Publications by authors named "James I Geller"

89 Publications

Comparison of 0.3-mSv CT to Standard-Dose CT for Detection of Lung Nodules in Children and Young Adults With Cancer.

AJR Am J Roentgenol 2021 Jul 7. Epub 2021 Jul 7.

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

CT is the imaging modality of choice to identify lung metastasis. The purpose of this study was to evaluate the performance of reduced-dose CT for detection of lung nodules in children and young adults with cancer. This prospective study enrolled patients 4-21 years old with known or suspected malignancy who were undergoing clinically indicated chest CT. Study participants underwent an additional investigational reduced-dose chest CT in the same imaging encounter. Separated deidentified CT examinations were reviewed in blinded fashion by three independent radiologists. One reviewer performed a subsequent secondary review to match nodules between the standard- and reduced-dose examinations. Diagnostic performance was computed for the reduced-dose examinations, using clinical examinations as reference standard. Intraobserver and interobserver agreement were calculated using Cohen's Kappa. A total of 78 patients (44 male, 34 female; mean age 15.2±3.8 years) were enrolled. Mean estimated effective dose was 1.8±1.1 mSv for clinical CT and 0.3±0.1 mSv for reduced-dose CT, an 83% reduction. Forty-five (58%) patients had 162 total lung nodules (mean size 3.4±3.3 mm) detected on the clinical CT examinations. A total of 92% of nodules were visible on reduced-dose CT. Sensitivity and specificity of reduced-dose CT for nodules ranged from 63%-77% and 80%-90% respectively across the three reviewers. Intraobserver agreement between clinical and reduced-dose CT was moderate to substantial for presence of nodules (κ=0.45-0.67), and good to excellent for number of nodules (κ=0.68-0.84) and nodule size (κ=0.69-0.86). Interobserver agreement for the presence of nodules was moderate for both reduced-dose (κ=0.53) and clinical (κ=0.54) CT. A median of 1 nodule was present on clinical CT in patients with a falsely negative reduced-dose CT examination. Reduced-dose CT depicts greater than 90% of lung nodules in children and young adults with cancer. Reviewers identified the presence of nodules with moderate sensitivity and high specificity. CT performed at 0.3 mSv mean effective dose has acceptable diagnostic performance for lung nodule detection in children and young adults and has the potential to reduce patient dose or expand CT utilization (e.g., to replace radiography in screening or monitoring protocols).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2214/AJR.21.26183DOI Listing
July 2021

Prognostic Factors for Wilms Tumor Recurrence: A Review of the Literature.

Cancers (Basel) 2021 Jun 23;13(13). Epub 2021 Jun 23.

Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.

In high-income countries, the overall survival of children with Wilms tumors (WT) is ~90%. However, overall, 15% of patients experience tumor recurrence. The adverse prognostic factors currently used for risk stratification (advanced stage, high risk histology, and combined loss of heterozygosity at 1p and 16q in chemotherapy-naïve WTs) are present in only one third of these cases, and the significance of these factors is prone to change with advancing knowledge and improved treatment regimens. Therefore, we present a comprehensive, updated overview of the published prognostic variables for WT recurrence, ranging from patient-, tumor- and treatment-related characteristics to geographic and socioeconomic factors. Improved first-line treatment regimens based on clinicopathological characteristics and advancing knowledge on copy number variations unveil the importance of further investigating the significance of biological markers for WT recurrence in international collaborations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13133142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268923PMC
June 2021

Indocyanine green is a sensitive adjunct in the identification and surgical management of local and metastatic hepatoblastoma.

Cancer Med 2021 Jul 12;10(13):4322-4343. Epub 2021 Jun 12.

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

Background: Hepatoblastoma is the most common primary pediatric liver malignancy. Indocyanine green (ICG) has been described as an adjunct to resection in small series. Its utility remains undefined in larger cohorts.

Methods: Records for 29 patients diagnosed with hepatoblastoma who received ICG prior to surgical resection from 2017 to 2020 at a single institution were retrospectively reviewed. The primary outcome was correlation between intraoperative ICG-avidity and histologic presence of hepatoblastoma. A secondary outcome included the histologic margin designation for resected liver specimens.

Results: ICG sensitivity was 91% for 120 resected thoracic specimens from 21 patients. Specificity was 57%. In 10% of operations, HB-positive specimens were resected solely on ICG-avidity. In an additional 40% of cases, ICG assisted in localizing a preoperatively diagnosed lesion. ICG sensitivity during thoracotomy and thoracoscopic surgery was 95 and 74%, respectively; primary and relapsed disease demonstrated sensitivity of 94 and 73%, respectively. Sensitivity was 92% for 25 resected liver specimens from nine patients with all parenchymal margins grossly negative for disease. Four multifocal lesions were identified with two resected solely by ICG-avidity.

Conclusions: ICG is a sensitive adjunct for identifying local and metastatic hepatoblastoma, including lesions not visualized on preoperative imaging, and delineating margins during liver resection. False positives limit specificity; however, there were no adverse outcomes from additional resections. We noted that thoracoscopic surgery can be completed safely in patients with less significant disease burden, and conversion to thoracotomy, if necessary, is straightforward.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267136PMC
July 2021

Unmet needs for relapsed or refractory Wilms tumour: Mapping the molecular features, exploring organoids and designing early phase trials - A collaborative SIOP-RTSG, COG and ITCC session at the first SIOPE meeting.

Eur J Cancer 2021 Feb 18;144:113-122. Epub 2020 Dec 18.

Department of Medical Oncology and Hematology, Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.

