Gabriella Bernini

Neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity : A joint study by the italian and scandinavian sarcoma groups

PURPOSE To explore the effect of high-dose ifosfamide in first-line treatment for patients < or = 40 years of age with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination. RESULTS No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence. CONCLUSION The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.

Neoadjuvant Chemotherapy for Extremity Osteosarcoma: Preliminary Results of the Rizzoli's 4th Study

A neoadjuvant chemotherapy protocol (1/93-1/95) for extremity osteosarcoma preoperatively using high-dose methotrexate (HDMTX) as single agent per cycle and three different combinations of other drugs (CDP/IFO,CDP/ADM,IFO/ADM) is reported. The four drugs were used postoperatively as single agents. Treatment was uniform, but suspended earlier if total necrosis was attained. An improvement was found in the results of the previous study using only IFO postoperatively, with 16/119 patients (97%) avoiding amputation, and 38 (32%) attaining complete necrosis. At a 3-year (2-4 years) mean follow-up, 92 patients (76%) remained continuously disease-free, 2 died of chemotherapy-related toxicity and 25 suffered relapse. Projected 3-year DFS also improved (75% vs. 60%; p = 0.04). Despite limb salvage, local recurrences (6.3%) and infections were few, although postoperative chemotherapy was restarted within a week. Therefore, until new effective drugs are found, expertise in using the four known drugs may improve cure rate and help to avoid amputation in almost all patients.

Neoadjuvant Chemotherapy for Osteosarcoma of the Extremity: Intensification of Preoperative Treatment Does Not Increase the Rate of Good Histologic Response to the Primary Tumor or Improve the Final Outcome

Purpose The aim of this study was to compare the results in terms of histologic response to primary chemotherapy of two sequential studies in osteosarcoma patients preoperatively treated with methotrexate, doxorubicin, cisplatin, and ifosfamide, given at different doses Patients and Methods Between January 1993 and March 1995, 171 patients with osteosarcoma of the extremity were treated according to a protocol of neoadjuvant chemotherapy with preoperative methotrexate, cisplatin, doxorubicin, and ifosfamide. From April 1995 to December 1999, 196 osteosarcoma patients were preoperatively treated with the same drugs at higher doses. Postoperatively, patients received the same treatment in both studies used, but poor responders (tumor necrosis <95%) had more cycles of treatment than good responders. Results Comparing the two chemotherapy regimens, there were no significant differences in terms of good histologic response to chemotherapy (69% vs. 62%), 5-year event-free survival (60% vs. 65%), 5-year overall survival (74% vs. 80%), and rate of local recurrence (6% vs. 4%). The 5-year event-free survival was significantly related to the serum level of alkaline phosphatase before treatment (77% for patients with normal values vs. 46% for patients with high values) and the degree of histologic response to preoperative chemotherapy (69% for good responders vs. 54% for poor responders). Conclusions Increasing the doses of preoperative chemotherapy does not improve the rate of good histologic response and survival in osteosarcoma of the extremity. The degree of necrosis induced by preoperative treatment probably reflects an innate sensitivity to chemotherapy, which is not altered by increasing drug doses.

Sex cord stromal tumors of the ovary in children: a clinicopathological report from the Italian TREP project.

Ovarian sex‐cord stromal tumors (SCST) are rare in childhood and include a variety of neoplasms with different clinical features and biologic behavior. Aim of the analysis was to report the clinical findings and treatment results of a series of patients with SCST of the ovary, registered in a multi‐institutional Italian network on rare tumors in children and adolescent between 2000 and 2009.

Pediatric peripheral blood progenitor cell collection: haemonetics MCS 3P versus COBE Spectra versus Fresenius AS104

BACKGROUND: An increasing number of apheresis machines are becoming available for peripheral blood progenitor cell (PBPC) collection in children. STUDY DESIGN AND METHODS: At the Childrens Hospital of Florence (Italy), three apheresis machines were evaluated: MCS 3P (Haemonetics) (10 procedures in 4 patients, aged 10–12 years, weight 23.5‐64 kg), Spectra, (COBE) (8 procedures in 3 patients, aged 4–17 years, weight 19–59 kg), and AS104 (Fresenius) (24 procedures in 9 patients, aged 2–16 years, weight 13.6‐60 kg). For PBPC quantitative analysis, CD34 cytofluorimetry was employed. Relevant variables analyzed included efficiency of CD34+ cell extraction and enrichment, mononuclear cell purity and red cell contamination of the apheresis components, and platelet count decreases after leukapheresis. RESULTS: No significant differences in CD34+ cell‐extraction abilities were found. However, the AS104 provided consistently purer leukapheresis components in terms of mononuclear cell and CD34+ cell enrichment (441 +/− 59%, vs. 240 +/− 35% and 290 +/− 42% for MCS 3P and Spectra, respectively). Postapheresis platelet counts dropped the least with the AS104. The smallest patient who underwent apheresis with MCS 3P (the only machine working on discontinuous flow and hence with greater volume shifts) weighed 23.5 kg and tolerated the procedure well, with no signs of hemodynamic instability. No significant complications were observed. CONCLUSION: All machines seem to have comparable PBPC extraction efficiency, but the AS104 seems to give the component with the greatest PBPC enrichment. This feature might be relevant for further ex vivo cell processing (CD34+ cell selection, expansion, and so on).

