Publications by authors named "James I Geller"

89 Publications

Comparison of diagnostic performance of CT and MRI for abdominal staging of pediatric renal tumors: a report from the Children's Oncology Group.

Pediatr Radiol 2015 Feb 19;45(2):166-72. Epub 2014 Aug 19.

Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: CT and MRI are both used for abdominal staging of pediatric renal tumors. The diagnostic performance of the two modalities for local and regional staging of renal tumors has not been systematically evaluated.

Objective: To compare the diagnostic performance of CT and MRI for local staging of pediatric renal tumors.

Materials And Methods: The study population was derived from the AREN03B2 study of the Children's Oncology Group. Baseline abdominal imaging performed with both CT and MRI within 30 days of nephrectomy was available for retrospective review in 82 renal tumor cases. Each case was evaluated for capsular penetration, lymph node metastasis, tumor thrombus, preoperative tumor rupture, and synchronous contralateral lesions. The surgical and pathological findings at central review were the reference standard.

Results: The sensitivity of CT and MRI for detecting capsular penetration was 68.6% and 62.9%, respectively (P = 0.73), while specificity was 86.5% and 83.8% (P = 1.0). The sensitivity of CT and MRI for detecting lymph node metastasis was 76.5% and 52.9% (P = 0.22), and specificity was 90.4% and 92.3% (P = 1.0). Synchronous contralateral lesions were identified by CT in 4/9 cases and by MRI in 7/9 cases.

Conclusion: CT and MRI have similar diagnostic performance for detection of lymph node metastasis and capsular penetration. MR detected more contralateral synchronous lesions; however these were present in a very small number of cases. Either modality can be used for initial loco-regional staging of pediatric renal tumors.
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http://dx.doi.org/10.1007/s00247-014-3138-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337797PMC
February 2015

Prechemotherapy robotic-assisted laparoscopic radical nephrectomy for an adolescent with Wilms tumor.

J Pediatr Hematol Oncol 2015 Mar;37(2):e125-7

Divisions of *Pediatric Urology ‡Pediatric Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH †Department of Surgery, Division of Urology, University of Colorado School of Medicine and the Children's Hospital Colorado, Aurora, CO.

Although Wilms tumor (WT) is the most common pediatric renal tumor, adolescent and adult WT is rare. Nevertheless, adolescent renal tumors as a group are sufficiently uncommon that WT must be included in the differential diagnosis for such patients, and in doing so affects the oncologic considerations of the surgery. Herein, we describe a 14-year-old female presenting with a 1-month history of right flank pain. Subsequent work-up revealed a localized, centrally located, enhancing right renal mass. The patient underwent robotic-assisted laparoscopic radical nephrectomy and pathology demonstrated stage II, favorable histology WT. Herein, we will discuss the pertinent details regarding adolescents with renal tumors and the risks and benefits of using a minimally invasive surgical approach.
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http://dx.doi.org/10.1097/MPH.0000000000000193DOI Listing
March 2015

Feasibility of using CT volume as a predictor of specimen weight in a subgroup of patients with low risk Wilms tumors registered on COG Study AREN03B2: implications for central venous catheter placement.

J Pediatr Urol 2014 Oct 15;10(5):969-73. Epub 2014 Mar 15.

University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address:

Objective: Patients with stage I Wilms tumor, age ≤ 2 years, tumor ≤ 550 g may not require therapy beyond nephrectomy. This study's aims were to determine: (1) if a linear relationship exists between tumor weight and computed tomography (CT) estimated volume; (2) describe the accuracy of a slope-intercept equation in estimating weight; and (3) determine the potential impact of weight estimation on port placement decisions.

Materials And Methods: Tumor weight and port placement information were abstracted from 105 patients, age ≤ 2 years, with tumors ± 550 g, enrolled in COG AREN03B2. One radiologist estimated tumor size from CT scan. Prolate ellipse volume (PEV) was calculated, linear regression performed, slope-intercept equation calculated, equation estimated weight determined, and potential impact of the on port placement evaluated.

