Liver allografts from donors with peritoneal contamination: report of two cases.

Organs from deceased donors with traumatic abdominal injury, peritoneal contamination and open abdomen are usually discarded due to risks of transmission of severe infections to the recipient. There are no specific recommendations regarding organ utilization from these donors, but they might be an unexplored source able to attenuate organ shortage. Herein, the first successful report of a case involving liver transplantation using a liver allograft procured from a deceased donor with an open abdomen is outlined. This donor was a young trauma patient in which peritoneal contamination had occurred following a gunshot wound. Also included in this the report is liver transplant from a donor, who also was a trauma victim with an enteric perforation. The decision-making process to accept liver allografts from donors with a greater risk of peritoneal infection involved the absence of uncontrolled sepsis or visible contamination of the cavity. Appropriate donor-recipient matching and adequate anti-infectious management might have contributed to a favorable outcome, which suggest that these donors can be used as alternatives to reduce organ shortage.

Long-term outcome for patients with non-metastatic Ewing's sarcoma treated with adjuvant and neoadjuvant chemotherapies. 402 patients treated at Rizzoli between 1972 and 1992.

We evaluated the long-term results obtained in 402 patients with non-metastatic Ewing's sarcoma (ES) of the bone treated in a single institution with adjuvant and neoadjuvant chemotherapies between 1972 and 1992. Multivariate analyses showed male gender, age older than 14 years, high serum lactate dehydrogenase (LDH) level, axial location of the tumour, use of radiotherapy alone as a local treatment, and poor histological response to chemotherapy, to be independent, adverse prognostic factors for event-free survival (EFS). At a mean follow-up of about 18 years (10-30 years), 177 patients (44.0%) remained continuously free of disease, 2 died of doxorubicin-induced cardiotoxicity and 8 developed a second neoplasm (5 died, and 3 are alive and free of disease). 215 patients relapsed with metastases and/or local recurrence: 14 are alive and free of disease, 1 is alive with uncontrolled disease, and 200 died. The overall survival (OS) at real follow-ups of 5-, 10-, 15- and 20-years was 57.2, 49.3, 44.9 and 38.4%, respectively. We conclude that since local or systemic relapses, treatment-complications and second malignancies are more common after 5 years or more from the beginning of treatment; a long-term follow-up is mandatory for patients with ES.

[Malignant primary tumors of the liver in childhood]. / I tumori maligni primitivi del fegato in età pediatrica. Esperienza di un singolo centro.

Twenty-one children (16 males, 5 females) with malignant primary hepatic tumors were admitted to the Pediatric Clinic of the University of Bologna between June 1973 and July 2001. The diagnosis was hepatoblastoma (HBL) in 16 cases; hepatocellular carcinoma (HCA) in 3 cases; undifferentiated sarcoma in 1, malignant rhabdoid tumour of the liver in 1. Median age at diagnosis was 1.8 year (1 mounth-13 years). As to intrahepatic tumor's extension, patients were classified in groups (from I to IV) according to International Society of Pediatric Oncology staging. 2 patients were ascribed to group I; 9 to group II; 9 to group III and I to group IV. At diagnosis 3 pts presented lung metastases. Seventeen patients (81%) were treated with surgery, in 11 cases as first approach to the tumor. In 10 patients, initially with unresesectable tumor, chemotherapy was started first. Drugs used were mostly Cisplatinum or Carboplatinum with Doxorubicin. Sussequently 6 patients were submitted to surgery. At a median follow up of 12.5 years, 52.3% of patients is alive without disease. This percentage rises to 58% taking into consideration only HBL and HCA cases (alive 11/19). We conclude that excluding metastases at diagnosis (3 deaths), the main prognostic factor is resectability and radical surgery: in our experience 4 patients with unresectable tumor died, as 2 patients with microscopical residual after surgery.

Primary follicular lymphoma of the testis in childhood: an entity with peculiar clinical and molecular characteristics.