Wilms tumour (WT) accounts for about 6% of all childhood cancers and overall survival of WT is about 90% in international protocols. However, for WT subgroups with much poorer prognoses, i.e. typically high-risk (unfavorable) histology and/or relapse, there is an unmet need to better understand the biology of WT and to translate biological findings into clinics through early phase clinical trials that evaluate innovative therapies. The main challenges are the small numbers of children suitable for early phase trials, the genetic heterogeneity of WT and the low number of somatic mutations that are currently considered 'druggable'. Accordingly, a joint meeting between clinical and biology experts from the international cooperative groups of the Renal Tumour Study Group of the International Society of Paediatric Oncology, the Renal Tumour Committee of the Children's Oncology Group and the European Innovative Therapies for Children with Cancer consortium and parents representatives was organised during the first SIOPE meeting in Prague, 2019. We reviewed WT molecular features, ongoing/planned early phase trials and explored available knowledge on organoid technology. The key messages were: (1) relapsed WT should undergo whenever possible thorough molecular characterization and be enrolled in protocols or trials with systematic data collecting and reporting; (2) WT displays few known 'actionable' targets and currently no novel agent has appeared promising; (3) we need to improve the enrolment rate of WT candidates in early phase trials especially for the relatively small subgroup of relapses with an adverse prognostic signature; (4) despite some agnostic early phase trials existing, development of WT-focused trials are warranted; (5) growing organoids with parallel testing of drug panels seems feasible and may direct individual treatment and encourage clinical researchers to incorporate the most promising agents into early phase trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.11.012DOI Listing
February 2021

A prospective study of pediatric and adolescent renal cell carcinoma: A report from the Children's Oncology Group AREN0321 study.

Cancer 2020 12 14;126(23):5156-5164. Epub 2020 Sep 14.

Division of Pediatric Oncology, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC.

Background: To the authors' knowledge, AREN0321 is the first prospective clinical study of pediatric and adolescent renal cell carcinoma (RCC). Goals of the study included establishing epidemiological, treatment, and outcome data and confirming that patients with completely resected pediatric RCC, including lymph node-positive disease (N1), have a favorable prognosis without adjuvant therapy.

Methods: From 2006 to 2012, patients aged <30 years with centrally reviewed pathology of RCC were enrolled prospectively.

Results: A total of 68 patients were enrolled (39 of whom were male; median age of 13 years [range, 0.17-22.1 years]). Stage was classified according to the American Joint Committee on Cancer TNM stage seventh edition as stage I in 26 patients, stage II in 7 patients, stage III in 26 patients, and stage IV in 8 patients, and was not available in 1 patient. Sixty patients underwent resection of all known sites of disease, including 2 patients with stage IV disease. Surgery included radical nephrectomy (53 patients [81.5%]), partial nephrectomy (12 patients [18.5%]), and unknown (3 patients [4.4%]). Histology was TFE-associated RCC (translocation-type RCC; tRCC) in 40 patients, RCC not otherwise specified and/or other in 13 patients, papillary RCC in 9 patients, and renal medullary carcinoma (RMC) in 6 patients. Lymph node status was N0 in 21 patients, N1 in 21 patients (tRCC in 15 patients, RMC in 3 patients, papillary RCC in 2 patients, and not otherwise specified and/or other in 1 patient), and Nx in 26 patients. The 4-year event-free survival and overall survival rates were 80.2% (95% CI, 69.6%-90.9%) and 84.8% (95% CI, 75.2%-94.5%), respectively, overall and 87.5% (95% CI, 68.3%-100%) and 87.1% (95% CI, 67.6%-100%), respectively, for the 16 patients with N1M0 disease. Among patients presenting with metastases, 2 of 8 patients (2 of 5 patients with RMC) were alive (1 with disease) at the time of last follow-up, including 1 patient who was lost to follow-up (succinate dehydrogenase deficiency). The predominant RCC subtypes associated with mortality were tRCC and RMC.

Conclusions: Favorable short-term outcomes can be achieved without adjuvant therapy in children and adolescents with completely resected RCC, independent of lymph node status. A prospective study of patients with tRCC and RMC with M1 or recurrent disease is needed to optimize treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717658PMC
December 2020

ADVL1522: A phase 2 study of lorvotuzumab mertansine (IMGN901) in children with relapsed or refractory wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor, or synovial sarcoma-A Children's Oncology Group study.

Cancer 2020 12 11;126(24):5303-5310. Epub 2020 Sep 11.

University of Minnesota Medical Center, Minneapolis, Minnesota.

Background: Lorvotuzumab mertansine (IMGN901) is an antibody-drug conjugate linking an antimitotic agent (DM1) to an anti-CD56 antibody (lorvotuzumab). Preclinical efficacy has been noted in Wilms tumor, rhabdomyosarcoma, and neuroblastoma. Synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST), and pleuropulmonary blastoma also express CD56. A phase 2 trial of lorvotuzumab mertansine was conducted to assess its efficacy, recommended phase 2 dose, and toxicities.

Methods: Eligible patients had relapsed after or progressed on standard therapy for their tumor type. Lorvotuzumab mertansine (110 mg/m per dose) was administered at the adult recommended phase 2 dose intravenously on days 1 and 8 of 21-day cycles. Dexamethasone premedication was used. Pharmacokinetic samples, peripheral blood CD56-positive cell counts, and tumor CD56 expression were assessed.

Results: Sixty-two patients enrolled. The median age was 14.3 years (range, 2.8-29.9 years); 35 were male. Diagnoses included Wilms tumor (n = 17), rhabdomyosarcoma (n = 17), neuroblastoma (n = 12), synovial sarcoma (n = 10), MPNST (n = 5), and pleuropulmonary blastoma (n = 1). Five patients experienced 9 dose-limiting toxicities: hyperglycemia (n = 1), colonic fistula (n = 1) with perforation (n = 1), nausea (n = 1) with vomiting (n = 1), increased alanine aminotransferase in cycle 1 (n = 2), and increased alanine aminotransferase in cycle 2 (n = 1) with increased aspartate aminotransferase (n = 1). Non-dose-limiting toxicities (grade 3 or higher) attributed to lorvotuzumab mertansine were rare. The median values of the maximum concentration, half-life, and area under the curve from zero to infinity for DM1 were 0.87 µg/mL, 35 hours, and 27.9 µg/mL h, respectively. Peripheral blood CD56+ leukocytes decreased by 71.9% on day 8. One patient with rhabdomyosarcoma had a partial response, and 1 patient with synovial sarcoma achieved a delayed complete response.

Conclusions: Lorvotuzumab mertansine (110 mg/m ) is tolerated in children at the adult recommended phase 2 dose; clinical activity is limited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732143PMC
December 2020

Characteristics and Outcome of Children with Renal Cell Carcinoma: A Narrative Review.

Cancers (Basel) 2020 Jul 3;12(7). Epub 2020 Jul 3.

Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.

