Biomedical subjects

F Fossati-Bellani

Publications and source records attributed to F Fossati-Bellani.

At least 19 recordsLinked to original sources

PubMed2005

Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment.

The aim of the present study was to evaluate the effectiveness of two consecutive nonrandomised treatment programs applied between 1989 and 1999 at the Istituto Nazionale Tumori of Milan in an unselected cohort of 59 children over the age of one with stage 4 neuroblastoma. Both treatment programs consisted of two phases, the induction of the remission phase and the consolidation phase. The induction of the remission phase consisted of intensive chemotherapy, and remained the same throughout the study period. The consolidation phase consisted of sequential hemi-body irradiation (HBI) (10 Gy per session, 6 weeks apart) in the first period (1988-June 1994) and sequential high-dose cyclophosphamide, etoposide, mitoxantrone+L-PAM and autologous haemopoietic stem cell transplantation in the second (July 1994-1999). Intention-to-treat analysis revealed a significantly better outcome for patients treated with the second program, the 5-year event-free survival probability being 0.12 for program 1 and 0.31 for program 2 (P=0.03). This finding led us to conclude that sequential HBI is useless as consolidation treatment. The high-dose chemotherapy adopted in the second program enabled a proportion of patients to obtain long-term survival but, since the clinical results remain unsatisfactory, new treatment strategies are warranted.

Adolescent↗

PubMed2001

Refinement within single yeast artificial chromosome clones of a minimal region commonly deleted on the short arm of chromosome 7 in Wilms tumours.

Cytogenetic and molecular data indicate an involvement of genes mapped to the proximal portion of the short arm of chromosome 7 (7p) in Wilms tumours (WTs). We have analysed 38 WTs using a panel of eight microsatellite markers mapped to proximal 7p. Loss of heterozygosity (LOH) in tumour, compared with matched constitutional DNA, was identified in eight cases. To define better the minimal region commonly deleted in these tumours, they were analysed with nine additional markers, mapped within the region of interest. One tumour (case 30) showed LOH for only one marker (D7S510), while maintaining heterozygosity for the two immediately flanking loci (D7S555 and D7S668). This result was confirmed by fluorescence in situ hybridisation analysis, which showed that in the majority (65%) of nuclei from tumour 30 hybridising with a bacterial artificial chromosome clone containing the D7S510 locus, only one signal was visible. Noticeably, both markers defining the limits of the observed deleted region are simultaneously present within two distinct overlapping yeast artificial chromosome (YAC) clones mapped to chromosome bands 7p13-p14. This suggests that the maximum length of the missing DNA fragment was approximately 1.3 Mb, corresponding to the length of the smaller of the two YAC clones. In all other cases that showed LOH, the deletion encompassed the 7p13-p14 region. For this reason, we speculate that the identified interval contains a gene whose inactivation is important for the development of at least a fraction of WTs.

Child↗

PubMed2001

Childhood malignant ovarian germ cell tumors: a monoinstitutional experience.

OBJECTIVES: We reviewed our 23-year monoinstitutional exprience with childhood malignant ovarian germ cell tumors (MOGCT), with respect to survival and iatrogenic sequelae. METHODS: Twenty-nine patients (median age 12 years) with newly diagnosed MOGCT were treated: all girls but 2 underwent surgery as initial treatment. There were 9 pure dysgerminomas and 20 nondysgerminoma tumors (5 immature teratomas, 4 yolk sac tumors, and 11 mixed histology tumors). According to the FIGO classification, 9 girls were classified as stage I, 4 as II, 11 as III, and 3 as IV, and 2 were not evaluable because they were submitted to primary chemotherapy. Twenty-four received chemotherapy with VAC, PVB, or PEB regimens, according to the ongoing protocols through the years. Three stage I girls did not receive adjuvant chemotherapy because of their histology (2 dysgerminomas, 1 immature teratoma) and stage. In the early years, postoperative radiotherapy was given alone in advanced dysgerminoma stages. RESULTS: Five patients died of their disease: 2 dysgerminomas (stage IIIc and IV) and 3 nondysgerminomas (2 stage II and 1 stage IIIc). OS and EFS rates at a median of 112 months were 81.8%. Among 24 survivors, 4 experienced iatrogenic amenorrhea because of radiotherapy and/or bilateral oophorectomy. CONCLUSIONS: MOGCT are highly chemosensitive and curable, with preservation of reproductive function. The management of recurrent disease remains an open issue.