BACKGROUND/AIMS: Paediatric primary follicular lymphoma of the testis (PPFLT) is exceptional: the few reported cases seem to lack BCL-2 gene rearrangement and/or protein expression. The aim of this study was to characterise a PPFLT arising in a 4 year old boy. METHODS: This case was characterised using conventional histological analysis, immunohistochemistry, and a polymerase chain reaction based method for the detection of immunoglobulin V(H) chain rearrangements. RESULTS: The neoplasm was staged I(E)/A; left orchiectomy and chemotherapy were performed, producing complete remission. Histology showed a predominantly follicular lymphoid infiltrate mainly composed of centroblast-like cells. The phenotype was CD20(+), CD79a(+), CD10(+), bcl-6(+), B cell specific activating protein(+), kappa light chain(+), CD30(-/+), interferon regulating factor 4(-/+), c-myc(-/+), lambda light chain(-), CD3(-), bcl-2(-), p53(-), cytokeratin(-), and placental alkaline phosphatase(-). Lymphomatous elements were found within a CD21(+) follicular dendritic cell network and 70% were positive for Ki-67/MIB-1. Molecular analysis revealed monoclonal immunoglobulin heavy chain gene rearrangement and BCL-6 mutations, in the absence of BCL-2 major breakpoint and BCL-2 minor cluster region rearrangements, p53 mutations, and death associated protein kinase gene hypermethylation. CONCLUSIONS: These findings suggest a different pathogenesis of PPTFL compared with adult follicular lymphoma and might explain its favourable course in spite of aggressive histology.

Hereditary thrombocytopenia due to reduced platelet production--report on two families and mutational screening of the thrombopoietin receptor gene (c-mpl).

Hereditary thrombocytopenias represent heterogeneous clinical and genetic syndromes. They include a consistent group of families which are considered as a separate clinical entity, characterized by autosomal dominant transmission, incomplete penetrance in females, chronic thrombocytopenia with early age of onset and frequently increased platelet volume, without any other hematologic abnormality. The molecular defect in these families is still unknown. We describe 2 families in 3 generations (10 patients), and report the first study of the TPO/c-mpl system in autosomal dominant thrombocytopenia. We performed mutational screening of c-mpl coding, flanking introns and promoter regions in 2 probands from the two families by DNA sequencing. The results do not provide evidence of c-mpl sequence alterations in either of the 2 families investigated. Moreover, the normal TPO serum levels detected in 5 patients from each family leads us to exclude the possibility of a defect in TPO production in our families. Finally, the involvement of both c-mpl and TPO genes in the pathogenesis of thrombocytopenia in these two families was excluded by negative results of linkage analysis.

Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience.

BACKGROUND: In 1991, the Italian Association for Pediatric Hematology-Oncology and the National Council of Research (CNR) initiated an Italian Cooperative Study (SE 91-CNR Protocol) with the main objective of improving the overall survival (SUR) and the event free survival (EFS) of children and young adults with localized Ewing sarcoma and primitive neuroectodermal tumors of bone compared with a previous study (IOR/Ew2 Protocol). METHODS: Between November 1991 and November 1997, 165 patients were enrolled in this study, 160 of whom were evaluable. The patients were treated with a multimodal approach characterized by intensified chemotherapy, hyperfractionated and accelerated radiation therapy, and the addition of ifosfamide and etoposide to standard chemotherapy with vincristine, actinomycin-D, doxorubicin, and cyclophosphamide. RESULTS: After a median follow-up of 37 months, 126 of the 160 evaluable patients remained free of disease recurrence. Thirty-one patients developed a disease recurrence (20 with disseminated disease). CONCLUSIONS: The 3-year SUR and EFS rates found in the current study (83.6% and 77.8%, respectively) may be considered satisfactory. Only age at diagnosis < or =14 years and a good histologic response appeared to affect the outcome of patients with localized Ewing sarcoma positively. These results appear to demonstrate the efficacy of the addition of ifosfamide in induction chemotherapy to four-drug standard combination chemotherapy, as confirmed by the improved outcome in terms of 3-year EFS reported in the SE 91-CNR Protocol compared with the IOR/Ew2 Protocol (77.8% vs. 60.7%). In addition, the better outcome also could be explained by the change in treatment strategy with a trend toward the use of more surgery than radiation therapy compared with the authors' previous protocol.