Pediatric renal cell carcinoma (RCC) is a rare type of kidney cancer, most commonly occurring in teenagers and young adolescents. Few relatively large series of pediatric RCC have been reported. Knowledge of clinical characteristics, outcome and treatment strategies are often based on the more frequently occurring adult types of RCC. However, published pediatric data suggest that clinical, molecular and histological characteristics of pediatric RCC differ from adult RCC. This paper summarizes reported series consisting of ≥10 RCC pediatric patients in order to create an up-to-date overview of the clinical and histopathological characteristics, treatment and outcome of pediatric RCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12071776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407101PMC
July 2020

Results of Treatment for Patients With Multicentric or Bilaterally Predisposed Unilateral Wilms Tumor (AREN0534): A report from the Children's Oncology Group.

Cancer 2020 08 27;126(15):3516-3525. Epub 2020 May 27.

Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.

Background: A primary objective of Children's Oncology Group study AREN0534 (Treatment for Patients With Multicentric or Bilaterally Predisposed, Unilateral Wilms Tumor) was to facilitate partial nephrectomy in 25% of children with bilaterally predisposed unilateral tumors (Wilms tumor/aniridia/genitourinary anomalies/range of developmental delays [WAGR] syndrome; and multifocal and overgrowth syndromes). The purpose of this prospective study was to achieve excellent event-free survival (EFS) and overall survival (OS) while preserving renal tissue through preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response.

Methods: The treating institution identified whether a predisposition syndrome existed. Patients underwent a central review of imaging studies through the biology and classification study AREN03B2 and then were eligible to enroll on AREN0534. Patients were treated with induction chemotherapy determined by localized or metastatic disease on imaging (and histology if a biopsy had been undertaken). Surgery was based on radiographic response at 6 or 12 weeks. Further chemotherapy was determined by histology. Patients who had stage III or IV disease with favorable histology received radiotherapy as well as those who had stage I through IV anaplasia.

Results: In total, 34 patients were evaluable, including 13 males and 21 females with a mean age at diagnosis of 2.79 years (range, 0.49-8.78 years). The median follow-up was 4.49 years (range, 1.67-8.01 years). The underlying diagnosis included Beckwith-Wiedemann syndrome in 9 patients, hemihypertrophy in 9 patients, multicentric tumors in 10 patients, WAGR syndrome in 2 patients, a solitary kidney in 2 patients, Denys-Drash syndrome in 1 patient, and Simpson-Golabi-Behmel syndrome in 1 patient. The 4-year EFS and OS rates were 94% (95% CI, 85.2%-100%) and 100%, respectively. Two patients relapsed (1 tumor bed, 1 abdomen), and none had disease progression during induction. According to Response Evaluation Criteria in Solid Tumor 1.1 criteria, radiographic responses included a complete response in 2 patients, a partial response in 21 patients, stable disease in 11 patients, and progressive disease in 0 patients. Posttherapy histologic classification was low-risk in 13 patients (including the 2 complete responders), intermediate-risk in 15 patients, and high-risk in 6 patients (1 focal anaplasia and 5 blastemal subtype). Prenephrectomy chemotherapy facilitated renal preservation in 22 of 34 patients (65%).

Conclusions: A standardized approach of preoperative chemotherapy, surgical resection within 12 weeks, and histology-based postoperative chemotherapy results in excellent EFS, OS, and preservation of renal parenchyma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769115PMC
August 2020

Clinical heterogeneity of pediatric hepatocellular carcinoma.

Pediatr Blood Cancer 2020 06 19;67(6):e28307. Epub 2020 Apr 19.

Division of Pediatric Hematology/Oncology, University of Illinois College of Medicine at Peoria, Peoria, Illinois.

Background: Hepatocellular carcinoma (HCC) is often a chemoresistant neoplasm with a poor prognosis. Pediatric HCC may reflect unique biological and clinical heterogeneity.

Procedure: An IRB-approved retrospective institutional review of patients with HCC treated between 2004 and 2015 was undertaken. Clinical, radiographic, and histologic data were collected from all patients.

Results: Thirty-two patients with HCC, median age 11.5 years (range 1-20) were identified. Seventeen patients had a genetic or anatomic predisposition. Histology was conventional HCC (25) and fibrolamellar HCC (7). Evans staging was 1 (12); 2 (1); 3 (10); 4 (9). Sixteen patients underwent resection at diagnosis and five patients after neoadjuvant chemotherapy. Surgical procedures included liver transplantation (LT, 11), hemihepatectomy (9), and segmentectomy (1). Eighteen patients had medical therapy (13 neoadjuvant, 5 adjuvant). Most common initial medical therapy included sorafenib alone (7) and cisplatin/doxorubicin-based therapy (8). Overall, 14 (43.8%) patients survived with a median follow-up of 58.8 months (range 26.5-157.6). Cause of death was most often linked to lack of primary tumor surgery (11). Of the survivors, Evans stage was 1 (11), 2 (1), and 3 (2, both treated with LT). Four of 18 patients (22%) who received medical therapy, 8 of 17 patients with a predisposition (47%), and 14 of 21 patients (66%) who underwent surgery remain alive.

Conclusions: Genetic and anatomic predisposing conditions were seen in over half of this cohort. Evans stage 1 or 2 disease was linked to improved survival. LT trended toward improved survival. Use of known chemotherapy agents may benefit a smaller group of pediatric HCC and warrants formal prospective study through cooperative group trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28307DOI Listing
June 2020

Outcome analysis of stage I epithelial-predominant favorable-histology Wilms tumors: A report from Children's Oncology Group study AREN03B2.

Cancer 2020 06 8;126(12):2866-2871. Epub 2020 Apr 8.

Department of Pathology and Laboratory Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Stage I epithelial-predominant favorable-histology Wilms tumors (EFHWTs) have long been suspected to have an excellent outcome. This study investigates the clinical and pathologic features of patients with stage I EFHWTs to better evaluate the potential for a reduction of chemotherapy and its associated toxicity.

Methods: All patients registered in the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 with stage I EFHWTs were identified. EFHWTs were defined as tumors with at least 66% epithelial differentiation, regardless of the degree of differentiation. Clinical information was abstracted from COG records. Event-free survival (EFS) and overall survival (OS) were calculated and compared between groups based on age and therapy.

