Roger Giller

Complete Surgical Excision Is Effective Treatment for Children With Immature Teratomas With or Without Malignant Elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study

PURPOSE To determine whether the 3-year event-free survival (EFS) of children with completely resected immature teratomas is greater than 85%. PATIENTS AND METHODS Patients with immature teratomas treated at Pediatric Oncology Group or Childrens Cancer Group institutions were eligible. Pathology was centrally reviewed to confirm diagnosis and tumor grading. Follow-up included physical examination, measurement of tumor markers (alpha fetoprotein and human chorionic gonadotropin), and imaging. All patients were monitored for events, defined as tumor recurrence, second malignancy, or death. RESULTS Seventy-three children (median age, 7.8 years) with extracranial immature teratomas were enrolled on study. Primary tumor sites included ovarian (n = 44), testicular (n = 7), and extragonadal (n = 22). However, on review, 23 patients had foci of yolk sac tumor (n = 21) or primitive neuroectodermal tumor (n = 2), whereas 50 had pure immature teratomas. Twenty-five patients had increased alpha fetoprotein (n = 18), human chorionic gonadotropin (n = 5), or both (n = 2); nine had foci of yolk sac tumor on review. Pathology review identified 23 patients with grade 1, 29 with grade 2, and 21 with grade 3 immature teratomas. With a median follow-up of 35 months, the overall 3-year EFS was 93% (95% confidence interval, 86% to 98%), with 3-year EFS of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively. Only four of 23 patients with immature teratoma and malignant foci developed recurrence, suggesting that surgical resection followed by close observation are effective treatment. Overall, five patients had disease recurrence 4 to 7 months from diagnosis, and four (80%) are disease free after platinum-based therapy. The fifth patient has residual tumor after cisplatin, etoposide, and bleomycin treatment requiring further therapy. CONCLUSION Surgical excision is safe and effective treatment for 80% to 100% of children with immature teratoma.

Surgical resection alone is effective treatment for ovarian immature teratoma in children and adolescents: A report of the Pediatric Oncology Group and the Children’s Cancer Group☆☆☆★★★

OBJECTIVE In both adult women and children the potential for malignant recurrence from ovarian immature teratoma has prompted the standard use of chemotherapy after complete resection of the primary tumor. The efficacy of postoperative chemotherapy in children and adolescents with ovarian immature teratoma, however, has not been established. A pediatric intergroup trial (INT 0106) was designed to determine the need for postoperative chemotherapy in patients with ovarian immature teratoma after management with surgical resection only. STUDY DESIGN Between 1990 and 1995, 44 patients with completely resected ovarian immature tumor and without postoperative chemotherapy, who were able to undergo assessment, were accrued. Tumor tissue was evaluated by central pathology review to confirm diagnosis and determine tumor grading of immature neural elements. Patients were followed carefully for recurrence of disease with appropriate diagnostic imaging and serum marker studies. RESULTS Thirty-one patients had pure ovarian immature teratoma with a tumor grade of 1 (n = 17), 2 (n = 12), or 3 (n = 2). Age at diagnosis ranged between 1.5 and 15 years (median, 10). Of the 29 patients studied, the serum alpha-fetoprotein level was elevated in 10 (34%); the median level was 25 ng/ml. Thirteen patients had ovarian immature teratoma plus microscopic foci of yolk sac tumor. Tumor grade was 1, 2, or 3 in 1, 6, and 6 patients, respectively. Age ranged between 6 and 20 years (median, 12). In the 12 patients evaluated for serum alpha-fetoprotein, 10 (83%) had elevated levels; the median level was 262 ng/ml. The 4-year event-free and overall survival for the ovarian immature teratoma group and for the ovarian immature teratoma plus yolk sac tumor group was 97.7% (95% confidence interval, 84.9%-99.7%) and 100%, respectively. The only yolk sac tumor relapse occurred in a child with ovarian immature teratoma and yolk sac tumor who was then treated with chemotherapy and is alive and free of disease 57 months after recurrence. CONCLUSION The results of this study suggest that surgery alone is curative for most children and adolescents with resected ovarian immature teratoma of any grade, even when elevated levels of serum alpha-fetoprotein or microscopic foci of yolk sac tumor are present. This experience strongly supports avoiding the long-term effects of chemotherapy in most children with ovarian immature teratoma by reserving postoperative therapy for cases with relapse.

