy in 24 (75%) eyes. On last examination, 64.41 ± 6.76 months from presentation, mean final VA was 20/283 (logMAR equivalent of 1.15 ± 0.15). On univariate analysis, presentation age, foveal retinoblastoma (at initial examination), use of TTT, and tumor-foveola distance (at last visit) were found to be significant risk factors for worse VA (P < .026). On multivariate analysis, however, only TTT was found to be significant (P = .010). At last visit, 6 of 27 (22%) patients had nystagmus and 12 of 20 (60%) bilaterally salvaged patients had strabismus (n = 10 exotropia and n = 2 esotropia).

Conclusions: After multimodality treatments initiated with IVC, 50% of salvaged Group D retinoblastoma eyes had <20/200 vision, with TTT being a risk factor for worse vision; 60% had strabismus; and 22% had nystagmus.
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http://dx.doi.org/10.1016/j.ajo.2017.05.003DOI Listing
July 2017

High-Risk Histopathology Features in Primary and Secondary Enucleated International Intraocular Retinoblastoma Classification Group D Eyes.

Ophthalmology 2017 06 13;124(6):851-858. Epub 2017 Mar 13.

Ocular Oncology Service, Moorfields Eye Hospital, London, United Kingdom; Retinoblastoma Service, Royal London Hospital, London, United Kingdom; National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London, Institute of Ophthalmology, London, United Kingdom.

Purpose: To evaluate the rate and identify the risk factors for high-risk histopathologic features in group D retinoblastoma eyes enucleated as primary or secondary treatment.

Design: Retrospective analysis.

Participants: A total of 64 enucleated group D eyes (62 patients), of which 40 (40 patients) were primary and 24 (22 patients) were secondary to other treatments.

Methods: Clinicopathologic correlation of consecutive group D eyes enucleated from 2002 to 2014. High-risk histopathologic features were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body/muscle infiltration, massive (≥3 mm) choroidal invasion, retrolaminar optic nerve invasion, or combined non-massive choroidal and prelaminar/laminar optic nerve invasion.

Main Outcome Measures: High-risk histopathologic features, metastasis, and death.

Results: Of the 64 group D eyes, 37 (58%) were classified as cT2bN0M0H0, 24 (38%) were classified as cT2bN0M0H1, and 3 (5%) were classified as cT2aN0M0H1, according to the 8th edition cTNMH Retinoblastoma Staging. High-risk histopathologic features were detected in 10 eyes (16%) in the entire cohort, 5 eyes (13%) of the primary enucleated group (pT3aNxM0, n = 2 and pT3bNxM0, n = 3, 8th edition pTNM), and 5 eyes (21%) of the secondary enucleated group (pT2bNxM0, n = 2, pT3aNxM0, n = 2 and pT3cNxM0, n = 1). Absence of vitreous seeds at presentation was the only predictive factor found for high-risk histopathologic features in the primary enucleation group (P = 0.042), whereas none were found in the secondary group (P ≥ 0.179). Invasion of the anterior structures (anterior chamber, iris, ciliary body/muscle) was detected significantly more after secondary enucleation (P = 0.048). All patients with high-risk histopathologic features were treated with adjuvant chemotherapy, and no metastases were recorded in a median follow-up time of 73.2 months (mean, 71.5; range, 13.7-153.0).

Conclusions: The choice of primary treatment for group D retinoblastoma should be carefully weighed, because according to this study, 13% of eyes harbor high-risk histopathologic features at presentation, with the absence of vitreous seeds being a potential risk factor. It is of special importance in group D eyes being considered for nonsystemic treatment, such as primary intraophthalmic artery chemotherapy. Secondary enucleated group D eyes with high-risk histopathologic features more commonly involved anterior structures, warranting meticulous clinical and histologic examinations for this subset of patients.
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http://dx.doi.org/10.1016/j.ophtha.2017.01.048DOI Listing
June 2017

Primary intravenous chemotherapy for group D retinoblastoma: a 13-year retrospective analysis.

Br J Ophthalmol 2017 Jan 13;101(1):82-88. Epub 2016 Dec 13.

Ocular Oncology Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Background: Eye salvage rate for group D retinoblastoma using intravenous chemotherapy (IVC) as a primary modality is <50%. To report on 13 years' experience with the use of primary IVC for group D retinoblastoma.

Methods: A retrospective analysis of 64 group D eyes (52 patients) treated with primary IVC, from 2002 to 2014.