Adolescent↗

PubMed2001

Undifferentiated nasopharyngeal carcinoma in children and adolescents: comparison between staging systems.

BACKGROUND: New criteria for classifying nasopharyngeal carcinoma were defined in the 5th edition of the American Joint Committee on Cancer (AJCC) staging manual. We investigated the clinical implications of the new system by comparing it with the 4th edition in a cohort of pediatric undifferentiated nasopharyngeal carcinoma (UNPC). PATIENTS AND METHODS: We retrospectively restaged 54 patients younger than 17 years who had biopsy-proven UNPC, treated between 1965 and 1999 in a single institution. RESULTS: Using the 5th edition an overall downstaging of the population according to T status, N status, and stage grouping was evident along with a better correlation with likelihood of survival. The comparison between local and advanced disease according to T stage (T1+T2 vs. T3+T4) became highly significant in the new system (P = 0.0011 vs. P = 0.067 in the 4th edition). CONCLUSIONS: As far as prognostic categories are concerned, the 5th edition of the AJCC staging manual appears to be an improvement over the previous classification, even though for pediatric patients a uniform distribution among stages cannot be observed because most children present with advanced disease. The overall downstaging should be taken into consideration for the stratification of patients in future trials.

Adolescent↗

PubMed2001

Effects of recombinant human granulocyte-macrophage colony-stimulating factor in an intensive treatment program for children with Ewing's sarcoma.

BACKGROUND AND OBJECTIVES: A treatment program including polychemotherapy at progressively escalating doses and sequential hemi-body irradiation (HBI) was adopted between 1987-1994 at our Pediatric Unit for high risk Ewing's sarcoma. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was added to the treatment program in a phase II study fashion to evaluate, in a pediatric setting, its tolerability, as well as its impact on drug dose escalation and on the need for supportive care. DESIGN AND METHODS: The study was open-label and sequential; GM-CSF administration (5 microg/Kg s.c./d x10) was planned after each chemotherapy cycle and after each HBI session in 18 consecutive patients (group A). Thirty-eight additional patients (group B) were treated by the same therapeutic program, without GM-CSF. In 12 patients (6 in each group) long-term bone marrow cultures (LTBMC) were performed to evaluate the myeloproliferative potential throughout the chemotherapeutic program. RESULTS: Seven of 18 (39%) patients experienced side effects from GM-CSF; 3/7 discontinued GM-CSF due to anaphylactic symptoms. The degree of neutropenia, as well as the frequency of infectious episodes and the need for supportive care were significantly lower in group A than in group B. Iatrogenic thrombocytopenia, and the possibility of performing drug-dose escalation were similar in the two groups. The 5-year event-free survival probabilities for group A and B were similar. LTBMC showed that the chemotherapy-related depletion of myeloid precursors could be more pronounced in patients receiving GM-CSF cyclically. INTERPRETATION AND CONCLUSIONS: In this series, GM-CSF was shown to be effective on iatrogenic neutropenia and related complications, with no impact on thrombopoiesis, drug dose escalation and outcome.

Adolescent↗

PubMed2000

Management of medulloblastoma and ependymoma in infants: a single-institution long-term retrospective report.

To reduce the sequelae from CNS irradiation (RT), 16 children younger than 3 years with medulloblastoma-PNET (13 cases) and ependymoma (3 cases) were treated between 1987-1993 according to different postsurgical chemotherapy (CT) programs. None of these patients presented with metastases. Eleven patients were rendered disease-free by surgery, while 5 had residual tumor. Adjuvant therapy depended on patients' age, postsurgical status and parents' consent to radiotherapy (RT). Nine of the 16 infants remained alive in continuous complete remission from the first neoplasm (median follow-up 7 years). Three of them had been treated with CT alone and 6 with combined CT + RT (posterior fossa 4, whole CNS 2). Seven patients relapsed a median of 13 months after diagnosis, and all 7 of them died of their disease. Despite the omission of RT in 6 of the 16 patients and administration of only focal RT in 8 of the 16, the outcome of this series was satisfactory. Local failure (in 5/7 patients) was the major problem, despite the high dose of RT used in 2 of these 5. In 4 of 6 evaluable children school performance was satisfactory. One child in whom the entire CNS was irradiated developed glioblastoma multiforme 120 months after the first diagnosis of medulloblastoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Synovial sarcoma: report of a series of 25 consecutive children from a single institution.