Immature teratomas in children : Pathologic considerations a report from the combined Pediatric Oncology Group/Children's Cancer Group

Pediatric germ cell tumors (n = 135) with a major component of immature teratoma (IT) registered on Pediatric Oncology Group/Childrens Cancer Group treatment protocols from 1990 to 1995 were reviewed. Sixty cases were pure IT with no malignant component and 75 were mixed tumors with a major component of IT. Foci of yolk sac tumor (YST) were present in all 75 mixed tumors; additional malignant components were present in 15. The IT component was as follows: 47% grade 3, 29% grade 2, 24% grade 1. There were no significant correlations between tumor grade and patient age by specific subsets or overall (all p > 0.10). Significant correlations were detected between stage and the presence of foci of YST (p = 0.0145) and grade and the presence of foci of YST (p < 0.001). Serum alpha-fetoprotein concentrations were elevated at diagnosis in 96% of ovarian tumors with foci of YST and were mildly elevated (< 60 ng/dL) in only 16% of tumors without YST. Overall 2- to 6-year survival rate was 96% and was related to the presence of YST. Central pathologic review revealed aspects of morphologic diagnosis that were most frequently misinterpreted by contributing pathologists. These included the classification of differentiating tissues as immature and the failure to recognize two well-differentiated patterns of YST (the hepatoid pattern resembling fetal liver and the well-differentiated glandular pattern resembling fetal lung or intestine). Such foci were often overlooked. The authors conclude that the presence of microscopic foci of YST, rather than the grade of IT, per se, is the only valid predictor of recurrence in pediatric IT at any site.

Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease

We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease.

Treatment of Children and Adolescents With Stage II Testicular and Stages I and II Ovarian Malignant Germ Cell Tumors: A Pediatric Intergroup Study—Pediatric Oncology Group 9048 and Children's Cancer Group 8891

PURPOSE To determine whether children with localized gonadal malignant germ cell tumors (MGCT) stage II testicular and stages I and II ovarian treated with four cycles of standard-dose cisplatin combined with etoposide and low-dose bleomycin (PEB) have an event-free survival (EFS) of at least 85% without significant toxicity. PATIENTS AND METHODS Between May 1990 and July 1995, eligible pediatric patients with stage II or recurrent from stage I (as a stage II) testicular MGCT and stages I and II ovarian MGCT were enrolled onto this Pediatric Oncology Group and Childrens Cancer Group study. PEB chemotherapy consisted of bleomycin 15 U/m2 on day 1, cisplatin 20 mg/m2/d on days 1 to 5, and etoposide 100 mg/m2/d on days 1 to 5. Patients received four cycles of therapy at 21-day intervals. RESULTS Seventy-four patients with a median age of 10.5 years (range, 8.7 months to 16.7 years) were enrolled. Primary sites included: stage II testicular (n = 17), stage I ovarian (n = 41), and stage II ovarian MGCT (n = 16). Treatment with standard PEB resulted in 6-year EFS of 95% and overall survival (OS) of 95.7%. EFS and OS by primary site were as follows: stage II testicular, 100% and 100%; stage I ovarian, 95.1% and 95.1%; and stage II ovarian, 87.5% and 93.8%, respectively. Two patients died from recurrent disease, and one patient died of secondary acute myelocytic leukemia. Infrequent grade 3 to 4 hematologic toxicity was reported. No grade 3 to 4 renal, pulmonary, or ototoxicity was observed. CONCLUSION Combination chemotherapy with PEB results in excellent EFS and OS with minimal toxicity in children and adolescents with localized gonadal MGCT.

Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita

Dyskeratosis congenita (DC) is characterized by reticular skin pigmentation, oral leukoplakia and abnormal nails. Patients with DC have very short telomeres and approximately one-half have mutations in telomere biology genes. A majority of patients with DC develop BM failure (BMF). Hematopoietic cell transplantation (HCT) represents the only known cure for BMF in DC, but poses significant toxicities. We report six patients who underwent allogeneic HCT with a novel nonmyeloablative conditioning regimen specifically designed for DC patients. Graft sources included related PBSCs (1), unrelated BM (2) and unrelated double umbilical cord blood (3). Complete donor engraftment was achieved in five of six patients. One patient had initial autologous hematopoietic recovery, which was followed by a second transplant that resulted in 88% donor chimerism. With a median follow-up of 26.5 months, four patients are alive, three of whom were recipients of unrelated grafts. We conclude with this small study that encouraging short-term survival can be achieved with HCT in patients with DC using a preparative regimen designed to promote donor engraftment and minimize life-threatening disease-specific complications such as pulmonary fibrosis. Long-term follow-up will be crucial with respect to individualized patient care with each of the transplanted individuals.