Results: The median age at presentation was 11.0 months (mean: 18.6, range: 0.6-144.0), 35 (67%) patients had bilateral disease, 38 (73%) germline disease and 8 (15%) cases were familial. In addition to IVC, patients received a median number of three treatments (mean: 6, range: 0-24), including thermotherapy/cryotherapy, plaque radiotherapy, intra-ophthalmic artery chemotherapy (IAC) and/or intravitreous chemotherapy. External beam radiotherapy (EBRT) was used in five eyes, all of which were eventually enucleated. In a median follow-up time of 55 months (mean: 64, range: 14-156), 63% of eyes were salvaged. By the Kaplan-Meier survival analysis, globe salvage rate was 83%, 70%, 59% and 45% at 1, 3, 5 and 10 years, respectively. There were no cases of metastatic spread from intraocular retinoblastoma and no deaths. IVC-related adverse events included febrile neutropenia in 21 (40%) patients and anaphylactic reaction to carboplatin in 2 (4%), all conservatively resolved. Of the patients receiving IAC, third and sixth nerve palsies were documented in two (10%) and one (5%) eyes, respectively.

Conclusions: Primary IVC for group D eyes, with adjuvant treatments as required, was found to be a safe and efficient approach, achieving 63% eye salvage rate, no metastatic spread from intraocular retinoblastoma and no deaths. IAC has now replaced EBRT as a successful salvage treatment.
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http://dx.doi.org/10.1136/bjophthalmol-2016-309710DOI Listing
January 2017

Adaptive dosing of anticancer drugs in neonates: facilitating evidence-based dosing regimens.

Cancer Chemother Pharmacol 2016 Apr 13;77(4):685-92. Epub 2016 Feb 13.

Great Ormond Street Hospital, London, WC1N 3JH, UK.

Purpose: Selection of the most appropriate chemotherapy dosing regimens for neonates treated within the first weeks of life represents a significant clinical dilemma. Due to a lack of information relating to the clinical pharmacology of anticancer drugs in these challenging patients, current dosing guidelines are based on limited scientific rationale. In the current study, we investigate the utilisation of therapeutic drug monitoring approaches in neonates with localised hepatoblastoma, Wilms' tumour and stage 4S neuroblastoma, being treated with widely used anticancer drugs.

Methods: Plasma concentrations of cisplatin, vincristine, etoposide and carboplatin were quantified in two neonates being treated within the first 3 weeks of life and in a 32-week preterm infant treated at a gestational age of 40 weeks. Therapeutic drug monitoring was carried out where appropriate, based on the pharmacokinetic data obtained in conjunction with clinical response and toxicity.

Results: Treatment of a child aged 2 weeks with a recommended cisplatin dose reduction for weight to 1.8 mg/kg resulted in achievement of unbound cisplatin plasma concentrations of 0.01-0.08 µg/mL, markedly lower than exposures previously reported in infants and older children. A dose increase to 2.7 mg/kg was implemented, leading to the achievement of levels more in-line with those previously reported. This increased dose level was well tolerated over six courses of treatment, resulting in a good response to cisplatin monotherapy and the patient remains in remission at 3.5 years. In contrast, a 50 % vincristine dose reduction for weight in a 3-week-old neonate resulted in plasma concentrations comparable to levels observed in older children, leading to successful treatment and continued remission at 2 years. In a third patient, etoposide and carboplatin clearance values normalised to body weight were comparable to those reported in older children, resulting in comparatively lower exposures following reduced dosing.

Conclusions: The current report provides unique data on the pharmacokinetics of several widely used anticancer drugs in neonates treated within the first few weeks of life. The provision of these data acts as a useful reference point to support future dosing decisions to be made by clinicians in the treatment of these challenging patients.
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http://dx.doi.org/10.1007/s00280-016-2975-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819938PMC
April 2016

Distant metastatic spread of molecularly proven infantile fibrosarcoma of the chest in a 2-month-old girl: case report and review of literature.

J Pediatr Hematol Oncol 2014 Apr;36(3):231-3

Departments of *Pediatric Oncology ‡Pathology, Great Ormond Street Hospital for Children NHS Trust §Unit of Molecular Hematology and Cancer Biology, Institute of Child Health, University College London, London, UK †Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.