Results: The 4-year EFS rate was 96.2% (95% confidence interval, 92%-100%), and the OS rate was 100%; EFS and OS did not statistically significantly differ with the age at diagnosis (<48 vs ≥48 months; P = .37) or treatment (EE4A vs observation only; P = .55). Six events were reported. Three patients developed contralateral tumors and did not otherwise relapse; none of these had nephrogenic rests or a recognized predisposition syndrome. Three patients developed metastatic recurrence; all 3 had received EE4A as their primary therapy after nephrectomy.

Conclusions: These findings demonstrate an excellent outcome for stage I EFHWTs with >95% EFS and OS. These data support the utility of investigating the treatment of stage I EFHWTs with observation alone after nephrectomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717680PMC
June 2020

Imaging Characteristics of Nephrogenic Rests Versus Small Wilms Tumors: A Report From the Children's Oncology Group Study AREN03B2.

AJR Am J Roentgenol 2020 05 11;214(5):987-994. Epub 2020 Mar 11.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S Kingshighway, Campus Box 8131, St. Louis, MO 63110.

Distinguishing nephrogenic rests from small Wilms tumors can be challenging. This retrospective study was performed to determine if imaging characteristics can be used to distinguish nephrogenic rests from Wilms tumors. All cases of pathologically confirmed nephrogenic rests and Wilms tumors smaller than 5 cm in maximum dimension on imaging in patients younger than 5 years old were identified from the Children's Oncology Group AREN03B2 study (July 2006-August 2016). Exclusion criteria were chemotherapy before pathologic evaluation or more than 30 days between imaging and surgery; in addition, patients with nephrogenic rests occurring within or juxtaposed to a Wilms tumor and patients with diffuse hyperplastic perilobar nephroblastomatosis were excluded. Two radiologists who were blinded to pathology results assessed all lesions. The two-sample test was used for continuous variables, and the Fisher exact test was used for categoric variables. ROC analysis was performed to determine the optimal size cutoff for distinguishing between nephrogenic rests and Wilms tumors. Thirty-one pathologically confirmed rests (20 perilobar, 11 intralobar) and 26 Wilms tumors smaller than 5 cm met the eligibility criteria for study inclusion. The median diameter of the nephrogenic rests was 1.3 cm (range, 0.7-3.4 cm) and the median diameter of the Wilms tumor was 3.2 cm (range, 1.8-4.9 cm) ( < 0.001). Imaging findings supportive of Wilms tumors were spherical ( < 0.001) and exophytic ( < 0.001) lesions. Perilobar rests (17/20) were more likely to be homogeneous than intralobar rests (3/11) or Wilms tumor (3/26) ( < 0.001). ROC analysis showed that the optimal size cutoff for distinguishing between nephrogenic rests and Wilms tumors was 1.75 cm. In children younger than 5 years old, the diagnosis of a Wilms tumor should be favored over a nephrogenic rest when a renal mass is spherical, exophytic, or larger than 1.75 cm. Homogeneity favors the diagnosis of perilobar nephrogenic rests, whereas intralobar rests and Wilms tumors are more likely to be inhomogeneous.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2214/AJR.19.22301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756929PMC
May 2020

Activity of Vincristine and Irinotecan in Diffuse Anaplastic Wilms Tumor and Therapy Outcomes of Stage II to IV Disease: Results of the Children's Oncology Group AREN0321 Study.

J Clin Oncol 2020 05 5;38(14):1558-1568. Epub 2020 Mar 5.

Division of Oncology, Children's National Medical Center, Center for Cancer and Blood Disorders, George Washington University School of Medicine and Health Sciences, Washington, DC.

Purpose: AREN0321 evaluated the activity of vincristine and irinotecan (VI) in patients with newly diagnosed diffuse anaplastic Wilms tumor (DAWT) and whether a regimen containing carboplatin (regimen UH1) in addition to regimen I agents used in the National Wilms Tumor Study 5 (NWTS-5; vincristine, doxorubicin, cyclophosphamide, and etoposide plus radiotherapy) would improve patient outcomes.

Patients And Methods: Patients with stage II to IV DAWT without measurable disease received regimen UH1. Patients with stage IV measurable disease were eligible to receive VI (vincristine, 1.5 mg/m per day intravenously on days 1 and 8; irinotecan, 20 mg/m per day intravenously on days 1-5 and 8-12 of a 21-day cycle) in an upfront window; those with complete (CR) or partial response (PR) had VI incorporated into regimen UH1 (regimen UH2). The study was designed to detect improvement in outcomes of patients with stage II to IV DAWT compared with historical controls treated with regimen I.

Results: Sixty-six eligible patients were enrolled. Of 14 patients with stage IV measurable disease who received VI, 11 (79%) achieved CR (n = 1) or PR (n = 10) after 2 cycles. Doses of doxorubicin, cyclophosphamide, and etoposide were reduced midstudy because of nonhematologic toxicity. Four patients (6%) died as a result of toxicity. Four-year event-free survival, relapse-free survival, and overall survival rates were 67.7% (95% CI, 55.9% to 79.4%), 72.9% (95% CI, 61.5% to 84.4%), and 73.7% (95% CI, 62.7% to 84.8%), respectively, compared with 57.5% (95% CI, 47.6% to 67.4%; = .26), 57.5% (95% CI, 47.6% to 67.4%; = .048), and 59.2% (95% CI, 49.4% to 69.0%; = .08), respectively, in NWTS-5.

Conclusion: VI produced a high response rate in patients with metastatic DAWT. AREN0321 treatment seemed to improve outcomes for patients with stage II to IV DAWT compared with NWTS-5, but with increased toxicity. The UH2 regimen warrants further investigation with modifications to reduce toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.01265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213587PMC
May 2020

Aggressive pediatric renal tumors.

Semin Pediatr Surg 2019 12 16;28(6):150860. Epub 2019 Nov 16.

Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, United States.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sempedsurg.2019.150860DOI Listing
December 2019

Genetic predisposition to cancer: Surveillance and intervention.

Semin Pediatr Surg 2019 Dec 20;28(6):150858. Epub 2019 Nov 20.

