Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms' tumor: a CIBMTR retrospective analysis.

Despite the marked improvement in the overall survival (OS) for patients diagnosed with Wilms' tumor (WT), the outcomes for those who experience relapse have remained disappointing. We describe the outcomes of 253 patients with relapsed WT who received high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplant (HCT) between 1990 and 2013, and were reported to the Center for International Blood and Marrow Transplantation Research. The 5-year estimates for event-free survival (EFS) and OS were 36% (95% confidence interval (CI); 29-43%) and 45% (95 CI; 38-51%), respectively. Relapse of primary disease was the cause of death in 81% of the population. EFS, OS, relapse and transplant-related mortality showed no significant differences when broken down by disease status at transplant, time from diagnosis to transplant, year of transplant or conditioning regimen. Our data suggest that HDT followed by autologous HCT for relapsed WT is well tolerated and outcomes are similar to those reported in the literature. As attempts to conduct a randomized trial comparing maintenance chemotherapy with consolidation versus HDT followed by stem cell transplant have failed, one should balance the potential benefits with the yet unknown long-term risks. As disease recurrence continues to be the most common cause of death, future research should focus on the development of consolidation therapies for those patients achieving complete response to therapy.

Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma.

BACKGROUND: The potential for surgical resection of primary hepatoblastoma tumours was assessed at diagnosis, and after two and four cycles of neoadjuvant chemotherapy. METHODS: Available radiographic images for patients with stage III and IV hepatoblastoma diagnosed between 1991 and 2008 were reviewed. The extent of disease was determined at diagnosis using the PRETEXT staging system, and after two and four cycles of therapy by POST-TEXT staging. Tumour resectability based on radiographic studies was assessed independently by two surgeons with expertise in hepatic surgery who were blinded to treatment and clinical outcome. RESULTS: Radiographic images from 20 patients with hepatoblastoma were reviewed. Six of 20 tumours were downstaged after two cycles, and three additional tumours were downstaged following four cycles. All PRETEXT stage III and IV tumours were determined to be surgically unresectable at diagnosis. The number of tumours considered unresectable decreased from 16 of 20 at diagnosis to seven of 20 after two cycles, and to four of 20 after four cycles. Five of the seven tumours that were unresectable after two cycles, and all four tumours that were unresectable after four cycles would have qualified for liver transplant based on radiographic studies. CONCLUSION: The majority of stage III and IV hepatoblastomas achieved radiographic resectability after two cycles of chemotherapy. There may be an opportunity for earlier surgical intervention and potential for a reduction in chemotherapy in a considerable number of patients.

Incidence and outcomes of patients with late recurrence of Wilms' tumor.

BACKGROUND: Most relapses from Wilms' tumor occur within 2 years from diagnosis. This study aims to describe the incidence and outcome of patients who experienced a late recurrence (LR) more than 5 years after diagnosis across several clinical trials, and to develop evidence-based recommendations for follow-up surveillance. METHODS: Available records on children with Wilms' tumor enrolled onto 10 national or international cooperative clinical trials were reviewed to identify patients who experienced a LR. RESULTS: Seventy of 13,330 (0.5%) patients with Wilms' tumor experienced a LR. No gender bias was observed. Median time elapsing between initial Wilms' tumor diagnosis and first recurrence was 13.2 years (range: 5.1-17.3 years). Initial tumor stage was: stage I (15); stage II (19); stage III (14); stage IV (8); bilateral disease stage V (14). The most frequent sites of relapse were--abdomen: 21, lungs: 20, and contralateral kidney: 15. Thirty-five children died of disease progression. Recurrence in the contralateral kidney was associated with a better outcome (13/15 patients alive), while initial tumor stage did not seem to influence the post-recurrence outcome. Therapies administered at recurrence varied between centers, preventing any conclusion about the best salvage treatment. CONCLUSIONS: LR of Wilms' tumor is rare and associated with similar outcome to those experiencing earlier recurrence. The low rate of LR does not justify prolonged monitoring. Further study of the biology of these tumors may give us some insights in regards to mechanisms on tumor cell dormancy or cancer stem cell maintenance.

Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: Children younger than 24 months with small (< 550 g), favorable histology (FH) Wilms tumors (WTs) were shown in a pilot study to have an excellent prognosis when treated with nephrectomy only. PATIENTS AND METHODS: A study of nephrectomy only for the treatment of selected children with FH WT was undertaken. Stringent stopping rules were designed to insure closure of the study if the true 2-year relapse-free survival rate was 90% or lower. RESULTS: Seventy-five previously untreated children younger than 24 months with stage I/FH WTs for which the surgical specimen weighed less than 550 g were treated with nephrectomy only. Three patients developed metachronous, contralateral WT 1.1, 1.4, and 2.3 years after nephrectomy, and eight patients relapsed 0.3 to 1.05 years after diagnosis (median, 0.4 years; mean, 0.51 years). The sites of relapse were lung (n = 5) and operative bed (n = 3). The 2-year disease-free (relapse and metachronous contralateral WT) survival rate was 86.5%. The 2-year survival rate is 100% with a median follow-up of 2.84 years. The 2-year disease-free survival rate (excluding metachronous contralateral WT) was 89.2%, and the 2-year cumulative risk of metachronous contralateral WT was 3.1%. CONCLUSION: Children younger than 24 months treated with nephrectomy only for a stage I/FH WT that weighed less than 550 g had a risk of relapse, including the development of metachronous contralateral WT, of 13.5% 2 years after diagnosis. All patients who experienced relapse on this trial are alive at this time. This approach will be re-evaluated in a clinical trial using a less conservative stopping rule.

Mycotic aneurysm of the thoracic aorta due to Aspergillus terreus: case report and review.

Mycotic aneurysms of the aorta caused by fungi are uncommon. We describe an unusual case of aortic aneurysm infection caused by Aspergillus terreus, which most likely spread from an adjacent pulmonary focus. Successful treatment included partial pneumonectomy, resection of the aneurysm with graft repair, and prolonged sequential administration of amphotericin B and itraconazole. A review of the published experience with aortic aneurysms caused by Aspergillus species is also presented. When invasive aspergillosis is suspected in proximity to areas with major vascular structures in immunocompromised patients, further investigation to rule out vascular invasion may be warranted. If the diagnosis is confirmed, aggressive and prompt treatment with antifungal agents combined with surgical debridement is essential to improve outcome.

Presence of well-differentiated rhabdomyoblasts at the end of therapy for pelvic rhabdomyosarcoma: implications for the outcome.

The presence of well-differentiated rhabdomyoblasts at the end of therapy for rhabdomyosarcoma has been noted. This study was undertaken to investigate the therapeutic implications of the presence of well-differentiated rhabdomyoblasts at the end of therapy for pelvic rhabdomyosarcoma. Six patients with pelvic rhabdomyosarcoma (bladder-prostate, 4; vulvovaginal, 2) with disease diagnosed between the years 1974 and 1992 were sequentially investigated by cystoscopic or vaginoscopic examination and biopsy during and after completing therapy. All six patients received treatment according to prevailing therapeutic protocols. Biopsy material from all six patients at the end of therapy documented the presence of well-differentiated rhabdomyoblasts. Repeated biopsies demonstrated the presence of rhabdomyoblasts; however, they appeared to decrease in number with time. Mitotic activity was not observed in the biopsy materials obtained. All six patients are alive without evidence of disease from 37 to 233 months after therapy ended. The presence of well-differentiated rhabdomyoblasts at the end of therapy for pelvic rhabdomyosarcoma is a common finding. The biologic nature of these well-differentiated rhabdomyoblasts is not completely known, but they do not appear to connote the persistent presence of malignant disease and are not an indication for the continuation of therapy.

Feasibility and toxicity of chemoembolization for children with liver tumors.