Results: A strong relationship exists between PEV and weight (R(2) = 0.87). The slope-intercept equation for weight was: weight = 1.04(PEV) + 58.75. Overall median relative error for the equation was 0.9%, and -3% in tumors weighing 350-750 g. Fifty-five ports were placed, 29 in patients with tumor weight ≤ 550 g, and six not placed in patients with tumor weight > 550 g.

Conclusions: The relationship between PEV and weight produced a reliable weight prediction equation. Preoperative consideration of specimen weight may diminish the number of ports placed in this population.
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http://dx.doi.org/10.1016/j.jpurol.2014.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339089PMC
October 2014

The initial experience with RENAL Nephrometry in children, adolescents, and young adults with renal tumors.

Pediatr Blood Cancer 2014 Aug 9;61(8):1434-9. Epub 2014 Mar 9.

Division of Urology, University of Colorado School of Medicine, Aurora, Colorado; Division of Urology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Background: No standardized manner exits to objectively compare renal tumor complexity in children and adolescents. However, the RENAL Nephrometry scoring system has been recently developed in adults and shown to predict tumor complexity and correlate with clinical outcomes. Thus, the study objective was to evaluate RENAL Nephrometry tumor score in a population of children, adolescents, and young adults and correlate it with tumor features and pathology.

Methods: Patients at the study institution who underwent attempted renal tumor resection from 2002 to 2012, and had pre-operative imaging available for scoring were retrospectively reviewed. A Nephrometry score for each affected kidney was calculated separately by two blinded reviewers and the final score was based on consensus review. Tumor characteristics and oncologic outcomes were compared between the low-, moderate-, and high-complexity masses.

Results: Sixty-five patients and 67 kidneys met study criteria. This included: 5 (7.5%) low-complexity, 11 (16.4%) moderate-complexity, and 51 (76.1%) high-complexity lesions. In comparing the clinical and pathologic features between groups, it was observed that less complex masses were observed in older patients, were more commonly managed with nephron-sparing surgery, and more often represented renal cell carcinoma (RCC) and other non-Wilms tumor pathology. No statistically significant correlation was observed between tumor complexity score and blood loss, operative time, transfusion requirement, positive margins or tumor rupture.

Conclusion: In general, renal lesions in this population are highly complex. In its current form, RENAL Nephrometry appears most useful in evaluating tumor complexity in RCC and masses in older children and adolescents.
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http://dx.doi.org/10.1002/pbc.25027DOI Listing
August 2014

DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma.

Mod Pathol 2014 Sep 31;27(9):1267-80. Epub 2014 Jan 31.

1] Division of Pathology, and Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA [2] Center for Genetic Medicine Research, Children's Research Institute, Minneapolis, MN, USA [3] International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA [4] Integrative Systems Biology, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.

The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.
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http://dx.doi.org/10.1038/modpathol.2013.242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117822PMC
September 2014

Urologic co-morbidities associated with sacrococcygeal teratoma and a rational plan for urologic surveillance.

Pediatr Blood Cancer 2013 Oct 17;60(10):1626-9. Epub 2013 Jun 17.

Division of Urology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Background: Sacrococcygeal teratoma (SCT) is one of the most common neonatal and fetal tumors. SCT pelvic mass effect and the need for aggressive surgical resection, create potential for urologic co-morbidity. We reviewed our experience with SCTs and propose a rational plan for urologic surveillance.

Methods: We retrospectively reviewed all patients with SCT evaluated at our institution from 2004 to 2011. We collected data on the need for reconstructive surgery related to the urologic co-morbidity, the time to detection of urologic co-morbidity, and length of follow-up.

Results: We identified 28 patients evaluated during the study period with a median follow-up of 3.1 year (range 0.14-13.4). The Altman classifications were--type I: 7 (25%), II: 15 (53.6%), and III: 6 (21.4%). Eighteen (64.3%) patients had an associated urologic co-morbidity: 12 (42.9%) patients had hydronephrosis, VUR--10 (35.7%), NGB--13 (46.4%), and 4 (14.3%) developed ≥CKD2. When comparing the patients according to Altman classification, there was a trend towards more urologic co-morbidity in patients with increasing pelvic involvement, P = 0.06. Eleven patients (39.3%) had delayed urologic evaluation and five (17.9%) required reconstructive urologic surgery. In comparing these groups, 4 of 11 (36.4%) undergoing delayed urologic evaluation progressed to reconstruction, as opposed to only one of 17 (5.7%) with urologic evaluation within first year of life (P-value = 0.06).