Infantile fibrosarcoma (IFS) is a malignant neoplasm, arising in children younger than 2 years of age and with a hallmark chromosomal translocation t(12;15)(p13;q26) encoding an ETV6-NTRK3 fusion oncoprotein. A review of the world literature found no reported cases of molecularly proven IFS with distant metastatic spread at presentation. We report the case of a 2-month-old infant girl presenting with a chest wall primary IFS bearing and expressing the ETV6-NTRK3 fusion, who had several pulmonary metastatic deposits at diagnosis. She achieved complete remission with chemotherapy and surgery. To our knowledge, this is the first reported case of molecularly proven IFS with distant metastatic spread.
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http://dx.doi.org/10.1097/MPH.0000000000000055DOI Listing
April 2014

Persistent complete response after single-agent sunitinib treatment in a case of TFE translocation positive relapsed metastatic pediatric renal cell carcinoma.

J Pediatr Hematol Oncol 2013 Jan;35(1):e1-3

Department of Oncology, Great Ormond Street Hospital, UCL Institute of Child Health, London, UK.

Forty percent of renal cell carcinomas (RCCs) in childhood are characterized by translocation involving transcription factor E3 (TFE3) family members. Here, we describe a case of TFE3-positive RCC in which metastatic relapse to the mediastinal lymph nodes and pulmonary nodules was treated with single-agent sunitinib, a multitargeted tyrosine inhibitor. Complete radiologic remission was achieved after only 3 courses of treatment, and surgical exploration of metastases failed to identify any residual viable disease. The published experience of sunitinib in TFE-RCC is limited, and prospective evaluation of its activity in a larger number of patients is warranted.
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http://dx.doi.org/10.1097/MPH.0b013e318266bf34DOI Listing
January 2013

Ultrasound-guided core needle biopsy for the diagnosis of rhabdomyosarcoma in childhood.

Pediatr Blood Cancer 2009 Sep;53(3):356-60

Department of Oncology, Great Ormond Street Hospital, London, UK.

Background: Most commonly a tissue diagnosis of rhabdomyosarcoma (RMS) in children is made by biopsy as opposed to primary resection. Open surgical procedures are often recommended to obtain sufficient material for accurate and complete diagnostic work up. Our institution has routinely used image-guided needle biopsies for soft tissue tumour diagnosis. We therefore sought to assess diagnostic accuracy and completeness, and procedure safety of consecutive patients diagnosed by needle biopsies in a single institution.

Methods: A retrospective review of consecutive biopsies of patients who were diagnosed with RMS or undifferentiated sarcoma in a single institution over a 9-year period.

Results: There were 24 children diagnosed with RMS or undifferentiated sarcoma who underwent 37 procedures (30 primary site and 7 draining lymph nodes). In the primary site diagnostic procedures, definitive diagnosis was made in all cases. In the majority of cases there was sufficient material for molecular analysis, cytogenetics and freezing. There were no complications of biopsy.

Conclusions: In the hands of experienced operators, image-guided needle biopsies of RMSs allow for accurate diagnosis, allow sufficient material to be obtained for supplementary studies and research, and are associated with minimal morbidity.
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http://dx.doi.org/10.1002/pbc.22059DOI Listing
September 2009

Insights from clinical studies into the role of the MLL gene in infant and childhood leukemia.

Blood Cells Mol Dis 2008 Mar-Apr;40(2):192-9. Epub 2007 Oct 1.

Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London, UK.

Translocations involving the Mixed Lineage Leukemia (MLL) gene at 11q23 are found in both acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML), but have different prognostic implications depending on the phenotype of the leukemia in de novo pediatric cases. The majority of MLL gene rearrangements are associated with infant ALL, and their presence predicts a poor prognosis which worsens with earlier age of presentation. Rearrangements of the MLL gene are found in most cases of infant AML and regardless of age confer an intermediate risk. The treatment of MLL-rearranged ALL in children involves increased intensification of chemotherapy, and infants with ALL are treated with an intensive regimen of ALL- and AML-like chemotherapy, with the proportion of MLL-rearranged cases being responsible for the poor outcome in this age group. The use of DNA microarray analysis to distinguish a particular gene signature for MLL-rearranged leukemias is shedding light on the molecular mechanisms and potential therapeutic targets of these leukemias. It may also prove to have a useful role in both diagnosis and prognosis. This review considers recent advances in our understanding of the role of MLL gene rearrangements in pediatric clinical practice.
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http://dx.doi.org/10.1016/j.bcmd.2007.07.005DOI Listing
May 2008