PURPOSE: To determine the feasibility, toxicity, and efficacy of hepatic arterial chemoembolization (HACE) in pediatric patients with refractory primary malignancies of the liver. PATIENTS AND METHODS: Six patients with hepatoblastoma (HB), three with hepatocellular carcinoma (HCC), and two with undifferentiated sarcoma of the liver were treated with HACE every 2 to 4 weeks until their tumors became surgically resectable or they showed signs of disease progression. All but one newly diagnosed patient with HCC had previously received systemic chemotherapy. RESULTS: All patients with HB and HCC responded to HACE, as measured by imaging studies and alpha-fetoprotein levels. Surgical resection (complete or microscopic residual disease) was feasible in five of 11 patients, and three patients remain alive with no evidence of disease. Elevated liver transaminase and bilirubin levels were seen after each one of the 46 courses of HACE. Other toxicities included fever, pain, nausea, vomiting, and transient coagulopathy. CONCLUSION: HACE is feasible, well tolerated, and effective in inducing surgical resectability of primary hepatic tumors in children.

Complications of cancer therapy in children: a radiologist's guide.

As advances in cancer therapy improve the prognosis of patients with childhood malignancies, awareness of the consequences of treatment methods assumes increasing importance. All cancer treatment modalities are associated with toxic effects, and the spectrum of therapy-induced complications involves all organ systems. Radiologists have a pivotal role in detecting these sequelae, which can be categorized by the affected organ system and by whether they occur (a) at diagnosis or during initial therapy or (b) after the completion of treatment. The first group consists of oncologic emergencies, infectious complications, and irritant effects. Oncologic emergencies can be further categorized as space-occupying lesions (e.g., superior vena cava syndrome or spinal cord compression), vascular abnormalities (e.g., hyperleukocytosis, anemia, coagulopathy), and metabolic emergencies (e.g., tumor lysis syndrome). Common complications developing after completion of treatment include leukoencephalopathy and neurocognitive defects; cataract formation; cardiomyopathy and congestive heart failure; hepatic dysfunction, fibrosis, and cirrhosis; radiation enteritis; renal dysfunction or failure; scoliosis and short stature; hypothyroidism; gonadal dysfunction; graft-versus-host disease; and development of secondary malignancies. Physician awareness of these complications will permit more effective patient surveillance, which may afford patients the opportunity for earlier intervention in these situations and improved quality of life.

Risk factors for early infection of central venous catheters in pediatric patients.

BACKGROUND: In an effort to avoid infections that can lead to the premature removal of indwelling central venous catheters (CVCs), the surgical technique and host factors present in pediatric recipients of permanent CVCs were reviewed. STUDY DESIGN: All patients receiving CVCs over a 17-month period were identified. Those patients with fever and positive blood cultures drawn through the CVC within 45 days of line placement were labeled as having early infection. A case-control design was used to select two control patients for each infected patient. Charts from both the infection and control groups were reviewed for several factors present at the time of CVC placement, including fever, neutropenia (absolute neutrophil count [ANC] < 500 and ANC < 1,000), use of perioperative antibiotics, diagnosis, CVC site, and type of CVC. Chi-square test with Yates correction was used to compare the groups. Odds ratios (ORs) and 95% confidence intervals were derived. RESULTS: Among the 473 CVCs placed, early infections developed in 53 patients (12%). The control group consisted of 106 patients. Neutropenia was present in 16 of 53 infected patients versus 8 of 106 controls (p = 0.004, OR = 5.30). Perioperative antibiotics were given to 25 of 53 infected patients versus 72 of 106 controls (p = 0.02, OR = 0.42). Fever was present in 12 of 53 infected patients versus 14 of 106 controls (p = 0.19, OR = 1.92). Factors that were equally prevalent between the groups and that did not appear to influence the CVC infection rate included a diagnosis of malignancy, CVC type, and site of placement. Of the 53 infected catheters, 16 (30%) could not be cleared of infection and were removed. CONCLUSIONS: This study documents that neutropenia and failure to administer prophylactic antibiotics are risk factors for the development of early CVC infection in pediatric patients. To avoid early infection and possible premature CVC removal, we recommend that placement of permanent CVCs be postponed until the ANC is > 1,000. Perioperative antibiotics should be given. A trend toward higher infection rates was seen in patients with preoperative fever.

Chemotherapy plus local treatment in the management of intraocular retinoblastoma.