Long-term bone marrow cultures in Diamond-Blackfan anemia reveal a defect of both granulomacrophage and erythroid progenitors.

The hematopoietic defect of Diamond-Blackfan anemia (DBA) results in selective failure of erythropoiesis. Thus far, it is not known whether this defect originates from an intrinsic impediment of hematopoietic progenitors to move forward along the erythroid pathway or to the impaired capacity of the bone marrow (BM) microenvironment to support proliferation and differentiation of hematopoietic cells. Reduced longevity of long-term bone marrow cultures, the most physiologic in vitro system to study the interactions of hematopoietic progenitors and hematopoietic microenvironment, is consistent with a defect of an early hematopoietic progenitor in DBA. However, stromal adherent layers from DBA patients generated in a long-term culture system, the in vitro counterpart of BM microenvironment, did not show evidence of any morphologic, phenotypic, or functional abnormality. Our major finding was an impaired capacity of enriched CD34+ BM cell fraction from DBA patients, cultured in the presence of normal BM stromal cells, to proliferate and differentiate along the erythroid pathway. A similar impairment was observed in some DBA patients along the granulomacrophage pathway. Our result points to an intrinsic defect of a hematopoietic progenitor with bilineage potential that is earlier than previously suspected as a relevant pathogenetic mechanism of the disease. The finding of impaired granulopoiesis in some DBA patients underlines the heterogeneity of this rare disorder.

Neoadjuvant chemotherapy for Ewing's sarcoma of bone: no benefit observed after adding ifosfamide and etoposide to vincristine, actinomycin, cyclophosphamide, and doxorubicin in the maintenance phase--results of two sequential studies.

BACKGROUND: Ifosfamide (IF) alone or combined with etoposide (ET) was reported to be effective in the treatment of patients with Ewing's sarcoma who relapsed after treatment with the VACA regimen, which consisted of vincristine (VC), actinomycin (AC), cyclophosphamide (CP), and doxorubicin (AD). The purpose of this article is to report the results achieved in a new neoadjuvant protocol in which IF and ET were added to the conventional VACA regimen and administered to patients with localized disease. METHODS: In this study, eighty-two patients were treated between May 1988 and October 1991. Chemotherapy consisted of two induction cycles of VC/CP/AD followed by alternating cycles of VC/AD/CP, VC/IF/AC, IF/ET, and VC/CP/AC after local treatment. Twenty-two patients (27%) were treated with surgery only, 22 (27%) underwent surgery followed by radiation therapy, and 38 (46%) received radiotherapy only. RESULTS: At a median follow-up of 6.7 years (range, 4-9 years), 43 patients (52%) remained continuously disease free, and 39 relapsed (34 with metastases, 4 with local recurrence and metastases, and 1 with a local recurrence). These results were similar to those obtained at the same institute in a previous neoadjuvant study (March 1983 and April 1988) that included 108 patients treated with the conventional 4-drug regimen. The 5-year disease free and overall survival in the current study were 54% and 59%, respectively, and in the first study were 50% and 56%, respectively. CONCLUSIONS: The comparison of these two sequential studies, although not randomized, referred to homogeneous groups of patients observed at the same institution who were treated by the same medical team. No advantage was observed when IF and ET were added to the VACA regimen.

G-CSF-primed peripheral blood progenitor cells (PBPC) support in high-risk Ewing sarcoma of childhood.