Clinical and In Vitro Evaluation of Cidofovir for Treatment of Adenovirus Infection in Pediatric Hematopoietic Stem Cell Transplant Recipients

Post-hematopoietic stem cell transplantation (HSCT) adenovirus infections were identified in 31 of 204 consecutive pediatric HSCT patients, 18 of whom had severe manifestations of infection. Cidofovir treatment led to clinical improvement in 8 of 10 patients with severe infection and to virologic clearance in 9 patients. In vitro susceptibility to cidofovir was demonstrated in 12 clinical adenovirus isolates. Cidofovir is a promising treatment option for this population.

How Evolution of Mutations Conferring Drug Resistance Affects Viral Dynamics and Clinical Outcomes of Cytomegalovirus-Infected Hematopoietic Cell Transplant Recipients

ABSTRACT Infection with cytomegalovirus (CMV) remains a significant cause of morbidity and mortality among hematopoietic cell transplant (HCT) recipients. We describe two pediatric HCT recipients who developed persistent and severe drug-resistant CMV infections. CMV resistance to foscarnet and ganciclovir was detected after only 6 and 11 weeks of therapy, respectively. Viral pol mutations associated with drug resistance in these patients included T838A (a novel mutation) and D588N, which were shown by marker transfer to confer foscarnet and multidrug resistance, respectively. Each of these mutations significantly reduced in vitro replication of CMV, suggesting that they may decrease viral fitness. This finding was further supported by the disappearance of mutations upon withdrawal of antiviral pressure in one patient. Novel antivirals or combination therapy may be required for the treatment of drug-resistant CMV in HCT recipients and perhaps in other severely immunocompromised patients.

The prepubertal testis (prenatal and postnatal): its relationship to intratubular germ cell neoplasia: a combined Pediatric Oncology Group and Children's Cancer Study Group.

Seminiferous tubules adjacent to germ cell tumors (GCT) in prepubertal boys frequently contain increased germ cells with abundant, clear cytoplasm. These cells are placental alkaline phosphatase (PLAP) negative and are usually not considered to represent intratubular germ cell neoplasia (ITGCN). A recent case report found p53 and proliferating cell nuclear antigen (PCNA) positivity in such cells and equated these PLAP-negative cells with ITGCN. Because the proto-oncogene c-kit is also a marker of ITGCN, immunohistochemical tests for c-kit and PLAP were performed on 28 testes adjacent to prepubertal GCT in children aged 2 to 45 months. Additional slides from testes not associated with GCT from 18 preterm infants and children ages 19 weeks to 7 years were also tested. An adult testis with seminoma and ITGCN served as a positive control. PCNA, PLAP, and p53 were tested on available slides. No intratubular germ cells adjacent to GCT in prepubertal children were positive for PLAP or c-kit; five of seven were positive for PCNA; p53 was present in the two examined. These results indicate that germ cells adjacent to infantile GCT are proliferative but not neoplastic and offer additional evidence that intratubular germ cells and GCT in prepubertal boys are different from those of adolescents and adults.

Second Unrelated Donor Hematopoietic Cell Transplantation for Primary Graft Failure

Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We describe the results of 122 patients reported to the National Marrow Donor Program between 1990 and 2005, who received a second unrelated donor HCT after failing to achieve an absolute neutrophil count of >or=500/microL without recurrent disease. Patients were transplanted for leukemia (n = 83), myelodysplastic disorders (n = 16), severe aplastic anemia (n = 20), and other diseases (n = 3). The median age was 29 years. Twenty-four patients received second grafts from a different unrelated donor. Among 98 patients who received a second graft from the same donor, 28 received products that were previously collected and cryopreserved for the first transplantation. One-year overall survival (OS) after second transplant was 11%, with 10 patients alive at last follow-up. We observed no differences between patients who received grafts from the same or different donors, or in those who received fresh or cryopreserved product. The outcomes after a second allogeneic HCT for primary graft failure are dismal. Identifying risk factors for primary graft failure can decrease the incidence of this complication. Further studies are needed to test whether early recognition and hastened procurement of alternative grafts can improve transplant outcomes for primary graft failure.