BACKGROUND: The role of postoperative radiotherapy and adjuvant chemotherapy in the treatment of synovial sarcoma remains to be determined. PROCEDURE: Twenty-five children were treated during a 23-year period with a multimodality approach. All of them had resection of the primary tumor (three amputations), followed by surgical retreatment in eight. Postoperative radiotherapy was delivered to 16 patients and adjuvant chemotherapy was given to 22. RESULTS: At the time of the report, 19 patients were alive and without evidence of disease. Six developed distant metastases (one associated with local recurrence); five of them died of their disease and one was alive in complete remission at 4 years from relapse. With a median follow-up of 9 years (range 2-23), the survival and the event-free survival at 5 years were 80% (SE 8.2) and 74% (SE 9.2), respectively. All relapsing patients had been classified as T2B. CONCLUSIONS: Multimodality treatment yielded satisfying survival results using limb-preserving surgery in most cases. Tumor size > 5 cm and invasiveness, which defined stage T2B, were the most important predictors of poor outcome. Evaluation of the role of adjuvant chemotherapy and radiotherapy awaits prospective studies, even if T2B patients, as well as children having nonradical surgery, seem worth managing by adjuvant treatments.

Adolescent↗

PubMed1999

Molecular analysis of 1p32 genetic involvement in pediatric T-cell non-Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVE: T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic T-cell non-Hodgkin's lymphoma (T-NHL) are closely related disorders, and distinguishing between the two may be difficult. Cytogenetic investigations of large NHL series reported different recurring chromosomal alterations. Among these, aberrations of chromosome 1p seem to be associated with T-cell differentiation, the region most frequently involved in breakpoints being band 1p32-36. Deletions and translocations involving the same chromosomal region are frequently observed in T-ALL, in which one of the most common genetic changes is the breakage of the TAL1 gene, mapped to the 1p32 chromosomal region. The objective of this study was to assess the possibility of TAL1 involvement also in T-NHL. DESIGN AND METHODS: A series of 17 pediatric T-NHL patients was molecularly characterized by microsatellite markers analysis and by TAL1 gene microdeletions. RESULTS: TAL1 gene rearrangement was found in one case, while loss of heterozygosity (LOH) and microsatellite instability (MI) was identified in another case. INTERPRETATION AND CONCLUSIONS: Overall our findings indicate that, differently from T-ALL, neither TAL1 gene involvement nor LOH or MI at 1p32 appear particularly relevant in the oncogenic process of T-NHL transformation.

Adolescent↗

PubMed1999

Cytogenetic and molecular characterization of T-cell acute lymphoblastic leukemia as a second tumor after anaplastic large-cell lymphoma in a boy.

We report a case of acute T-cell lymphoblastic leukemia which developed in a boy 8.5 years after successful treatment for anaplastic large-cell lymphoma. Cytogenetic and molecular characterizations of the second tumor were performed. The cytogenetic investigation revealed a complex pattern of karyotypic alterations, including double minutes, ring chromosomes, and a duplication of the p21-32 region of chromosome 1. The microsatellite DNA analysis excluded rearrangement or deletion of the TAL1 gene in the tumor cells; rearrangements of the MLL gene were excluded by Southern blot analysis. To the best of our knowledge, this is the first report of T-cell lymphoblastic leukemia arising after treatment of CD 30+ anaplastic large-cell lymphoma. The different T-cell receptor rearrangement evidenced in the two tumors indicates that this second malignancy most likely emerged de novo, but was plausibly related to the previous radiation and chemotherapy.

Child↗

PubMed1998

The management of paratesticular rhabdomyosarcoma: a single institutional experience with 44 consecutive children.

