Molecular profiling of osteosarcoma in children and adolescents from different age groups using a next-generation sequencing panel.

Osteosarcoma (OS) is a malignant bone tumor, with a peak of incidence in the second decade of life and possibly associated with the presence of germline mutations. Besides, clinicians have pointed to a second, rarer group of patients that develops OS before 10 years old. Here we access, through next-generation sequencing (NGS) strategy, the genetic alterations present in OS and blood samples from patients diagnosed before and during the second decade of life. A custom NGS panel, designed for the main alterations described in childhood and adolescence neoplasms, named Oncomine Childhood Cancer Research Assay (OCCRA©), was used. Of all 84 OS samples investigated, 42 (50%) presented some somatic variant, with TP53, MYC, CDK4, RB1 and PDGFRA genes harboring the most observed genetic variants. MYC CNVs were more frequent in tumors from patients diagnosed before 10 years old (X21= 5.18, p = 0.023). Additionally, patients diagnosed during the second decade of life presented a higher percentage of somatic and germline variants. Germline variants in TP53 and RB1 were found in 5 of the 11 (45.5%) patients analyzed. Clinical variables and tumor histopathological characteristics were also collected and correlated with our molecular findings.

Results of the Brazilian Osteosarcoma treatment group studies III and IV: prognostic factors and impact on survival

To evaluate the impact of chemotherapy and surgery on the outcome of osteosarcoma (OS) of the extremities and to identify prognostic factors in Brazilian patients. A total of 225 patients with metastatic and nonmetastatic OS of the extremities were enrolled and assessed in two consecutive studies designed and implemented by the Brazilian Osteosarcoma Treatment Group. The 5-year survival and event-free survival rates for the 209 assessable patients were 50.1% and 39%, respectively; for the 178 patients with nonmetastatic disease at diagnosis, the rates were 60.5% and 45.5%, respectively. The multivariate analysis showed that the following variables were associated with a shorter survival: metastases at diagnosis (P < .001), necrosis grades 1 and 2 (P = .046), and tumor size (P = .0071). The overall 5- and 10-year survival rates were lower than the rates reported in North American and European trials. A pattern of advanced disease at diagnosis was often present, with a high proportion of patients having metastases (20.8%) and large tumor size (42.9%). However, these features were not necessarily associated with longer duration of prediagnostic symptoms. These findings were considered in the strategic planning of the current Brazilian cooperative study, with the aim of improving survival and quality of life of a large number of patients with OS.

Resource utilization and cost of episodes of febrile neutropenia in children with acute leukemias and lymphomas.

The resource utilization and cost of 51 episodes of febrile neutropenia in children with leukemia and lymphomas who were admitted to the Pediatric Oncology Institute (GRAAC) of the Federal University of São Paulo were analyzed. Patients aged 60 days to 21 years with confirmed diagnoses of acute myeloid leukemia, acute lymphoid leukemia, non-Hodgkin lymphoma, or Hodgkins disease who presented axillary temperature above 38 degrees C at least once episode, or between 37.5 degrees C and 38 degrees C on three occasions during a 24-h period, neutrophil count below 500/mm(3), or between 500/mm(3)and 1,000/mm(3) but expected to fall below 500/mm(3) were included in the study. The patients' ages varied between 1 and 15.6 years, and 67% of the patients were male. The median cost per treated episode was US dollars 2,660 (2,039). Hospitalization costs accounted for 62% of the total cost of the treatment, antibacterials accounting for 23%. Episodes in patients with documented infections had a higher median direct cost than episodes in patients with fever of unknown origin (P=0.018). There was a trend for a higher median direct cost in episodes among patients with a worse prognostic factor, such as type of underlying disease, presence of documented infection, and longer duration of neutropenia. This is the first study to evaluate the economics of febrile neutropenia episodes in Brazil, and serves as a basis for resource utilization and costs incurred in the treatment of such patients in this country.