Conclusion: Urologic co-morbidities are common in children with SCT and appear most common in patients with more pelvic tumor involvement (≥Altman II). A risk-adapted approach to urologic surveillance is proposed.
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http://dx.doi.org/10.1002/pbc.24627DOI Listing
October 2013

Multifocal hepatic neoplasia in 3 children with APC gene mutation.

Am J Surg Pathol 2013 Jul;37(7):1058-66

Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039 , USA.

Hepatoblastoma (HB), the most common hepatic neoplasm in children is associated with germline mutations in adenomatous polyposis coli tumor-suppressor gene that cause familial adenomatous polyposis syndrome. Individuals with familial adenomatous polyposis have a 750 to 7500× the risk of developing HB. We report 3 children with APC gene mutation, who underwent resection or liver transplant for HB. In addition to HB, all 3 patients had multiple independent adenoma-like nodules lacking qualities of intrahepatic metastases. Twenty-five nodules were subjected to immunohistochemical analysis using a panel of antibodies including glypican-3 (GPC3), β-catenin, cytokeratin AE1/AE3, CD34, Ki-67, glutamine synthetase (GS), and fatty acid binding protein. The nodules were round, ranged in size from 0.2 to 1.5 cm, and paler than the background liver. All lacked the chemotherapy effect. The nodules were circumscribed but nonencapsulated and composed of well-differentiated hepatocytes with occasional minor atypical features and absent or rare portal tracts. One lesion displayed a "nodule-within-nodule" pattern. The nodules demonstrated diffuse GS overexpression. Nine (36%) nodules were focally reactive for GPC3, and 1 (4%) displayed focal nuclear β-catenin expression. The associated HB showed diffuse expression of GS, GPC3, and β-catenin nuclear staining. We interpret these nodules as neoplastic with most being adenomas (GPC3 negative) that show features of independent origin and represent early stages of carcinogenesis, implying potential to progress to HB or hepatocellular carcinoma. To our knowledge, this is the first report of multifocal neoplasms in patients with HB and APC gene mutation.
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http://dx.doi.org/10.1097/PAS.0b013e31828aeb18DOI Listing
July 2013

Renal rhabdomyosarcoma in a pancake kidney.

Urology 2013 Aug 29;82(2):458-60. Epub 2013 Apr 29.

Division of Pediatric Surgery of Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Renal rhabdomyosarcoma (RMS) is a rare pediatric tumor. Pancake kidneys are unusual anatomic anomalies resulting when both upper and lower poles of the embryonic kidney become fused. We report on a 4-year-old boy who was discovered to have a stage 4, group IV renal embryonal RMS arising from a pancake kidney with metastases to the lung, pelvis, and bone marrow. Treatment included multimodal therapy, consisting of neoadjuvant chemotherapy, complete surgical resection, and adjuvant chemotherapy. He remains in clinical remission 7 months after resection.
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http://dx.doi.org/10.1016/j.urology.2013.03.003DOI Listing
August 2013

Update on pediatric cancer predisposition syndromes.

Pediatr Blood Cancer 2013 Aug 26;60(8):1247-52. Epub 2013 Apr 26.

Center for Children's Cancer Research and Department of Pediatrics, University of Utah, Salt Lake City, Utah 84112, USA.