Since 1993 pediatric patients affected by high-risk Ewing sarcoma for the presence at onset of a large pelvic mass and/or metastatic disease, were enrolled in a national pilot study comprehensive, finally, of a high-dose chemotherapy (HDCT) procedure with hemopoietic stem cell support. The HDCT procedure considered as consolidation of the disease status obtained after the first-line therapy was followed by the reinfusion of granulokine colony-stimulating factor-primed (G-CSF) peripheral blood progenitor cell (PBPCT). Here we present the results in terms of treatment-related toxicity, hospitalization and rescue of the bone marrow function, in 17 pediatric patients enrolled in such a pilot protocol and submitted to HDCT and PBPCT at the end of first-line therapy.

Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity.

The role of ifosfamide as first-line chemotherapy treatment of non metastatic Ewing's sarcoma of the extremity is still under discussion. The purpose of this paper is to report the results achieved in a neoadjuvant protocol (REN-3) in which ifosfamide, added to the conventional VACA regimen, was employed since the induction phase. Induction chemotherapy consisted of vincristine, cyclophosphamide, doxorubicin, actinomycin-D and ifosfamide. After local treatment, patients received the drugs used in the induction phase and etoposide. Between November 1991 and November 1994, 61 patients with non metastatic Ewing's sarcoma of the extremity were treated. Forty-nine patients underwent surgery and 73.5% of them had a good histologic response. At a median follow-up of 60 months (range 32-76), 48 patients (79%) remained continuously disease-free. The 5-year event-free and overall survival were 77% and 87%, respectively. These results were significantly better both in terms of histologic response or event-free and overall survival than those obtained in 58 patients with non metastatic Ewing's sarcoma of the extremity treated in a previous protocol (REN-2) in which the same drugs were used, but ifosfamide was employed only in the maintenance phase. The present study suggests the importance of early use of ifosfamide in the treatment of patients with non metastatic Ewing's sarcoma of the extremity.

Predictive factors of histological response to primary chemotherapy in Ewing's sarcoma.

Clinicopathologic variables associated with a good histological response to primary chemotherapy in Ewing's sarcoma are identified. The histological response to preoperative chemotherapy in 243 cases of Ewing's sarcoma treated with neoadjuvant chemotherapy was analyzed in relation to different clinicopathological features (sex and age of the patients, tumor size, serum lactate dehydrogenase (LDH) levels, tumor site) and to the type and schedule of anticancer drugs delivered preoperatively according to three consecutive chemotherapy regimens. A higher rate of good responses was achieved with the use of ifosfamide and dactinomycin in addition to a conventional three-drug VAC regimen, suggesting that these drugs should be included from the beginning in neoadjuvant regimens for the treatment of Ewing's sarcoma. The analysis of event-free survival in 158 patients with a 4-year minimum follow-up confirmed that histological response to preoperative chemotherapy is a reliable predictor of outcome in Ewing's sarcoma.

Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities.

PURPOSE: This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewing's sarcoma. PATIENTS AND METHODS: The response to chemotherapy was evaluated from the specimens of 118 Ewing's sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158). RESULTS: A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P < .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value. CONCLUSION: The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.

[The type of local treatment conditions the prognosis in patients with nonmetastatic Ewing's sarcoma of the extremities treated with adjuvant chemotherapy]. / Il tipo di trattamento locale condiziona la prognosi in pazienti con sarcoma di Ewing delle estremità non metastatico trattati con chemioterapia associata.

The results obtained in 172 cases of non metastatic Ewing's sarcoma of the extremities are reported. The patients were advised to undergo surgical treatment, followed by radiotherapy (40-45 Gy) in case of inadequate surgical margins. 48 patients who refused surgical treatment, were locally treated with radiotherapy alone (50-65 Gy). With a mean follow-up of 8 years (R. 3-15) 101 patients (58.7%) are free of disease and 68 relapsed with metastases and/or local recurrence. A radio-induced bone sarcoma developed in two patients, one patient died of ADM cardiomyopathy. No differences in terms of risk factors were observed between patients who were or were not treated with surgery. A better DFS was observed in the patients treated with surgery (66.9%) in comparison with those treated with radiotherapy alone. The higher percentage of local recurrences observed in patients treated with radiotherapy alone seems to be responsible for the worse prognosis observed in these patients. The authors' conclusion is that the local control in patients with non metastatic Ewing's sarcoma should always be achieved by means of surgery.