Use of Amifostine in the Therapy of Osteosarcomain Children and Adolescents

Amifostine protects normal tissue from the cytotoxic damage induced by radiation and chemotherapy. In this study, 39 consecutive newly diagnosed children with osteosarcoma were assessed; 20 received amifostine and 19 did not. The chemotherapy regimen included an induction phase of three cycles of cisplatin (100 mg/m2), carboplatin (500 mg/m2), and doxorubicin (60 mg/m2), followed by surgery. Alternating cycles of cisplatin/ifosfamide (9 mg/m2), ifosfamide/doxorubicin, carboplatin/doxorubicin, and ifosfamide/carboplatin were administered every 3 weeks to complete 26 weeks of treatment. Amifostine was administered 15 minutes before the infusions of cisplatin and carboplatin in a total of 193 infusions. Side effects during infusions and renal, hearing, and bone marrow toxicities were evaluated and compared between the two groups. Hypotension was observed in 28 (14.5%) infusions. No patient required discontinuation of therapy. Fewer than two episodes of vomiting occurred in 130 (71%) infusions and two to five episodes occurred in 51 (28%) infusions, and no patient had grade 4 toxicity. There was no difference between the two groups regarding renal toxicity (creatinine clearance). Neutropenia and leukopenia were significantly less frequent in the amifostine group. No difference was observed in platelet and hearing toxicities. Amifostine was well tolerated in doses of 740 mg/m2 in children and adolescents, and myelotoxicity was less severe in the amifostine group. This was a pilot study for further evaluation in a larger randomized trial.

Cecal duplication causing a disappearing abdominal mass in an infant.

Duplications of the alimentary tract are rare malformations. A case of a 2-year-old girl with an intestinal intussusception caused by a cystic duplication of the cecum is presented. This case report is justified by its clinical features and the difficult diagnosis, which was only confirmed during surgery. Ultrasonography had documented an abdominal mass that then disappeared and later reappeared, leading to surgical indication. During surgery, the intussusception within the abdomen was reduced, and right hemicolectomy was performed around the mass in the interior part of the cecum and appendix, with ileocolic anastomosis. On resecting the cecum, a cystic duplication measuring 4 x 3 cm was observed, with a granular mucous layer, an ulcerated hole in its interior, and inflammatory reaction. The patient had an uneventful recovery and was discharged on the fourth postoperative day.

Management of Wilms' tumor with intracardiac extension.

We review our experience and the literature in treating 4 patients with Wilms' tumor (WT) with intracardiac extension among 92 patients with this neoplasm. Cardiopulmonary bypass with circulatory arrest and profound hypothermia was used. There were 3 boys (3 years, 4 years 5 months, and 15 years) and 1 girl (6 years). The follow-up periods were 8 months, 3 years, 2 years 6 months, and 15 years, respectively. We had no surgical complications and conclude that the preoperative diagnosis is extremely important. These patients must be transferred to institutions where concomitant cardiac procedures can be performed. In treating patients with WT, Doppler ultrasound must be used preoperatively in all cases, not only those in which clinical and radiologic signs of intravascular involvement are found. We propose that preoperative chemotherapy should be used, as it shrinks the thrombus and causes desirable adherence of the thrombus to the venous wall, reducing the probability of thromboembolism during the surgical procedure. We also find this method safer than in our 1st case, where neither cardiac arrest nor hypothermia was used. Our results agree with the literature that intracardiac extension of WT does not worsen its prognosis when a rational surgical approach is used.

Epiphyseal plate involvement in osteosarcoma.

Fourteen boys (56%) and 11 girls (44%) 4 to 17 years of age (mean, 12.2 years) who had osteosarcoma and open epiphyseal plates were studied. A possible correlation between transepiphyseal spread of osteosarcoma and radiologic and histopathologic findings was investigated. Epiphyseal plate invasion was detected radiologically in only 11 patients (44%), whereas histopathologic examination showed transepiphyseal extension in 21 patients (84%). The authors conclude that the epiphyseal plate is not a barrier against tumor growth and strongly recommend that limb salvage surgery preserving the epiphysis be planned carefully.

Oral ciprofloxacin vs. intravenous ceftriaxone administered in an outpatient setting for fever and neutropenia in low-risk pediatric oncology patients: randomized prospective trial.