OBJECTIVE: To describe platinum-based chemotherapy combined with local treatment modalities as an alternative to external beam radiotherapy for intraocular retinoblastoma. DESIGN: Platinum levels were measured by atomic absorption analysis in the tumors of 2 patients with retinoblastoma given carboplatin 5 or 2.5 hours before enucleation. Platinum levels in heated vs nonheated Greene melanoma tumors in rabbits were compared. A retrospective review of 172 affected eyes in 136 consecutive patients treated for retinoblastoma between January 1990 and December 1995 was performed. From 1990 to 1992, all treatable eyes initially received systemic carboplatin, 560 mg/m2, followed by 15 to 30 minutes of continuous diode laser hyperthermia (thermochemotherapy). Since 1992, larger tumors were treated initially with 3 monthly cycles of carboplatin, etoposide, and vincristine sulfate to reduce tumor volume (chemoreduction) followed by sequential aggressive local therapy (SALT) during examinations under anesthesia every 2 to 3 weeks. OUTCOME MEASURE: Treatment success was defined as eradication of tumor without enucleation or external beam radiotherapy. RESULTS: Significant therapeutic platinum levels were measured in the human tumors 2.5 and 5 hours after carboplatin administration. Increasing the temperature by 9 degrees C for 15 minutes doubled platinum levels in the rabbit model. Of the 38 eyes with Reese-Ellsworth group 1 through 5b tumors that were treated primarily with thermochemotherapy, all 24 eyes with group 1 and 2 tumors were treated successfully and two of the 4 eyes with group 3 tumors and all 10 eyes with group 5b tumors were treated unsuccessfully. Chemoreduction plus SALT was the primary treatment in 35 eyes and was successful in all 10 eyes with group 1 through 4 tumors and unsuccessful in all 7 eyes with extensive subretinal seeding and all 18 eyes with group 5b tumors with vitreous seeding. Seventy patients received carboplatin or carboplatin, vincristine, and etoposide, with myelosuppression, occasionally associated with bacteremia, being the main side effect. Transfusions were required in 15% of patients. Radiation retinopathy occurred in all 6 eyes treated with iodine 125 plaques. CONCLUSIONS: Thermochemotherapy is successful primary treatment for Reese-Ellsworth group 1 and 2 retinoblastomas. For larger tumors in the absence of vitreous or extensive subretinal seeding, 3 cycles of chemoreduction followed by SALT eradicates residual viable tumor. Chemoreduction plus SALT was not successful in eyes with diffuse vitreous or extensive subretinal seeding. Prior chemotherapy increases the risk for radiation retinopathy following 125I plaque therapy. External beam radiotherapy can safely be avoided in the primary treatment of Reese-Ellsworth groups 1 through 4 nondispersed retinoblastoma.

A prospective study of vancomycin pharmacokinetics and dosage requirements in pediatric cancer patients.

Pharmacokinetics of vancomycin and dosage requirements were evaluated prospectively in 28 pediatric cancer patients 9 months to 13 years of age. The predictive performance of a two-compartment Bayesian forecasting program was also evaluated. A mean (+/- SD) daily dosage of 75 +/- 22 mg/kg/day was necessary to attain a mean peak serum vancomycin concentration (SVC) of 23.1 +/- 5.8 mg/liter and a mean trough SVC of 6.2 +/- 2.3 mg/liter. Mean vancomycin clearance, volume of distribution and serum half-life were 0.153 +/- 0.033 liter/hour/kg, 0.63 +/- 0.08 liter/kg and 2.95 +/- 0.48 hours. Final peak SVCs, which reflected the last dosage regimens received, were predicted with minimal bias (mean prediction error, -1.2 mg/liter) and accurate precision (root mean-squared prediction error, 2.0 mg/liter) whereas trough SVCs were predicted with even smaller bias (mean prediction error, -0.1 mg/liter) and greater precision (root mean-squared prediction error, 0.8 mg/liter). This study showed that pediatric cancer patients with normal renal function required vancomycin dosage regimens substantially greater than the standard 40 mg/kg/day to attain the desired SVCs.

Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group.