Hereditary cancer syndromes in children and adolescents are becoming more recognized in the field of pediatric hematology/oncology. A recent workshop held at the American Society of Pediatric Hematology/Oncology (ASPHO) 2012 Annual Meeting included several interactive sessions related to specific familial cancer syndromes, genetic testing and screening, and ethical issues in caring for families with inherited cancer risk. This review highlights the workshop presentations, including a brief background about pediatric cancer predisposition syndromes and the importance of learning about them for the practicing pediatric hematologists/oncologists. This is followed by a brief summary of the newly described cancer predisposition syndromes including Rhabdoid Tumor Predisposition Syndrome, Hereditary Paragangliomas and Pheochromocytoma Syndrome, and Familial Pleuropulmonaryblastoma Tumor Predisposition (DICER1) Syndrome. The next section covers genetic testing and screening for pediatric cancer predisposition syndromes. Ethical issues are also discussed including preimplantation genetic diagnosis or testing (PGD/PGT), suspicious lesions found on tumor screening, and incidental mutations discovered by whole genome sequencing. Finally, the perspective of a family with Li-Fraumeni Syndrome is shared.
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http://dx.doi.org/10.1002/pbc.24555DOI Listing
August 2013

High-grade transitional cell carcinoma of the bladder in a 5-year-old boy successfully treated with partial cystectomy and intravesical bacillus Calmette-Guerin.

J Pediatr Hematol Oncol 2014 May;36(4):e234-6

Divisions of *Oncology, Cancer, and Blood Diseases Institute †Pathology ‡Pediatric Urology, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH.

Pediatric transitional cell carcinomas of the bladder are typically characterized by low-grade histology, adolescent and young adult age, and cure with surgical resection. Here, we report a high-grade transitional cell carcinoma of the bladder in a 5-year-old boy treated with a partial cystectomy and adjuvant intravesical Bacillus Calmette-Guerin.
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http://dx.doi.org/10.1097/MPH.0b013e31828e508fDOI Listing
May 2014

Primary nephrectomy and intraoperative tumor spill: report from the Children's Oncology Group (COG) renal tumors committee.

J Pediatr Surg 2013 Jan;48(1):34-8

Seattle Children's Hospital and University of Washington, Seattle, WA 98105, USA.

Purpose: Initial Children's Oncology Group (COG) management for Wilms' tumor (WT) consists of primary nephroureterectomy with lymph node sampling. While this provides accurate staging to define further treatment, it may result in intraoperative spill (IOS), which is associated with higher recurrence rates and therefore requires more intensive therapy. The purpose of this study is to determine current rates and identify factors which may predispose a patient to IOS.

Methods: The study population was drawn from the AREN03B2 renal tumor banking and classification study of the Children's Oncology Group. All children with a first time occurrence of a renal mass were eligible for the study. At the time of enrollment and prior to risk stratification, the institution is required to submit operative notes, pathology specimens, a chest computed tomography scan (CT), and a contrast-enhanced CT or magnetic resonance imaging (MRI) of the abdomen and pelvis for central imaging review. These data are then used to determine an initial risk classification and therapeutic protocol eligibility. Patients who had a unilateral nephroureterectomy for favorable histology WT underwent further review to assure data accuracy and to clarify details regarding the spill. Analyses were performed using chi square and logistic regression. Odd ratios (OR) are shown with 95% confidence intervals.

Results: There were 1,131 primary nephrectomies for unilateral WT with an IOS rate of 9.7% with an additional 1.8% having possible tumor spill during renal vein or IVC tumor thrombectomy. IOS correlated with diameter (>12 cm, p<0.0001) and laterality (right, p=0.0414). Simple logistic regression indicated that IOS increased 2.7% [p=0.0240, OR 1.027 (1.004, 1.052)] with each 1 cm increase in diameter (3 - 21 cm) and 4.7% [p=0.0147 OR 1.047 (1.009, 1.086)] with each 100 g increase in weight (80 - 1800 g). Multiple logistic regression indicated that laterality [right p=0.048, OR 1.46 (1.004, 2.110)] and weight (p=0.03, OR 1.039 (1.003, 1.075) were predictive of IOS when diameter was included as a continuous variable. Diameter as a binary variable was highly prognostic of IOS (p=0.0002), while laterality and weight were not significant.

Conclusions: Intraoperative tumor spill occurs in about one out of every ten cases of primary nephroureterectomies for WT. Right-sided and larger tumors are at higher risk of IOS.
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http://dx.doi.org/10.1016/j.jpedsurg.2012.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556229PMC
January 2013

Children's Oncology Group's 2013 blueprint for research: renal tumors.