PURPOSE: We report a single institutional experience with 44 consecutive children treated from 1976 to 1996 for paratesticular rhabdomyosarcoma. MATERIALS AND METHODS: After primary surgical excision, 27 cases were classified as Intergroup Rhabdomyosarcoma Study (IRS) group I, 1 as group II, 8 as group III and 8 as group IV. Except for the first 5 patients, retroperitoneal node dissection was not a required staging procedure and was performed only for radiologically suspicious node metastases. Adjuvant chemotherapy was administered to all patients. Additional radiotherapy was given when nodal involvement or residual disease was documented. RESULTS: The 5-year event-free survival rate was 77% for the entire series of patients, 93% for those in groups I and II, 62.5% in group III and 37.5% in group IV with a median followup of 11 years (range 2 to 20). CONCLUSIONS: Our report confirms the excellent prognosis of localized paratesticular rhabdomyosarcoma. Due to the accuracy of computerized tomography potential morbidity of lymphadenectomy, low rate of retroperitoneal recurrence and presumed efficacy of chemotherapy for controlling microscopic disease, retroperitoneal lymph node dissection seems unnecessary for localized disease.

Adolescent↗

PubMed1998

No evidence of WT1 involvement in a Burkitt's lymphoma in a patient with Denys-Drash syndrome.

BACKGROUND: We previously reported the case of a patient affected with Denys-Drash syndrome (DDS), who developed disseminated EBV-related Burkitt's lymphoma (BL) after kidney transplantation. Here, we describe the molecular characterisation of the WT1 gene in the constitutional and tumour DNA of this patient. PATIENTS AND METHODS: WT1 exons 2 to 10 were sequenced in constitutional and tumour DNAs. By Southern blotting the latter was also investigated for the presence of gene rearrangements. Gene expression analysis in tumour cells was performed by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: A germline missense mutation affecting one of the zinc finger domains of the gene, and previously reported in other DDS cases, was observed. No alterations of the constitutionally wild-type WT1 allele and no expression of the gene were observed in BL cells. A small group of BLs from other paediatric patients showed a variable expression of WT1. CONCLUSIONS: Our findings indicate that WT1 is unlikely to be involved in the onset of BL in our case. However, a possible role of the gene in at least a subset of these lymphoproliferative diseases may be suggested.

Abnormalities, Multiple↗

PubMed1997

Treatment of childhood post-irradiation sarcoma of bone in cancer survivors.

PATIENTS AND METHODS: This is a retrospective review of five children with post-irradiation bone sarcoma (PIS). Age at PIS onset ranged between 10 and 17 years (median 11). They were treated with a chemotherapy regimen, similar to that in use for primary osteogenic sarcoma, consisting of vincristine and high-dose methotrexate alternated with cisplatinum and ifosfamide, given for 12 months. RESULTS: In all children chemotherapy induced a complete clinical remission. Four of them were alive in continuous complete remission at 1, 2, 4, and 12 years from the diagnosis of bone sarcoma. One girl recurred 3 years from PIS diagnosis and was salvaged by repeating the same chemotherapy program: she remained alive in second complete remission 8 years from relapse. CONCLUSIONS: In spite of an intensive treatment previously given for the primary tumor, this drug schedule proved to be feasible and short-term side effects were manageable. Chemotherapy alone, using an intensive regimen effective for primary osteogenic sarcoma, may be an adequate therapy for childhood post-irradiation sarcoma.

Adolescent↗

PubMed1996

Mapping of a putative tumor suppressor locus to proximal 7p in Wilms tumors.

Different findings suggest that alterations of chromosome 7 genes play a role in the development of Wilms tumors. To define the positions of these genes, we have accomplished a combined cytogenetic and molecular study on 11 sporadic Wilms tumors. In one case, where both chromosomes 7 were rearranged, the karyotypic picture was consistent with the presence of a tumor suppressor gene at 7p15. To test this hypothesis, a loss of heterozygosity analysis was performed using microsatellite markers. This revealed a common region of allele losses mapped to the proximal short arm of chromosome 7 and defined the position of the gene(s) involved in Wilms tumors within an interval of approximately 25 cM.