BACKGROUND: Infections are one of the major complications in children undergoing chemotherapy. Monotherapy with either ciprofloxacin or ceftriaxone is safe and efficient in low-risk patients (solid tumors and stage I/II lymphomas). The same drugs may be used in an outpatient setting, decreasing costs and the risk of nosocomial infections. PROCEDURE: Low-risk patients (N = 70) with episodes of fever and neutropenia (N = 116) were randomized to receive either oral ciprofloxacin or intravenous ceftriaxone as outpatients. Only one patient had a central venous catheter. RESULTS: Episodes of fever and neutropenia were classified as fever of unknown origin (41% vs. 32%) or clinically documented infection (56% vs. 63%) in the ciprofloxacin and ceftriaxone groups, respectively. Most of these infections were of upper respiratory tract, skin, or gastrointestinal origin. The mean duration of neutropenia was 5 vs. 6 days. Fever persisted for 1-9 days (mean 2 vs. 3 days). Therapy was successful with no modifications in 83% vs. 75% of the episodes. Patients were admitted in 7% vs. 4% of the episodes. No bone or joint side effects were seen in either group. All patients survived. CONCLUSIONS: Outpatient therapy with either oral ciprofloxacin or intravenous ceftriaxone for fever and neutropenia is effective and safe in pediatric patients with solid tumors and stage I/II non-Hodgkin lymphoma (low-risk patients).

Activity of intraarterial carboplatin as a single agent in the treatment of newly diagnosed extremity osteosarcoma.

BACKGROUND: Chemotherapy has dramatically improved the rates of cure and survival of patients with localized and metastatic osteosarcoma. Nonetheless, the number of chemotherapeutic agents active against osteosarcoma is limited to doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide. Carboplatin, a cisplatin analogue, has been tested as a single agent in patients with recurrent osteosarcoma or as part of multiagent chemotherapy in newly diagnosed patients. PROCEDURE: We tested the activity and toxicity of two cycles of intraarterial carboplatin as a "window therapy" (600 mg/m2 per cycle) in 33 consecutive patients with extremity osteosarcoma before the start of multiagent chemotherapy. Response was based on clinical (tumor diameter, local inflammatory signs, and range of motion) and radiological parameters (plain local films and arteriographic studies prior to drug administration). RESULTS: Patients' age ranged between 8 and 18 years (median age 13 years). Primary tumor originated from the femur (15 patients), tibia (10 patients), fibula (4 patients), humerus (3 patients), and calcaneus (1 patient). Only 7 patients (21%) had metastatic disease at diagnosis (5 in the lung and 2 in other bones). A favorable clinical and radiological response was documented in 81% and 73% of the patients, respectively. Clinical and radiological progression occurred in 12% and 9% of the patients, respectively. Seventeen of the patients remain alive and disease-free. Survival and event-free survival at 3 years for nonmetastatic patients are 71% (SE = 9%) and 65% (SE = 9%), respectively; for metastatic patients, the figures are 17% (SE = 15%) and 14% (SE = 13%), respectively. CONCLUSIONS: We conclude that carboplatin is an active agent in the treatment of newly diagnosed extremity osteosarcoma.

Guidelines for a therapeutic alliance between families and staff: a report of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology.

This, the fifth official document of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology, develops another important topic: the Therapeutic Alliance between families and staff. This is addressed to the Pediatric Oncology Community as Guidelines that could be followed. Every parent, medical staff member, and psychosocial professional involved in the care of the child should be responsible for cooperating in the child's best interest. Everyone must work together toward the common goal of curing the cancer and minimizing its medical and psychosocial side-effects.

Rhodotorula glutinis fungemia: a case report and literatura review

A fatal case of Rhodotorula glutinis fungenia in an 11-year-old boy with acute lymphoblastc leukemia undergoing third reinduction chemotherapy is reported. This is the first case of fungemia by Rhodotorula glutinis reported in Brazil.

Fever and neutropenia in children with cancer: a therapeutic approach related to the underlying disease.