Pediatr Blood Cancer 2013 Jun 19;60(6):994-1000. Epub 2012 Dec 19.

Division of Oncology, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC 20010, USA.

Renal malignancies are among the most prevalent pediatric cancers. The most common is favorable histology Wilms tumor (FHWT), which has 5-year overall survival exceeding 90%. Other pediatric renal malignancies, including anaplastic Wilms tumor, clear cell sarcoma, malignant rhabdoid tumor, and renal cell carcinoma, have less favorable outcomes. Recent clinical trials have identified gain of chromosome 1q as a prognostic marker for FHWT. Upcoming studies will evaluate therapy adjustments based on this and other novel biomarkers. For high-risk renal tumors, new treatment regimens will incorporate biological therapies. A research blueprint, viewed from the perspective of the Children's Oncology Group, is presented.
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http://dx.doi.org/10.1002/pbc.24419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127041PMC
June 2013

Radioembolisation for treatment of pediatric hepatocellular carcinoma.

Pediatr Radiol 2013 Jul 5;43(7):876-81. Epub 2012 Dec 5.

Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Transarterial radioembolisation with yttrium-90 (TARE-Y90), a catheter-directed therapy, has been used extensively in adults to treat primary and secondary hepatic malignancies. To our knowledge, the use of this palliative technique has not been described in children. We present two children with unresectable hepatocellular carcinoma (HCC) treated with TARE-Y90.
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http://dx.doi.org/10.1007/s00247-012-2568-yDOI Listing
July 2013

Adolescent urologic oncology: current issues and future directions.

Urol Oncol 2014 Feb 8;32(2):59-69. Epub 2012 Nov 8.

Division of Pediatric Urology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Recent Surveillance Epidemiology and End Results (SEER) data indicate that the annual cancer incidence in adolescents is higher than in children, and is on the rise. However, the amount of attention, research funding, and therapeutic progress made in the adolescent oncology population pales in comparison with that of pediatric oncology. Issues of adolescent oncology have only recently been acknowledged by leaders in the field, and current efforts now focus on raising awareness of this unique patient group. In urology, there have been many gains made in pediatric urologic oncology, most notably in Wilms tumor and genitourinary rhabdomyosarcoma (genitourinary [GU] rhabdomyosarcoma [RMS]); however, there has been little to no progress in the adolescent population. In general, adolescent cancer represents the interface between pediatric and adult oncology. Similarly, adolescent urologic oncology must be approached as a distinct entity because of the unique disease processes, treatment-related comorbidities, and psychosocial issues. This article will serve to review the most pertinent adolescent urologic oncologic diagnoses (testicular germ call malignancy, the second peak of the bimodal age distribution of GU-RMS, and adolescent renal malignancies). Also, we focus on such issues as the therapeutic impact on fertility, radiation exposure during therapy, and surveillance, risk of secondary malignancy, the long-term impact of chemotherapy, and the psychosocial burden of cancer in this population. Lastly, we highlight future directions and the foreseeable obstacles towards achieving the same research and therapeutic success enjoyed in pediatric urologic oncology.
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http://dx.doi.org/10.1016/j.urolonc.2012.08.002DOI Listing
February 2014

A robotic-assisted laparoscopic approach for pediatric renal cell carcinoma allows for both nephron-sparing surgery and extended lymph node dissection.

J Pediatr Surg 2012 Oct;47(10):1946-50

Division of Pediatric Urology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Partial nephrectomy has been previously reported as safe and effective in appropriately selected children with renal cell carcinoma (RCC). However, there are limited reports of laparoscopic or robotic partial nephrectomy for oncologic surgery in children. Additionally, nodal involvement is common in pediatric RCC, and may present even with small primary tumors. Also, it is suggested that lymph node dissection may provide therapeutic benefit. We present a case of pediatric RCC and demonstrate how the risk of nodal involvement may impact the surgical approach. Robotic-assisted laparoscopy can permit excellent exposure for an oncologically-sound resection, in this case a partial nephrectomy, as well as an extended lymph node dissection.
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http://dx.doi.org/10.1016/j.jpedsurg.2012.08.017DOI Listing
October 2012

Phase I trial and pharmacokinetic study of lexatumumab in pediatric patients with solid tumors.