G-CSF serum pharmacokinetics during peripheral blood progenitor cell mobilization: neutrophil count-adjusted dosage might potentially improve mobilization and be more cost-effective

The optimal dosing schedule of G-CSF for peripheral blood progenitor cell (PBPC) mobilization is still under investigation although many centers use 10 μg/kg/day in a single subcutaneous dose. However, G-CSF clearance increases with increasing absolute neutrophil count (ANC). Hence a G-CSF dosage adjusted to ANC might be a reasonable approach. We measured G-CSF trough serum levels by sandwich ELISA assay at different ANCs in eight patients undergoing treatment with filgrastim at 10 μg/kg/day in a single subcutaneous dose. A total of 26 samples were analyzed, and a strong correlation between increasing ANC and decreasing G-CSF levels was found by linear regression analysis (P < 0.0003, r2 = 0.4199). For ANC values above 5000/μl the trough serum levels, ie 24 h after administration, were consistently below the level that provides maximal clonogenic precursor stimulation in vitro (10 ng/ml). Serial serum G-CSF measurements performed in three patients at 0, 3, 6, 9 and 24 h after G-CSF administration, showed a reduction of the area under the curve (AUC) with increasing ANC. For an ANC of 20000/μl or greater, the G-CSF serum level fell under the maximal in vitro stimulation threshold of 10 ng/ml within 12 h. This preliminary pharmacokinetic data seems to suggest that an ANC-adjusted G-CSF dosing schedule might improve the design of PBPC mobilization regimens.

Painful procedures in children with cancer: comparison of moderate sedation and general anesthesia for lumbar puncture and bone marrow aspiration.

The study was conducted to compare moderate sedation (MS) with general anesthesia (GA) in the management of frequently performed lumbar puncture or bone marrow aspiration (BMA) during the treatment of childhood cancer.

Sex cord-stromal tumors of the testis in children. A clinicopathologic report from the Italian TREP project

PURPOSE Testicular sex cord-stromal tumors (SCSTs) are very rare in children and include a variety of neoplasms with different clinical features and biologic behavior. Aim of the study was to report the clinical findings and results observed in a series of patients with testicular SCST, registered in a multi-institutional Italian network on rare tumors in children and adolescents. MATERIALS AND METHODS The records of 11 patients, enrolled in 6 Italian centers from January 2000 to December 2008, were reviewed. The Childrens Oncology Group (COG) staging system was adopted. Chemotherapy was recommended in patients with incomplete surgery or metastatic disease. RESULTS A testicular mass was the most common symptom. All patients underwent primary removal of the tumor; orchiectomy with high ligation of spermatic cord was performed in 7 and tumor enucleation in 4. At histology, 4 patients had Leydig cell tumors, 4 juvenile granulosa cell tumors, 1 Sertoli cell tumor, 1 incompletely differentiated SCST, and 1 SCST with an intermediate pattern Sertoli cell tumor/mixed form. The histology of 8 of 11 cases was reviewed and investigated through immunohistochemical stains. Ten children were in stage I; 1 patient, who did not undergo hemiscrotectomy after enucleation through a transscrotal access, was considered stage II. All the patients are in first complete remission (mean follow-up, 59 months; range, 8-94). CONCLUSIONS Our experience confirmed the rarity of testicular SCST. They have to be considered in the differential diagnosis of testicular solid masses, taking into account that hormonal signs are present in a minority of cases. All patients were cured with surgery alone. The sparing surgery represented a choice in selected cases.

Advanced pediatric myelodysplastic syndromes: Can immunophenotypic characterization of blast cells be a diagnostic and prognostic tool?

The diagnosis of myelodysplastic syndromes (MDS) is mainly based on morphology and cytogenetic analysis. Several efforts to analyze MDS by flow cytometry have been reported in adults. These studies have focused on the identification of abnormalities in the maturation pathway of antigen expression of myelo‐monocytic cells, and characterization of blast populations. Therefore, phenotype has been proposed as a diagnostic and prognostic criterion tool for adult MDS. The current article provides data concerning the blast phenotype in pediatric MDS.

In vivo cytoreduction studies and cell sorting-enhanced tumor-cell detection in high-risk neuroblastoma patients: Implications for leukapheresis strategies

PURPOSE To improve autologous leukapheresis strategies in high-risk neuroblastoma (NB) patients with extensive bone marrow involvement at diagnosis. PATIENTS AND METHODS Anti-G(D2) immunocytochemistry (sensitivity, 1 in 10(5) to 10(6) leukocytes) was used to evaluate blood and bone marrow disease at diagnosis and during the recovery phase of the first six chemotherapy cycles in 57 patients with stage 4 NB and bone marrow disease at diagnosis. A total of 42 leukapheresis samples from the same patients were evaluated with immunocytology, and in 24 of these patients, an anti-G(D2) immunomagnetic enrichment step was used to enhance tumor-cell detection. RESULTS Tumor cytoreduction was much faster in blood compared with bone marrow (3.2 logs after the first cycle and 2.1 logs after the first two cycles, respectively). Bone marrow disease was often detectable throughout induction, with a trend to plateau after the fourth cycle. By direct anti-G(D2) immunocytology, a positive leukapheresis sample was obtained in 7% of patients after either the fifth or sixth cycle; when NB cell immunomagnetic enrichment was applied, 25% of patients had a positive leukapheresis sample (sensitivity, 1 in 10(7) to 10(8) leukocytes). CONCLUSION Standard chemotherapy seems to deliver most of its in vivo purging effect within the first four cycles. In patients with overt marrow disease at diagnosis, postponing hematopoietic stem-cell collection beyond this point may not be justified. Tumor-cell clearance in blood seems to be quite rapid, and earlier collections via peripheral-blood leukapheresis might be feasible. Immunomagnetically enhanced NB cell detection can be highly sensitive and can indicate whether ex vivo purging should be considered.