Department of Pediatrics, Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, United States. Electronic address:

Cancer is one of the leading causes of early mortality for children and adolescents. Identifiable genetic cancer predisposition conditions account for a growing proportion of pediatric and adolescent cancer, likely due to increasing knowledge about various predisposition conditions, more widespread cancer genetic counseling, and available diagnostics. Greater awareness, data-driven surgical intervention and clinical surveillance can help facilitate cancer prevention and early detection at cancer stages more amenable to cure. An extensive literature review of published studies and expert opinion with consensus guidelines are reviewed. Specific syndromes where genetics, imaging and surgical intervention are utilized to benefit affected patients and families are presented. In many tumor predisposition syndromes, the underlying genetic diagnosis is made concurrently, or after, malignancy is identified. Improved recognition of underlying predispositions, along with appropriate surgical interventions and imaging surveillance should lead to increased patient survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sempedsurg.2019.150858DOI Listing
December 2019

Novel therapy for pediatric and adolescent kidney cancer.

Cancer Metastasis Rev 2019 12;38(4):643-655

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Pediatric and adolescent renal tumors account for approximately 7% of all new cancer diagnoses in the USA each year. The prognosis and treatment are varied based on factors including the underlying histology and tumor stage, with survival rates ranging from greater than 90% in favorable histology Wilms tumor to almost universally fatal in other disease types, including those patients with advanced stage malignant rhabdoid tumor and renal medullary carcinoma. In recent years, our understanding of the underlying genetic drivers of the different types of pediatric kidney cancer has dramatically increased, opening the door to utilization of new targeted biologic agents alone or in combination with conventional chemotherapy to improve outcomes. Several ongoing clinical trials are investigating the use of a variety of targeted agents in pediatric patients with underlying genetic aberrations. In this manuscript, the underlying biology and early phase clinical trials relevant to pediatric renal cancers are reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10555-019-09822-4DOI Listing
December 2019

Volasertib preclinical activity in high-risk hepatoblastoma.

Oncotarget 2019 Nov 5;10(60):6403-6417. Epub 2019 Nov 5.

Children's Cancer Therapy Development Institute, Beaverton, OR, USA.

Relapsed and metastatic hepatoblastoma represents an unmet clinical need with limited chemotherapy treatment options. In a chemical screen, we identified volasertib as an agent with activity, inhibiting hepatoblastoma cell growth while sparing normal hepatocytes. Volasertib targets PLK1 and prevents the progression of mitosis, resulting in eventual cell death. PLK1 is overexpressed in hepatoblastoma biopsies relative to normal liver tissue. As a potential therapeutic strategy, we tested the combination of volasertib and the relapse-related hepatoblastoma chemotherapeutic irinotecan. We found both and efficacy of this combination, which may merit further preclinical investigation and exploration for a clinical trial concept.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849653PMC
November 2019

Augmentation of Therapy for Combined Loss of Heterozygosity 1p and 16q in Favorable Histology Wilms Tumor: A Children's Oncology Group AREN0532 and AREN0533 Study Report.

J Clin Oncol 2019 10 26;37(30):2769-2777. Epub 2019 Aug 26.

Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC.

Purpose: In National Wilms Tumor Study 5 (NWTS-5), tumor-specific combined loss of heterozygosity of chromosomes 1p and 16q (LOH1p/16q) was associated with adverse outcomes in patients with favorable histology Wilms tumor. The AREN0533/AREN0532 studies assessed whether augmenting therapy improved event-free survival (EFS) for these patients. Patients with stage I/II disease received regimen DD4A (vincristine, dactinomycin and doxorubicin) but no radiation therapy. Patients with stage III/IV disease received regimen M (vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide) and radiation therapy.

Methods: Patients were enrolled through the AREN03B2 Biology study between October 2006 and October 2013; all underwent central review of pathology, surgical reports, and imaging. Tumors were evaluated for LOH1p/16q by microsatellite testing. EFS and overall survival were compared using the log-rank test between NWTS-5 and current studies.

Results: LOH1p/16q was detected in 49 of 1,147 evaluable patients with stage I/II disease (4.27%) enrolled in AREN03B2; 32 enrolled in AREN0532. LOH1p/16q was detected in 82 of 1,364 evaluable patients with stage III/IV disease (6.01%) in AREN03B2; 51 enrolled in AREN0533. Median follow-up for 83 eligible patients enrolled in AREN0532/0533 was 5.73 years (range, 2.84 to 9.63 years). The 4-year EFS for patients with stage I/II and stage III/IV disease with LOH1p/16 was 87.3% (95% CI, 75.1% to 99.5%) and 90.2% (95% CI, 81.8% to 98.6%), respectively. These results are improved compared with the NWTS-5 updated 4-year EFS of 68.8% for patients with stage I/II disease ( = .042), and 61.3% for patients with stage III/IV disease ( = .001), with trends toward improved 4-year overall survival. The most common grade 3 or higher nonhematologic toxicities with regimen M were febrile neutropenia (39.2%) and infections (21.6%).

Conclusion: Augmentation of therapy improved EFS for patients with favorable histology Wilms tumor and LOH1p/16q compared with the historical NWTS-5 comparison group, with an expected toxicity profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.01972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001789PMC
October 2019

Treatment of stage I anaplastic Wilms' tumour: a report from the Children's Oncology Group AREN0321 study.

Eur J Cancer 2019 09 17;118:58-66. Epub 2019 Jul 17.

Division of Oncology, Children's National Medical Center, Center for Cancer and Blood Disorders, George Washington University School of Medicine and Health Sciences, 111 Michigan Avenue NW, Washington, DC 20010, USA. Electronic address:

Background: In the fifth National Wilms Tumor Study (NWTS-5), the 4-year event-free survival (EFS) and overall survival (OS) estimates for 29 patients with stage I focal (n = 10) or diffuse (n = 19) anaplastic Wilms' tumour (AWT) treated with vincristine and dactinomycin without flank radiation were 69.5% and 82.6%, respectively. The Children's Oncology Group AREN0321 study evaluated whether adding doxorubicin and flank radiation improves survival for these patients.

Patients And Methods: Tumour histology and stage were confirmed by real-time central pathology, surgery and radiology review. The patients received 25 weeks of vincristine, dactinomycin and doxorubicin (cumulative dose 150 mg/m) with flank radiation (1080 cGy). We retrospectively analysed outcomes of all patients with stage I AWT enrolled in NWTSs 1-5 and AREN0321 with respect to treatment regimens.