J Clin Oncol 2012 Nov 15;30(33):4141-7. Epub 2012 Oct 15.

National Cancer Institute, National Institutes of Health, 10 Center Dr, Building 10 CRC, Room 1W-3750, Bethesda, MD 20892-1104, USA.

Purpose: Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors.

Patients And Methods: This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age≤21 years with recurrent or progressive solid tumors.

Results: Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response.

Conclusion: Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects.
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http://dx.doi.org/10.1200/JCO.2012.44.1055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494837PMC
November 2012

Clinical heterogeneity of desmoplastic infantile ganglioglioma: a case series and literature review.

J Pediatr Hematol Oncol 2012 Aug;34(6):e232-6

Cancer and Blood Diseases Institute, Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati OH 45229-3039, USA.

Desmoplastic infantile gangliogliomas (DIG) are intracranial tumors described in 1987 as benign lesions of infancy. A literature review and the clinical course of 3 patients reported herein suggest that the initial description should be amended. Nearly 23% of DIG cases occur in children older than 24 months. Approximately 40% of DIG cases require additional medical, radiation, and/or further surgical intervention, and 15% of infants and children develop leptomeningeal spread or die from DIG. Such adverse outcomes, combined with the recognition that DIG represents a heterogeneous disease, underscore the need for an expanded biological and molecular investigation.
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http://dx.doi.org/10.1097/MPH.0b013e3182580330DOI Listing
August 2012

Hepatoblastoma imaging with gadoxetate disodium-enhanced MRI--typical, atypical, pre- and post-treatment evaluation.

Pediatr Radiol 2012 Jul 15;42(7):859-66. Epub 2012 Mar 15.

Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.

Gadoxetate disodium (Gd-EOB-DTPA) is a hepatobiliary MRI contrast agent widely used in adults for characterization of liver tumors and increasingly used in children. Hepatoblastoma is the most common primary hepatic malignancy of childhood. In this review, we describe our experience with this agent both before and after initiating therapy in children with hepatoblastoma.
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http://dx.doi.org/10.1007/s00247-012-2366-6DOI Listing
July 2012

Characterization of pediatric liver lesions with gadoxetate disodium.

Pediatr Radiol 2011 Sep 24;41(9):1183-97. Epub 2011 Jun 24.

Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnett Ave., Cincinnati, OH 45229-3039, USA.

Gadoxetate disodium (Gd-EOB-DTPA) is a relatively new hepatobiliary MRI contrast agent. It is increasingly used in adults to characterize hepatic masses, but there is little published describing its use in children. The purpose of this paper is to describe our pediatric MRI protocol as well as the imaging appearance of pediatric liver lesions using gadoxetate disodium. As a hepatocyte-specific MRI contrast agent, Gd-EOB-DTPA has the potential to improve characterization and provide a more specific diagnosis of pediatric liver masses.
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http://dx.doi.org/10.1007/s00247-011-2148-6DOI Listing
September 2011

Sirolimus therapy for fibromatosis and multifocal renal cell carcinoma in a child with tuberous sclerosis complex.

Pediatr Blood Cancer 2010 Jul;54(7):1035-7

Division of Hematology-Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

A male with tuberous sclerosis complex (TSC) developed a chest wall fibromatosis and bilateral multifocal renal cell carcinoma (RCC). The fibromatosis tumor was initially resected during infancy but recurred 5 years later. At that time, bilateral RCC was also detected, leading to the resection of the more extensively affected right kidney. In an attempt to avoid bilateral nephrectomies, the patient was treated with the mTOR inhibitor sirolimus. Within 6 months of therapy, the fibromatosis and remaining RCC tumors responded substantially with minimal adverse effects.
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http://dx.doi.org/10.1002/pbc.22401DOI Listing
July 2010

Adenovirus gene therapy for pediatric cancers: shall we gather at the liver?

Pediatr Blood Cancer 2009 Aug;53(2):133-5

Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.

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http://dx.doi.org/10.1002/pbc.22033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858055PMC
August 2009

Phase I study of paclitaxel with standard dose ifosfamide in children with refractory solid tumors: a Pediatric Oncology Group study (POG 9376).