Long-term follow-up for patients with Ewing's sarcoma of bone treated with adjuvant and neoadjuvant chemotherapy.

The long-term results obtained in 252 patients with non-metastatic Ewing's sarcoma of bone treated between March 1972 and June 1988 according to three sequential protocols of treatment were evaluated. Primary tumor was treated with radiotherapy in 125 cases, with surgery in 52 and with surgical resection followed by radiotherapy in 75. In the first protocol (REA 1; 1972-78) chemotherapy was performed with a 3-drug regimen (VCR, CPM, ADM), whereas in the REA 2 protocol (1979-82) and in the REN 1 protocol (1983-88) a 4-drug regimen was used (VCR, CPM, ADM, ACTD). Chemotherapy was delivered as adjuvant treatment in REA 1 and 2, and as neoadjuvant in the last study. At a mean follow-up of 14.8 years, with the 95% of patients with a minimum FU of 10 years, 101 pts (40%) remained continuously free of disease, 144 patients relapsed, two patients died of adriamycin cardiotoxicity and 5 patients developed a second neoplasm. 6% of the patients relapsed 5 or more years after the diagnosis with the latest recurrence registered at the tenth year. Type of local treatment, LDH serum level, chemotherapy protocol and sex were predictive factors of DFS after a multivariate analysis. The possibility of late relapse in Ewing's sarcoma has been confirmed by our retrospective study and for patients with Ewing's sarcoma, a 10-year follow up should be recommended.

G-CSF in an infant donor: a method of reducing harvest volume in bone marrow transplantation.

We report the case of a 4-year-old female with high-risk ALL in first CR who received a BMT from an 11-month-old matched sibling treated with G-CSF in order to obtain an adequate number of mononuclear cells in a limited volume of bone marrow. The absence of toxicity, efficacy of the procedure and quality of the post-transplant clinical outcome suggest such treatments are feasible and useful to overcome problems caused by donor age and/or body weight. In view of this experience we demonstrate how such an approach leads to a notable reduction in risks and in bone marrow donation costs.

[Neoadjuvant treatment of Ewing's sarcoma: results obtained in 122 patients treated with a 6-drug chemotherapeutic protocol (vincristine, adriamycin, cyclophosphamide, dactinomycin, ifosfamide and etoposide)]. / Trattamento neoadjuvante del sarcoma di Ewing: risultati ottenuti in 112 pazienti trattati con un protocollo chemioterapico a 6 farmaci (vincristina, adriamicina, ciclofosfamide, deactinomicina, ifosfamide ed etoposide).

From January 1988 to October 1991, one hundred and twelve patients with non metastatic Ewing's sarcoma of bone were treated with a 6 drugs neoadjuvant chemotherapy protocol (IOR/Ew2) in which, to the four drugs usually used in the treatment of this tumor (vincristine, adriamycin, cyclophosphamide and dactinomycin), Ifosfamide and VP-16 were added. The local treatment consisted of radiation therapy in 52 cases, a surgical treatment was performed in 27 cases and in the remaining 33 cases both the previous treatments were used. At a mean follow-up of 4.5 years (3-6.5), 62 patients (55.3%) remained continuously free of disease and 50 relapsed: 41 with metastases, 8 with mestastases and local recurrence and 1 with local recurrence alone. These results do not differ from the ones obtained in our Institution in 98 patients treated between 1983 and 1988 with a neoadjuvant protocol (IOR/Ew1) in which only VCR, ADM, CTX and actD were used (3 year CDFS: IOR/Ew2 = 60.7%-IOR/Ew1 = 55.1%). In IOR/Ew2 a higher DFS rate was observed in the patients with tumor located in the axile bones in comparison with that obtained in the previous study (IOR/Ew2 = 48.6%, IOR Ew1 = 25.6%). Despite the fact that these results came from a not-randomized study, the authors conclude that the addition of Ifosfamide and VP-16 to the four drugs standard regimen do not improve the outcome of patients with Ewing's sarcoma of bone, with the possible exception of the patients with tumor located in the axile bones. This data should be confirmed in further and larger studies.