Results: Eighteen patients with stage I AWT (8 focal and 10 diffuse) were enrolled on AREN0321. With a median follow-up of 4.6 years, the 4-year EFS and OS were 100%. One patient with diffuse AWT had pulmonary relapse 4.12 years after diagnosis. In the 112 patients with stage I AWT treated in NWTSs 1-5 and AREN0321, the EFS was significantly improved with doxorubicin treatment (p = 0.01; 4-year EFS: 97.2% [95% confidence interval {CI}: 91.3-100] vs. 77.5% [95% CI: 67.6-87.4]) but not by flank radiation (p = 0.15).

Conclusions: Treatment of stage I AWT with vincristine, dactinomycin, doxorubicin and flank radiation in AREN0321 yielded excellent survival outcomes. Retrospective analysis of AREN0321 and NWTS patients suggests that doxorubicin had a greater contribution to the excellent outcomes than radiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2019.05.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690766PMC
September 2019

Differentiated Thyroid Cancer in the Pediatric/Adolescent Population: Evolution of Treatment.

J Pediatr Hematol Oncol 2019 10;41(7):532-536

Cancer and Blood Diseases Institute.

Differentiated thyroid cancer (DTC) is the most common cancer in adolescents and young adults. In 2015, the American Thyroid Association published guidelines for management of pediatric DTC. We report our institutional experience and highlight changing practices and new opportunities. A retrospective analysis of all patients diagnosed with DTC from 2001 to 2016 was performed. Among 59 eligible patients, 31 (53%), 15 (25%), and 13 (22%) had low-risk, intermediate-risk, and high-risk disease, respectively. Half (15/31) of low-risk and all intermediate-risk/high-risk patients received radioactive iodine (I-131) ablation. For low-risk patients, average I-131 dose decreased from 80 to 42.05 mCi, and the percentage of patients who received I-131 decreased over time. Eleven of 16 patients with tumor genomic data were found to have somatic targetable (n=6) or germline (n=5) mutations. Persistent/recurrent disease was only present in high-risk (n=8) and intermediate-risk (n=1) patients. Two patients with iodine-refractory disease received trametinib to enhance radioiodine uptake. All patients were alive at follow-up (median, 5 y; range, 1 to 15 y). Coincident with the recent American Thyroid Association guidelines, the use of I-131 in low-risk patients has decreased over time in our practice. Tumor sequencing and cancer genetic evaluation may help redefine opportunities for treatment of high-risk patients and family counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000001493DOI Listing
October 2019

Treatment of advanced pediatric renal cell carcinoma.

Pediatr Blood Cancer 2019 08 23;66(8):e27766. Epub 2019 Apr 23.

Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.

Background: Pediatric renal cell carcinoma (pRCC) is the second most common renal malignancy of childhood; however, treatment data for advanced disease is lacking.

Methods: A retrospective analysis of pRCC patients (age < 21 years at diagnosis) treated between 2000 and 2015 at Cincinnati Children's Hospital Medical Center was undertaken, with specific focus on medical therapies, accompanied by a detailed literature review.

Results: Twenty-four patients (median age = 15 years) were identified; 11 were female. Past history of kidney pathology (4) and prior hematologic/oncologic diagnoses (5) were common associated findings. Translocation morphology RCC (tRCC) was the most common subtype (16; 64%), followed by papillary (6; 24%), clear cell renal cell carcinoma (ccRCC) (1), and chromophobe (1). The TNM stage distribution was I (8; 33%), II (2; 8%), III (3; 13%), and IV (11; 46%). Eleven patients with stage IV disease all had tRCC and received medicinal anticancer therapies, the most common being antiangiogenic (10), conventional chemotherapy (8), mTOR inhibition (7), and immunotherapy (3). Four patients also received small-port radiotherapy. The mean time to progression (TTP) was longest for axitinib (n = 2; TTP = 7.8 m; range 5.5-10 m) and sunitinib (n = 6; TTP = 4.7 m; range 0.3-12 m). Overall, 20 cases of pediatric RCC who received RCC-directed medicinal therapy with outcome data have been previously reported.

Conclusions: For patients with unresectable pRCC requiring systemic therapy, available data are scarce. Data herein support an increased TTP with antiangiogenic therapy in tRCC supporting a formal study of antiangiogenic therapies through multicooperative-group collaboration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27766DOI Listing
August 2019

Reply to L. Xie et al.

J Clin Oncol 2019 05 15;37(14):1264-1265. Epub 2019 Mar 15.

Elizabeth A. Mullen, MD, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA; Geetika Khanna, MD, Washington University School of Medicine, St Louis, MO; James I. Geller, MD, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Conrad V. Fernandez, MD, Dalhousie University, Halifax, Nova Scotia, Canada; and Jeffrey S. Dome, MD, PhD, Children's National Health System, Washington, DC.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.00012DOI Listing
May 2019

Hepatoblastoma-The Evolution of Biology, Surgery, and Transplantation.

Children (Basel) 2018 Dec 21;6(1). Epub 2018 Dec 21.

Division of General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA.

The most common primary malignant liver tumor of childhood, hepatoblastoma has increased in incidence over the last 30 years, but little is still known about its pathogenesis. Discoveries in molecular biology provide clues but have yet to define targeted therapies. Disease-free survival varies according to stage, but is greater than 90% in favorable risk populations, in part due to improvements in chemotherapeutic regimens, surgical resection, and earlier referral to liver transplant centers. This article aims to highlight the principles of disease that guide current treatment algorithms. Surgical treatment, especially orthotopic liver transplantation, will also be emphasized in the context of the current Children's Oncology Group international study of pediatric liver cancer (AHEP-1531).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/children6010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352070PMC
December 2018

Transarterial radioembolization with yttrium-90 of unresectable primary hepatic malignancy in children.

Pediatr Blood Cancer 2019 07 8;66(7):e27510. Epub 2018 Nov 8.

Cincinnati Children's Hospital, Cincinnati, Ohio.