Antibiotic monotherapy is increasingly an option for the initial empiric treatment of febrile neutropenic cancer patients. We noted in a previous study that response to empiric therapy was related more to disease classification (solid tumors vs. leukemia) than to the regimen chosen. In the present study we based empiric monotherapy on the underlying disease in treating 240 episodes of fever and neutropenia in 145 children. Patients with leukemia or Stage III/IV non-Hodgkin's lymphoma (higher risk group) were treated with imipenem-cilastatin, whereas those with solid tumors or Stage I/II non-Hodgkin's lymphoma (lower risk group) received ceftriaxone. The regimens were modified in 15% of lower risk and 45% of higher risk episodes. Overall successful outcomes were obtained in 93.2% of the higher risk (n = 119) and 97.5% of the lower risk (n = 121) episodes. The two groups differed significantly in duration of neutropenia, frequency of positive blood cultures and superinfection and the need for modification of the monotherapy (P < 0.05). Empiric monotherapy based on primary disease appears to be safe and effective for febrile neutropenic children with cancer at our Brazilian institution. Further studies will be needed before these findings can be generalized to patient populations in other settings.

Fever and granulocytopenia in children with cancer: a study of 299 episodes with two treatment protocols in Brazil.

In Brazil, 226 children with cancer presenting 299 episodes of fever and neutropenia (< or = 500/mm3) were treated with two consecutive empirical regimens. Regimen I-Cefoxitin Amikacin-Carbenicillin; and Regimen II Ceftriaxone-Amikacin. 67.0% of the patients had leukemias or lymphomas, documented infections occurred in 47.2%, superinfections occurred in 18.7% (Reg. I) and 17.8% (Reg. II) of the episodes. The most common agents identified in Reg. I and Reg. II were, respectively, Gram negative rods (55.0%) and Gram positive cocci (52.6%). The overall rate of success with modifications (Amphotericin B, Vancomycin, Clindamycin, Metronidazole) was higher in Reg. II (93.0%) than in Reg. I (84.0%). This study shows that the appropriate formula to maximize the successful treatment of children with cancer, fever and neutropenia in developing nations includes adherence to established principles of supportive care, utilizing the optimal antibiotic agents available in the country. It is important to promote the necessary modifications along the treatment having in mind the high index of resistant agents.

[Fever and neutropenia in children with cancer: a new therapeutic proposal]. / Febre e neutropenia em crianças com câncer: nova proposta terapêutica.

Based on our previous experience treating children with cancer, fever and neutropenia we selected two different empirical regimens: Ceftriaxone once a day, for patients with solid tumors and lymphomas I-II (Low Risk group--LR) and Imipenem for patients with leukemias and lymphomas III-IV (High Risk group--HR). From Oct 1988 to Nov 1989, 121 episodes of fever (F+) and granulocytopenia (G+) in LR Group and 119 in HR Group were studied: the HR had 51.3% documented infections and the LR 58.7%. In the HR Group the following organisms were isolated from the blood cultures: Gram + 52%, Gram - 20% and fungal 28%. In the LR Group 78% of the organisms were Gram+. Positive blood cultures was 21% for the HR Group and 8.3% for the LR Group. There were 23.5% superinfections in the HR Group vs 5.7% in the LR. The mean time and the median time of granulocytopenia was 11.5 and 8 days (HR) and 6.9 and 6.0 days (LR), respectively. There were 14.5% (LR) and 45.4% (HR) modifications to the initial empirical antibiotic regimen (Amphotericin B, Vancomycin and Amikacin). The overall success rate was 97.6% (LR) and 94.2% (HR) and for documented infection the success rate was 95.7% (LR) and 91.8% (HR). We conclude that: a) The allocation of patients to two risk groups aiming to use distinguished therapy, allowed us to delineate two different populations, predominantly based on time of granulocytopenia, disappearance of fever, rate of superinfection, causative organisms and need of additional drugs to the initial scheme.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased survival, limb preservation, and prognostic factors for osteosarcoma.

Preoperative intraarterial (IA) cisplatin (CDP) was administered to 92 patients with nonmetastatic osteosarcoma. The ages of the patients ranged from 4 to 28 years. Sixty-four patients (70%) received 2 or 3 preoperative courses and 28 (30%) received 4 or more. Sixty-two specimens were available for pathologic examination to assess the degree of tumor necrosis. More than 90% tumor destruction was observed in 16 of 42 patients (38%) who received 1 to 3 preoperative courses as opposed to 17 of 20 (85%) who received 4 or more courses. Patients who received 4 or more courses had a 2-fold probability of achieving more than 90% tumor necrosis, and 68% underwent conservative surgery. Of those who received 3 or less courses, 23% underwent conservative surgery. Postoperatively, patients were treated with intravenous (IV) CDP alternating with doxorubicin (ADR) (Adriamycin, Adria Laboratories, Columbus, OH). Pulmonary metastases developed in 36 patients, bone metastases in 2, and local recurrence in 6. Two patients died of cardiac failure without evidence of disease. Thus, 46 patients (50%) were continuously free of disease 18 to 78 months after diagnosis. Univariate and multivariate analyses showed that male sex, low grade preoperative chemotherapy-induced necrosis, and nonosteoblastic histologic condition were prognostic factors predictive of recurrence, while male sex and large tumor size were prognostic factors predictive of death. These results are comparable with those reported by other centers and are superior to our previous experiences that yielded survival rates of 5% to 10%. A substantial number of patients also had the opportunity to achieve tumor removal with conservative surgery.