Chromosome Mapping↗

PubMed1996

Breast cancer and other second neoplasms after childhood Hodgkin's disease.

BACKGROUND: Patients who survive Hodgkin's disease are at increased risk for second neoplasms. As survival times increase, solid tumors are emerging as a serious long-term complication. METHODS: The Late Effects Study Group followed a cohort of 1380 children with Hodgkin's disease to determine the incidence of second neoplasms and the risk factors associated with them. RESULTS: In this cohort, there were 88 second neoplasms as compared with 4.4 expected in the general population (standardized incidence ratio, 18.1; 95 percent confidence interval, 14.3 to 22.3). The estimated actuarial incidence of any second neoplasm 15 years after the diagnosis of Hodgkin's disease was 7.0 percent (95 percent confidence interval, 5.2 to 8.8 percent); the incidence of solid tumors was 3.9 percent (95 percent confidence interval, 2.3 to 5.5 percent). Breast cancer was the most common solid tumor (standardized incidence ratio 75.3; 95 percent confidence interval, 44.9 to 118.4), with an estimated actuarial incidence in women that approached 35 percent (95 percent confidence interval, 17.4 to 52.6 percent) by 40 years of age. Older age (10 to 16 vs. <10 years) at the time of radiation treatment (relative risk, 1.9) and a higher dose (2000 to 4000 vs. <2000 cGy) of radiation (relative risk, 5.9) were associated with significantly increased risk of breast cancer. The estimated actuarial incidence of leukemia reached a plateau of 2.8 percent (95 percent confidence interval, 0.8 to 4.8 percent) 14 years after diagnosis. Treatment with alkylating agents, older age at the diagnosis of Hodgkin's disease, recurrence of Hodgkin's disease, and a late stage of disease at diagnosis were risk factors for leukemia. CONCLUSIONS: The risk of solid tumors, especially breast cancer, is high among women who were treated with radiation for childhood Hodgkin's disease. Systematic screening for breast cancer could be important in the health care of such women.

Actuarial Analysis↗

PubMed1994

Long-term outcome of patients with monostotic Ewing's sarcoma treated with combined modality.

One hundred and twenty-one consecutive patients with monostotic Ewing's sarcoma (ES) were treated according to three consecutive combined modality programs from 1974 to 1986. Their 3-year progression free survival (PFS) rate from diagnosis of 59% was identical to the event free survival (EFS) rate, since all the 50 events occurring within 3 years from diagnosis were tumor recurrences. Primary tumor was treated with radiotherapy in 75 cases, surgical resection plus radiotherapy in 38, and radical surgery in 8. Chemotherapy was given to all patients and each program included adriamycin, vincristine, and cyclophosphamide +/- dactinomycin. Median follow-up was 12 years, ranging from 6 to 19 years. The PFS rate decreased to 49% at 6 years and plateaued at 46% after the 7th year from diagnosis, even though some relapses were observed as late as 14 years from diagnosis. Second malignancies developed in 7 patients free from progressive ES and were represented by osteogenic sarcoma in previously irradiated bone in 4 cases and by breast carcinoma in 3. No other event but tumor relapse or second malignancy occurred in this series. EFS rate was 47% at 6 years and 39% at 12 years, further decreasing in the following years because of a number of late events. A continuous PFS longer than 7 years may be consistent with cure in the majority of patients with monostotic ES. However, these patients should be followed indefinitely because of risk of second malignancies.

Adolescent↗

PubMed1994

Intracranial germ cell tumors: a comprehensive update of the European data.

Intracranial germ cell tumors are rare tumor entities in childhood and adolescents. Extra- and intracranial germ cell tumors are identical in their histologic pattern and occur in preferential midline localizations such as the pineal and the suprasellar region. Germ cell neoplasms show increasing incidence rates over the last 30 years. The majority of intracranial germ cell neoplasms are germinomas. About 90% of the patients with pure germinomas can be salvaged by radiotherapy alone according to modern protocols. Non-germinomatous malignant CNS-germ cell tumors are considered to have a poor prognosis. In order to improve the survival of patients affected by these tumors different treatment approaches adding chemotherapy to conventional surgery and radiotherapy have been initiated by various study groups throughout the world. Due to the rarity of these neoplasms only a very limited number of patients has been enrolled in each study. In 1993 an international working group on these tumors was established by the International Society of Pediatric Oncology (SIOP).