Background: Primary malignant liver tumors are rare, accounting for 1% to 2% of all childhood cancers. When chemotherapy fails, transarterial radioembolization with yttrium-90 (TARE-Y90) may offer an alternative therapy as a bridge to surgical resection or liver transplant or for palliation.

Methods: We conducted a retrospective review of 10 pediatric patients with histologically confirmed primary liver malignancy who received treatment with TARE-Y90.

Results: The median age at treatment was 5.5 years (range, 2-18 years). Median patient survival from initial diagnosis was 12.5 months (range, 10-28 months), and median patient survival after TARE-Y90 was 4 months (range, 2-20 months). Retreatment was well tolerated in three of 10 patients, with these patients demonstrating the longest survival times (range, 17-20 months). One patient was transplanted 6 weeks after TARE-Y90. By RECIST 1.1 criteria of all target lesions, eight of nine patients had stable disease, and one of nine had progressive disease. By mRECIST criteria (requiring postcontrast arterial phase imaging), two of seven patients had a partial response, four of seven had stable disease, and one of seven had progressive disease.

Conclusion: TARE-Y90 of unresectable primary liver malignancy is both technically feasible and demonstrates an anticancer effect, and retreatment is well tolerated. TARE-Y90 could be considered as adjunctive therapy in pediatric patients with unresectable hepatic malignancies and could be used as a bridge to surgical resection or liver transplant. More research is required to determine the efficacy of this treatment in children and to define the clinical scenarios where benefit is likely to be optimized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27510DOI Listing
July 2019

A study of axitinib, a VEGF receptor tyrosine kinase inhibitor, in children and adolescents with recurrent or refractory solid tumors: A Children's Oncology Group phase 1 and pilot consortium trial (ADVL1315).

Cancer 2018 12 5;124(23):4548-4555. Epub 2018 Nov 5.

Department of Pediatrics, Masonic Children's Hospital, University of Minnesota Medical Center, Minneapolis, Minnesota.

Background: Axitinib is an oral small molecule that inhibits receptor tyrosine kinases vascular endothelial growth factor receptors 1 to 3. A phase 1 and pharmacokinetic (PK) trial evaluating axitinib was conducted in children with refractory solid tumors.

Methods: Axitinib was administered orally twice daily in continuous 28-day cycles. Dose levels (2.4 mg/m /dose and 3.2 mg/m /dose) were evaluated using a rolling 6 design. Serial PKs (cycle 1, days 1 and 8) and exploratory biomarkers were analyzed.

Results: A total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. The median age of the patients was 13.5 years (range, 5-17 years). Two of 5 patients who were treated at dose level 2 experienced dose-limiting toxicities (palmar-plantar erythryodysesthesia syndrome in 1 patient and intratumoral hemorrhage in 1 patient). Frequent (>20%) grade 1 to 2 toxicities during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Nonhematological toxicities of grade ≥3 in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, the median time to peak plasma concentration was 2 hours, and the half-life ranged from 0.7 to 5.2 hours. Exposure and dose were not found to be significantly associated with hypertension. Five patients achieved stable disease for ≤6 cycles as their best response, including patients with malignant peripheral nerve sheath tumor (1 patient), Ewing sarcoma (1 patient), hepatocellular carcinoma (1 patient), and osteosarcoma (2 patients). One patient with alveolar soft part sarcoma achieved a partial response. Kidney injury biomarkers were found to be elevated at baseline; no trends were identified.

Conclusions: In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib appears to be 2.4 mg/m /dose, which provides PK exposures similar to those of adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.31725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289772PMC
December 2018

Impact of Surveillance Imaging Modality on Survival After Recurrence in Patients With Favorable-Histology Wilms Tumor: A Report From the Children's Oncology Group.

J Clin Oncol 2018 Oct 18:JCO1800076. Epub 2018 Oct 18.

Elizabeth A. Mullen, Dana-Farber Cancer Institute/Boston Children's Cancer and Blood Disorders Center, Boston, MA; Yueh-Yun Chi and Emily Hibbitts, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Katarina J. Steacy, University of Maryland Medical Center, Baltimore, MD; James I. Geller, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Daniel M. Green, St Jude Children's Research Hospital, Memphis, TN; Geetika Khanna, Washington University School of Medicine, St Louis, MO; Marcio H. Malogolowkin, University of California at Davis Comprehensive Cancer Center, Sacramento, CA; Paul E. Grundy, Stollery Children's Hospital, University of Alberta, Alberta; Conrad V. Fernandez, IWK Health Center, Dalhousie University Halifax, Nova Scotia, Canada; and Jeffrey S. Dome, Children's National Health System, George Washington University School of Medicine and Health Sciences, Washington, DC.

Purpose: The use of computed tomography (CT) for routine surveillance to detect recurrence in patients with Wilms tumor (WT) has increased in recent years. The utility of CT, despite increased risk and cost, to improve outcome for these patients is unknown. We conducted a retrospective analysis with patients enrolled in the fifth National Wilms Tumor Study (NWTS-5) to determine if surveillance with CT correlates with improved overall survival (OS) after recurrence compared with chest x-ray (CXR) and abdominal ultrasound (US).

Patients And Methods: Overall, 281 patients with recurrent unilateral favorable-histology WT were reviewed to assess how WT recurrence was detected: sign/symptoms (SS), surveillance imaging (SI) with CT scan, or SI with CXR/US.

Results: The estimated 5-year OS rate after relapse was 67% (95% CI, 61% to 72%). Twenty-five percent of recurrences were detected with SS; 48.5%, with CXR/US; and 26.5%, with CT. Patients with SS had a 5-year OS rate of 59% (95% CI, 46% to 72%) compared with 70% (95% CI, 63% to 77%; P = .23) for those detected by SI. Recurrences detected by CT had a shorter median time from diagnosis to recurrence (0.60 years) compared with SS (0.91 years) or CXR/US (0.86 years; P = .003). For recurrences detected by SI, more tumor foci at relapse ( P < .001) and size of the largest focus greater than 2 cm ( P = .02) were associated with inferior OS. However, there was no difference in OS after relapse when recurrence was detected by CT versus CXR/US (5-year OS rate, 65% v 73%; P = .20).