[Evaluation of antimicrobial schemes in episodes of fever and granulocytopenia in children with cancer]. / Evaluación de dos esquemas antimicrobianos en episodios de fiebre y granulocitopenia en niños con cáncer.

The efficacy of two antibiotic regimens used as initial empiric therapy was evaluated in 299 episodes of fever and granulocytopenia in children with cancer. Of these, 148 were treated with the combination cefoxitin-amikacin-carbenicillin and the remaining 151 with ceftriaxone-amikacin. All of the patients were evaluated at the beginning and 72 hours after starting treatment with laboratory tests and based on their clinical condition. Each was classified according to the type of infection. A few modifications were made to the initial treatment plan and in accordance with the clinical condition of each patient. Over 52% of the episodes were due to fever of unknown origin and 47.2% due to infections, of which 33.8% proved to be positive blood cultures mainly for Staphylococcus aureus and Pseudomonas aeruginosa. The modifications made to the basic treatment regimens were the addition of amphotericin B, clindamycin or vancomycin. An 89.2% therapeutic index percentage was obtained, independent from the use of either antibiotic scheme. The total therapeutic index for the study was 83.6%.

Adjustment to amputation among adolescent oncology patients.

With increased patient survival, the psychosocial consequences of amputation in cancer patients has become increasingly important. The following study examined the psychosocial correlates of amputation in 16 male and 17 female Brazilian adolescent patients aged 10-20 years who had lost a limb to cancer. Interviews were conducted within 12 months of amputation. Eighty-two percent indicated that they were involved in preoperative decision making, but only 58% understood the limitations in functioning after undergoing an amputation. Before surgery, the most frequently chosen confidante was the mother, followed by a sibling, staff member, and a friend. The major postoperative problems in these patients were walking, pain, and social issues. Overall, 75% of the amputees felt they were independent in and out of the home. Most individuals (66.6%) had, but fewer (58%) wore, their prosthesis. Prior to amputation, 30 patients were enrolled in school and 13 had a job. Of 15 who returned to school, 67% could not keep up with the school work and 93% had problems getting along with their classmates. Of five patients who returned to their jobs, no one reported discrimination in hiring or promotion; however, four workers felt they had lost a job because of their amputation, and two reproted having to change jobs. Many had altered their lifestyles to suit their disability, but the social and educational adjustment of these patients appears promising. Proper education of school faculty, classmates, and medical staff may enhance the adjustment of adolescent cancer amputees.

Evaluation of antimicrobial schemes in episodes of fever and granulocytopenia in children with cancer

The efficacy of two antibiotic regimens used as initial empiric therapy was evaluated in 299 episodes of fever and granulocytopenia in children with cancer. Of these, 148 were treated with the combination cefoxitin-amikacin-carbenicillin and the remaining 151 with ceftriaxone-amikacin. All of the patients were evaluated at the beginning and 72 hours after starting treatment with laboratory tests and based on their clinical condition. Each was classified according to the type of infection. A few modifications were made to the initial treatment plan and in accordance with the clinical condition of each patient. Over 52% of the episodes were due to fever of unknown origin and 47.2% due to infections, of which 33.8% proved to be positive blood cultures mainly for Staphylococcus aureus and Pseudomonas aeruginosa. The modifications made to the basic treatment regimens were the addition of amphotericin B, clindamycin or vancomycin. An 89.2% therapeutic index percentage was obtained, independent from the use of either antibiotic scheme. The total therapeutic index for the study was 83.6%