Brain↗

PubMed1993

Curability of advanced Burkitt's lymphoma in children by intensive short-term chemotherapy.

The treatment programme (regimen I) we designed in 1982 for advanced Burkitt's lymphoma was modified in 1986 as regimen IIA and IIB for patients presenting without or with bone marrow (BM) and/or nervous system involvement, respectively. Following a 5-week course of cytoreductive chemotherapy, including vincristine (VCR), cyclophosphamide (CPM), doxorubicin (DXR), high-dose methotrexate (HDMTX) and intrathecal methotrexate and cytarabine (ARAC), high-dose ARAC and cisplatin were given as a 4-day continuous infusion. Regimen I continued with an additional 3-week course including VCR, CPM, DXR and HDMTX, which was omitted in regimen IIA. In regimen IIB the initial cytoreductive chemotherapy was complemented by adding etoposide and increasing HDMTX doses, and by modifying the high-dose ARAC administration modality and was followed, once the bone marrow had recovered, by ifosfamide that concluded the programme. A total of 44 children (22 in regimen I and 22 in regimens IIA and IIB) were treated, with an overall response rate of 98%. 4 patients died as a result of treatment related complications. Survival, progression-free and event-free survival rates were 73, 70 and 63%, respectively, for regimen I, and 82, 90 and 82%, respectively, for regimen IIA and IIB. A short chemotherapeutic regimen, using alternating phase-specific and non-specific agents, is able to cure the majority of patients with advanced Burkitt's lymphoma.

Adolescent↗

PubMed1992

Phenotypic and functional analysis of lymphocytes infiltrating paediatric tumours, with a characterization of the tumour phenotype.

Tumour-infiltrating lymphocytes (TIL) of paediatric tumours obtained from 37 lesions of different histotype (12 osteosarcomas, 5 Wilms' tumours, 7 soft-tissue sarcomas, 5 neuroblastomas and 8 miscellaneous) were studied to establish their potential for therapy. Fresh isolated TIL were cultured for the first 2 weeks with low doses of interleukin-2 (IL-2) (20 Cetus U/ml) to select for "tumour-specific" lymphocytes potentially present in the neoplastic lesion, followed by culture with high doses of IL-2 (1000 Cetus U/ml) to achieve TIL expansion. TIL were grown with more than 10-fold expansion in only 9 cases (mean expansion: 58-fold, range 13.5-346). In 17 cases no viable cells were obtained. After 30 days of culture with IL-2 the proliferative ability of TIL declined sharply in the majority of cases and TIL became refractory to any further stimulus, including addition of IL-4, tumour necrosis factor alpha (TNF alpha) or interferon gamma, and activation with OKT3 in solid phase. In 20 out of 37 cases TIL were available for phenotypic and functional analysis. TIL after long-term culture were predominantly CD3+ but 2 cases of osteosarcoma showed a predominance of CD3+TcR gamma/delta cells. The CD4/CD8 ratio was more than 1 in 10 cases, without correlation with tumour histology, site of lesion or TIL growth. The number of CD16+ and CD25+ lymphocytes decreased progressively during culture, the latter concomitantly with a reduction of TIL growth rate. The lytic pattern of TIL against allogenic and autologous tumour (Auto-Tu) cells was variable, but specific lysis of Auto-Tu was seen in only one case (Wilms' tumour) after culture with TNF alpha and irradiated Auto-Tu cells. The immunohistochemical analysis of tumour lesions revealed a limited lymphocyte infiltrate, a low expression of histocompatibility leukocyte antigens (HLA) class I and of the adhesion molecules ICAM1, LFA3, and a significant production of transforming growth factor beta (TGF beta). These data indicate that TIL obtained from paediatric patients are difficult to expand at levels required for immunotherapy and lack a significant number of tumour-specific T lymphocytes. A low expression of immunomodulatory molecules on tumour cells or the production of suppressive factors may prevent activation and expansion of TIL in paediatric tumours.

Antigens, CD↗