Longitudinal growth and final height in long-term survivors of childhood leukaemia.

Survival of children with acute lymphoblastic leukaemia (ALL) has increased considerably in recent years and data on the spontaneous growth and final height of these children are conflicting. Therefore, we analysed the longitudinal growth and final height in 52 survivors (33 females, 19 males) of childhood ALL. These children were diagnosed and treated in a single institution, all remained in first remission and were submitted to cranial irradiation with either 2400 or 1800 cGy. None of the patients received testicular or spinal irradiation. Median age at diagnosis was 4.2 (range 1.3-9.6) years in the first group (2400 cGy) and 3.9 (0.8-10.5) years in the second (1800 cGy). Standing height was measured at diagnosis, at the end of treatment (median 3.1 years after diagnosis), 6, 12, 24 months after the end of treatment, and finally at the completion of growth. In girls a significant decrease of mean height standard deviation score (SDS) during treatment and a catch up in growth after the end of therapy was followed by a second period of reduced growth. Mean final height SDS was significantly lower than the value at diagnosis in both groups of girls, but only in males treated with 2400 cGy. Mean overall loss in height SDS from diagnosis to final height was higher in females (-1.24) than in males (-0.40) (P = 0.009). Females < or = 4 years of age at diagnosis showed a higher loss in final height than females > 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Wilms' tumor involving the inferior vena cava: preoperative evaluation and management.

Neoplastic invasion of the inferior vena cava due to renal tumors (especially Wilms' tumor) is uncommon in children. The tumor thrombus, according to the aggressiveness of the original neoplasm, can extend in diverse ways, obliterate the vascular lumen completely, and even reach the right atrium. The luminal thrombus might be accompanied by the involvement of the caval wall, which requires wide vascular resection. The purpose of this paper is to present our experience with 7 children, aged 18 months and 6 years, affected by caval invasion due to Wilms' tumor. Furthermore, the diagnostic techniques and the surgical treatment in simple caval thrombosis and in associated invasion of the caval wall are described.

Evaluation of stage 4 neuroblastoma patients by means of MIBG and 99mTc-MDP scintigraphy.

In a group of 22 patients with a stage 4 neuroblastoma, MIBG and 99mTc-MDP scintigraphy and radiological skeletal survey were performed at diagnosis to assess the presence of metastatic skeletal disease. In 20 out of 22 patients the MIBG scan was repeated during follow-up at a time when maximum tumoral regression was expected, i.e. after 3-4 cycles of chemotherapy; scan results were correlated to clinical and laboratory data. At diagnosis MIBG scan showed bone involvement in 19/22 patients, 99mTc-MDP in 20/22 and radiological skeletal survey in 11/22. In 1 patient only marrow aspirate revealed diffusion of disease beyond the primitive lesion. A total of 117/161 (72%) bone lesions were detected by MIBG, 89/161 (55%) by 99mTc-MDP and 47/161 (29%) by radiological skeletal survey. MIBG scintigraphy revealed bone marrow involvement in 11/22 patients in whom either marrow aspirate or bone biopsy were positive. In 5 patients 14 soft tissue lesions were also discovered and all but one primitive lesion accumulated MIBG. Although MIBG scan detected a greater number of bone lesions than 99mTc-MDP, in two patients in whom MIBG scan was negative 99mTc-MDP revealed the presence of bone involvement. Therefore we conclude that 99mTc-MDP scan is necessary to fully assess bone involvement in neuroblastoma at diagnosis. When MIBG scan was repeated after chemotherapy there was a general reduction of the number of detected lesions and in 8/17 patients both bone metastases and marrow involvement could no longer be detected.(ABSTRACT TRUNCATED AT 250 WORDS)