Conclusion: In patients with favorable-histology WT, elimination of CT scans from surveillance programs is unlikely to compromise survival but would result in substantial reduction in radiation exposure and health care costs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.00076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269130PMC
October 2018

Updated Recommendations on the Diagnosis, Management, and Clinical Trial Eligibility Criteria for Patients With Renal Medullary Carcinoma.

Clin Genitourin Cancer 2019 02 12;17(1):1-6. Epub 2018 Sep 12.

Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address:

Renal medullary carcinoma (RMC) is one of the most aggressive renal cell carcinomas. It predominantly afflicts young adults and adolescents with sickle cell trait and other sickle hemoglobinopathies, and is refractory to targeted and antiangiogenic therapies used in patients with clear-cell renal cell carcinoma. Platinum-based cytotoxic chemotherapy is the mainstay for RMC treatment. On the basis of recent advances in the diagnosis, management, and clinical trial development for RMC, a panel of experts met in October 2017 and developed updated consensus recommendations to inform clinicians, researchers, and patients. Because RMC often aggressively recurs while patients are still recovering from nephrectomy, upfront chemotherapy should be considered for most patients, including those with localized disease. After safety and dosing information has been established in adults, phase II and III trials enrolling patients with RMC should allow patients aged 12 years and older to be accrued. Patients with the very rare unclassified renal cell carcinoma with medullary phenotype variant should be included in RMC trials. Medical providers should be aware that RMC can afflict subjects of all races, and not only those of African descent, and that the presence of sickle cell trait, or of other sickle hemoglobinopathies, can affect drug responses and toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clgc.2018.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348017PMC
February 2019

Reply to D.M. Green.

J Clin Oncol 2018 Sep 13:JCO1800659. Epub 2018 Sep 13.

David B. Dix, British Columbia Children's Hospital, Vancouver, BC, Canada; Nita L. Seibel, National Cancer Institute, Bethesda, MD; Yueh-Yun Chi, University of Florida, Gainesville, FL; Geetika Khanna, Washington University School of Medicine, St Louis, MO; Elizabeth A. Mullen, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA; James I. Geller, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; John A. Kalapurakal, Lurie Comprehensive Cancer Centre of Northwestern University, Chicago, IL; Peter F. Ehrlich, University of Michigan, Ann Arbor, MI; Marcio H. Malogolowkin, University of California at Davis Comprehensive Cancer Center, Sacramento, CA; Conrad V. Fernandez, IWK Health Center, Dalhousie University, Halifax, NS, Canada; and Jeffrey S. Dome, Children's National Health System, George Washington University School of Medicine and Health Sciences, Washington, DC.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.00659DOI Listing
September 2018

Dose modifications and pharmacokinetics of adjuvant cisplatin monotherapy while on hemodialysis for patients with hepatoblastoma.

Pediatr Blood Cancer 2019 01 30;66(1):e27425. Epub 2018 Aug 30.

Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Hepatoblastoma can be associated with chronic kidney disease and genitourinary anomalies. Cisplatin is a key agent for treating hepatoblastoma but renal clearance and toxicity can limit its use in end-stage renal disease. We present pharmacokinetic data and clinical outcomes using cisplatin on hemodialysis for three patients with hepatoblastoma. All patients were initially treated with surgery and adjuvant cisplatin [1.67 mg/kg (2 patients) or 50 mg/m (1 patient)]. The patient treated with body surface area-based dosing had higher exposures and ototoxicity. Treating hepatoblastoma with cisplatin on hemodialysis using 1.67 mg/kg achieved clinical efficacy with minimal morbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27425DOI Listing
January 2019

Acquired ornithine transcarbamylase deficiency in pediatric and adolescent patients with fibrolamellar hepatocellular carcinoma.

Pediatr Blood Cancer 2018 12 9;65(12):e27392. Epub 2018 Aug 9.

Division of Pediatric Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Ornithine transcarbamylase deficiency (OTCD) disrupts the metabolic pathway responsible for converting nitrogenous waste to urea, allowing for excretion. When impaired, ammonia levels accumulate in the blood resulting in severe, sometimes life-threatening toxicities. Abnormalities of the urea cycle are often inherited, though there are some rarer acquired forms. We describe two cases of acquired OTCD in pediatric patients with fibrolamellar hepatocellular carcinoma (FL-HCC). We detail its presentation and management, explore potential underlying pathophysiology, and propose a practice change to optimize care of FL-HCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27392DOI Listing
December 2018

Surgical management of children and adolescents with upfront completely resected hepatocellular carcinoma.

Pediatr Blood Cancer 2018 11 3;65(11):e27293. Epub 2018 Jul 3.

Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Background: Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that is often chemoresistant. Complete surgical resection remains the mainstay of therapy. The role of liver transplantation (LT) in pediatric HCC is in evolution, as is the role of adjuvant chemotherapy for stage I disease.

Methods: A retrospective review of patients < 18 years of age with completely resected HCC treated with surgical intervention alone at our institution from 2004 to 2015 was conducted.

Results: Twelve patients with a median age of 12 years (range = 1-17; number of females = 7) with upfront resected HCC (Evans stage I) were identified. Four patients had HCC without identifiable risk factors (fibrolamellar-HCC = 2; early HCC arising in focal nodular hyperplasia = 1, well-differentiated [wd] HCC = 1). Four patients had early or wd-HCC in the context of portosystemic shunts (Abernethy = 2; mesocaval shunt and portal vein thrombosis = 2). Four patients had moderate to wd-HCC in the context of pre-existing liver disease with cirrhosis (progressive familial intrahepatic cholestasis type-2 = 2, alpha-1 antitrypsin deficiency = 1, Alagille syndrome = 1). Seven patients underwent LT (multifocal = 5; solitary = 2); five exceeded Milan criteria (MC) by imaging. Five patients underwent complete resection (segmentectomy = 2; hemihepatectomy = 3). Ten patients received no adjuvant chemotherapy. All patients are alive without evidence of disease with a median follow-up of 54.1 months (range = 28.1-157.7 months).

Conclusions: Pediatric and adolescent patients with upfront, completely resected HCC can be effectively treated without chemotherapy. LT should be considered for nonmetastatic HCC, especially in the context of pre-existing chronic liver disease, even when the tumor exceeds MC. Distinct pediatric selection criteria are needed to identify patients most suitable for LT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27293DOI Listing
November 2018
-->