We report treatment results in 93 children entered on study from 1978 to 1984 with malignant germ cell tumors (MGCTs), excluding dysgerminoma and tumors of the testis or brain. The estimated 4-year survival and event-free survival (EFS) for all 93 patients were 54% and 49%, respectively. For 30 children with ovarian tumors, the estimated 4-year survival was 67% and EFS was 63%. For 63 children with nongonadal tumors, survival and EFS were 48% and 42%, respectively. The comparison of EFS between ovarian and nongonadal tumors was significant at P = .03. The treatment plan included a second-look surgical procedure after 18 weeks of chemotherapy. Over half of 36 patients evaluated as having a residual mass present immediately before second-look surgery had no malignant tumor after review of surgical specimens. Age greater than 11 years at diagnosis, incomplete removal of tumor at first surgery, and more than one structure or organ involved at diagnosis increased the risk for adverse event. The histologic subtype of the primary tumor was not related to outcome. Diagnosis was verified by independent pathologic review, and treatment was uniform. Seventeen percent of all registered patients (21 of 127) were excluded because of ineligible pathologic diagnoses; sixty percent (13 of 21) were immature teratomas.

Germ cell tumors in infancy and childhood: a 45-year experience.

The clinical and pathologic features of germ cell tumors in 188 patients seen at the Childrens Hospital of Los Angeles from 1941 to 1986 are reviewed. There were 129 females and 59 males 19 years of age or younger. Tumors were seen in the ovary (73, 39%), sacrococcygeal region (67, 36%), testis (13, 7%), pineal region (10, 5%), mediastinum (8, 4%), and other sites (17, 9%). The mean age at diagnosis of patients with sacrococcygeal tumors was 11 months, and for those with ovarian tumors it was 9.3 years. Histologically, 56% of the tumors were benign, 15% had immature tissues, and 29% had frankly malignant tumors. Patients with immature tumors and elevated serum alpha-fetoprotein levels at diagnosis had a higher incidence of tumor relapse (p = .004). The histology of the recurrent tumors in these patients was embryonal carcinoma. Of 54 patients with malignant tumors, 27 are alive with no evidence of recurrence, 5 died of non-disease-related causes, and 22 (41%) had tumor recurrence within 3 years of initial diagnosis and eventually died of tumor progression. The 5-year survival rate for patients with benign tumors was 96%; for those with immature tumors, 83%; and for those with malignant tumors, 42%.

Immature teratomas: identification of patients at risk for malignant recurrence.

We investigated the significance of immature elements in an otherwise benign teratoma in 28 patients with immature teratomas diagnosed and treated at the Childrens Hospital of Los Angeles from 1941 to 1986. Different characteristics, including age, sex, primary tumor site, type of surgery (complete resection vs. partial resection or biopsy), and preoperative levels of alpha-fetoprotein (AFP) were analyzed to evaluate their association with risk of subsequent local malignant recurrence. After a median follow-up of 6 years, 21 patients are alive with no recurrence of the tumor (72% event-free survival). One patient died from infection after surgery and six patients had local malignant tumor recurrence within 1 year from diagnosis. Of the 28 patients, 12 had AFP levels measured at diagnosis. Eight patients had normal levels with no further evidence of tumor recurrence, and four had elevated levels with three tumor recurrences. Our experience demonstrates that only at the time of diagnosis do AFP levels correlate with a subsequent malignant behavior of these tumors (P = .004). Those patients with immature teratomas and elevated AFP levels at diagnosis should receive adjuvant chemotherapy after the initial surgical resection.

Tracing expert thinking in clinical trial design.

This paper describes a method for the analysis of the clinical trial design process used by experts. With this procedure, the scientific ideas and their sources can be identified and related to the clinical trial protocol actually prepared by the experts. An example is given using the work of the Intergroup Rhabdomyosarcoma Study Committee (IRS). That committee has been the primary contributor of information dealing with the treatment of rhabdomyosarcoma in children. The IRS-III protocol was used in this analysis of expert behavior because the protocol was adopted by the leading pediatric oncology clinical trial groups in North America and Europe. The analysis showed that the experts rely heavily, for much of the design, on ideas presented in numerical displays in published documents. Further, those aspects of the design which are innovative can be traced and better understood by applying the new procedure.