Pediatr Blood Cancer 2009 Mar;52(3):346-50

Department of Hematology-Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229-3039, USA.

Purpose: A dose-escalation Phase I study of taxol (paclitaxel) administered in combination with standard dose ifosfamide was conducted in children with relapsed or refractory solid tumors. Primary objectives were to estimate the maximum tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs).

Patients And Methods: Paclitaxel was administered as a 6-hr continuous infusion (hr 0-6), followed by intravenous ifosfamide (2 g/m(2)/day x 3 days) over 1 hr at hours 6-7, 24-25, and 48-49. Patients at dose level 1 received 250 mg/m(2) paclitaxel. Subsequent dose escalation proceeded using a standard 3 x 3 Phase I design.

Results: Fifteen patients received a combined 46 courses of therapy. The median age was 14.5 years (range, 2-19 years), and diagnoses included sarcoma (7), neuroblastoma (3), and other (5). Three patients received paclitaxel at 250 mg/m(2) (10 courses), six at 325 mg/m(2) (19 courses), three at 425 mg/m(2) (8 courses), and three at 550 mg/m(2) (9 courses). DLTs occurred in 2/3 patients at 550 mg/m(2) paclitaxel during cycle 1, including grade 3 hypotension and grade 4 anaphylaxis in 1 patient each. Common non-dose-limiting toxicities included bone marrow suppression and peripheral neuropathy. Response was evaluable in 14 patients and included mixed response (3), stable disease (5), and progressive disease (6).

Conclusion: Paclitaxel hypersensitivity reactions were dose limiting when the drug was administered as a 6-hr infusion. The MTD and recommended Phase II dose of paclitaxel administered as a 6-hr continuous intravenous infusion followed by standard dose intravenous ifosfamide is 425 mg/m(2) paclitaxel.
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http://dx.doi.org/10.1002/pbc.21820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744894PMC
March 2009

Translocation renal cell carcinoma: lack of negative impact due to lymph node spread.

Cancer 2008 Apr;112(7):1607-16

Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229-3039, USA.

Background: Pediatric renal cell carcinoma (RCC) is clinically distinct from adult RCC. Characterization of the unique biological and clinical features of pediatric RCC are required.

Methods: A retrospective review and biological analysis of all RCC cases presenting to Cincinnati Children's Hospital Medical Center (CCHMC) in the last 30 years was undertaken. Cases were classified according to the recent World Heath Organization morphologic classification and according to TFE3/TFEB status. A literature review of pediatric TFE+ cases was performed.

Results: Eleven cases of RCC with clinical data were identified in our institutional review as follows: 6 clear cell, 2 papillary, 2 translocation, and 1 sarcomatoid. Upon reanalysis, 1 papillary and 1 sarcomatoid were confirmed, 1 case was "unclassified", and 8 of 11 (72.7%) had features consistent with translocation morphology. Of these 8, all demonstrated immunoreactivity for TFE3 (7 patients) or TFEB (1 patient) protein. In 3 cases, cytogenetics was available, each demonstrating confirmatory MiTF/TFE translocations. Seven of 8 TFE+ RCC patients presented with TNM Stage III/IV disease. Literature analysis confirmed a significant increase in advanced stage presentation in pediatric TFE+ RCC compared with TFE- RCC. Fourteen of fifteen (93.3%) patients with TFE+ stage III/IV RCC due to lymph node spread (N+ M(0)) remain disease free with a median and mean follow-up of 4.4 and 6.3 years, respectively (range, 0.3-15.5).

Conclusions: Translocation morphology RCC is the predominant form of pediatric RCC, associated with an advanced stage at presentation. Patients with TFE+ N+ M(0) RCC maintain a favorable short-term prognosis after surgery alone. Young RCC patients should be screened for translocation morphology, and the screening information should be considered when debating adjuvant therapy.
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http://dx.doi.org/10.1002/cncr.23331DOI Listing
April 2008

Local lymph node involvement does not predict poor outcome in pediatric renal cell carcinoma.

Cancer 2004 Oct;101(7):1575-83

Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Background: Local lymph node involvement in adults with renal cell carcinoma (RCC) is associated with poor outcome. The prognostic significance of local lymph node involvement in children with RCC has not been studied systematically.

Methods: A retrospective review of patients treated at St Jude Children's Research Hospital (Memphis, TN) and an extensive review of the medical literature were undertaken to evaluate the prognostic significance of local lymph node involvement in pediatric RCC.

Results: Thirteen patients with the diagnosis of RCC were treated at St. Jude since the hospital's inception in 1962. Four patients presented with lymph node-positive, distant metastasis-negative (N + M0) disease, and all 4 remain disease free after resection without adjuvant therapy (follow-up duration, 2-9 years). A systematic review of the literature including 243 pediatric patients with RCC revealed stage-specific survival rates of 92.5%, 84.6%, 72.7%, and 12.7% for Stage I-IV disease, respectively. Of 58 children with N + M0 RCC for whom outcome data were available, 42 (72.4%) were alive without disease at last follow-up. Among patients whose therapy could be discerned, those who received no adjuvant therapy fared as well (15 of 16 alive) as those who received various adjuvant treatments (22 of 31 alive).

Conclusions: Children with lymph node-positive RCC in the absence of distant metastatic disease had a relatively favorable long-term prognosis, with survival rate nearly triple those of adult historical controls. Until highly effective therapies for RCC are identified, these children should not be exposed to adjuvant treatment. Further investigation of the biologic differences between adult and pediatric RCC is warranted.
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http://dx.doi.org/10.1002/cncr.20548DOI Listing
October 2004

P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase inhibitors in colorectal carcinoma cells.

Cancer Res 2004 Sep;64(17):6296-303

Division of Molecular Therapeutics, Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

We have demonstrated previously that interferon (IFN)-gamma sensitizes human colon carcinoma cell lines to the cytotoxic effects of 5-fluorouracil combined with leucovorin and to the thymidylate synthase inhibitor, ZD9331, dependent on thymineless stress-induced DNA damage, independent of p53. Here we demonstrate that the cyclin-dependent kinase (CDK) inhibitor p21(Cip1) regulates thymineless stress-induced cytotoxicity in these cells. HCT116 wild-type (wt) and p53-/- cells underwent apoptosis and loss in clonogenic survival when exposed to ZD9331, whereas p21Cip1-/- cells were resistant. In contrast, IFN-gamma induced marked cytotoxicity in p21Cip1-/- cells only. ZD9331 induced p21Cip1 up-regulation in all of the cell lines examined, as did thymidine deprivation in thymidylate synthase-deficient (thymidylate synthase-) cells. Furthermore, selective induction of p21Cip1 in RKO was sufficient to induce apoptosis. P21Cip1, cdk1, cdk2, and cyclin E mRNA expression increased coincident with S-phase accumulation in HT29 cells treated with ZD9331 or 5fluorouracil/leucovorin, as demonstrated by cDNA microarray analyses. Cell cycle analyses revealed that HCT116 wt and p21Cip1 -/- cells accumulated in S phase within 24 h of ZD9331 exposure; however, wt cells exited S-phase more rapidly, where apoptosis occurred before mitosis, either in late S or G2. Finally, the CDK inhibitor roscovitine potentiated the cytotoxic activity of ZD9331 in both wt and p21Cip1-/- cells, strongly suggesting a role for p21Cip1-dependent CDK inhibition in cytotoxicity induced by thymidylate synthase inhibition. In summary, p21Cip1 positively regulates the cytotoxic action of thymidylate synthase inhibitors, negatively regulates the cytotoxic action of IFN-gamma, and enhances S-phase exit after thymineless stress, possibly via interaction with CDK-cyclin complexes.
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http://dx.doi.org/10.1158/0008-5472.CAN-04-0863DOI Listing
September 2004

Tumor rupture and mitotic index in pediatric sex cord-stromal tumors.

J Clin Oncol 2004 May;22(10):2032-3; author reply 2033-5

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http://dx.doi.org/10.1200/JCO.2004.99.281DOI Listing
May 2004
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