Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours.

Multiple defects in apoptotic pathways have been described in peripheral neuroblastic tumours (NTs). Mitosis-karyorrhexis index (MKI) is a reliable morphological marker identifying favourable and unfavourable NTs. The extent to which apoptotic processes contribute to determine the clinical significance of MKI is still undefined. Apoptosis was investigated in a series of 110 peripheral NTs by comparing MKI to immunohistochemical and molecular apoptotic features. High MKI was found in 55 out of 110 NTs (50%) and was associated with advanced stage (P = 0.007), neuroblastoma (NB) histological category (P = 0.024), MYCN amplification (P < 0.001), and poor outcome (P = 0.011). Overall survival probability was 45% in patients with high MKI compared to 73% in patients with low MKI. In the same 110 NTs, the expression of Bcl-2, Bcl-XL, Bax and Mcl-1 was studied by immunohistochemistry, but no significant associations were found with clinicohistological features. Microarray analysis of apoptotic genes was performed in 40 out of 110 representative tumours. No significant association was found between the expression of apoptotic genes and MKI or clinicohistological features. Proliferative activity was assessed in 60 out of 110 representative tumours using Ki67 immunostaining, but no significant correlations with MKI or clinicobiological features were found. In NTs, the combination of apoptosis and proliferation as expressed by MKI is a significant prognostic parameter, although neither of them is per se indicative of the clinicobiological behaviour and outcome.

A single-institution Wilms' tumor and localized neuroblastoma series.

Since January 1980, 120 children affected by Wilms' tumor have been treated at Bambino Gesù, mostly with multimodality treatment according to Société Internationale d'Oncologie Pediatrique (SIOP) protocols, including chemotherapy, surgery and radiotherapy in selected cases. This treatment approach emphasizes the role of preoperative (neoadjuvant) chemotherapy as opposed to the approach favored by the National Wilms' Tumor Study, which is focused on optimizing postoperative chemotherapy after primary surgery. Thus, using SIOP guidelines, staging occurs at the time of surgery, after chemotherapy administration. These differences will constitute the baseline for a comparison between the two experiences. Bilaterality, nephroblastomatosis, partial nephrectomy in unilateral Wilms' tumor and thrombosis of the vena cava are the main topics discussed. For the present study, the analysis was restricted to 98 consecutive cases diagnosed until December 1999, for whom at least 24 mo of follow-up is available. The more recent experience of treating resectable neuroblastoma in cooperative studies dates back to 1979, when the first Italian Cooperative Group Neuroblastoma protocol was introduced. This experience was continued within the frame of the first Localized Neuroblastoma European Study Group protocol (LNESG 94), and will be compared to North American Cooperative Group approaches and outcomes. Preoperative evaluation of surgical risk factors, intraoperative complications and their management, and long-term outcome will be discussed.

Neurovesical dysfunction in children after treating pelvic neoplasms.

OBJECTIVE: To evaluate 10 years of experience, and thus define the occurrence and causes, of neurogenic lower urinary tract dysfunction in children with pelvic neoplasms treated by surgery. PATIENTS AND METHODS: From 1991 to 2000, 33 children were operated by the same surgeons for pelvic neoplasms; 11 were analysed, comprising four each with sacrococcygeal teratoma (ST) and ganglioneuroma, and one each with yolk sac tumour (YST), neuroblastoma and myofibroblastic bladder sarcoma (MBS). The other patients were not assessed because eight had died or were in severe progression, three were treated by bladder substitution and the others were lost to follow-up or refused a urological evaluation. All 11 children were evaluated at >/= 6 months after surgery with a questionnaire about bowel and voiding habits, a neurological and orthopaedic assessment, a noninvasive urodynamic study, renal ultrasonography and spinal and pelvic magnetic resonance imaging (MRI). All patients with signs of bladder dysfunction were evaluated by a pressure-flow study. The results were analysed for surgical approach and anatomical involvement, i.e. group A, extensive surgery for complete tumour excision in the sacral area (ST and YST); group B, surgery for tumour resection in the paraspinal ganglia area (neuroblastoma and ganglioneuroma); and group C, bladder tumour with partial bladder resection (MBS). RESULTS: Eight patients had signs or symptoms related to bladder sphincter dysfunction. One child refused the invasive urodynamic evaluation, leaving seven for analysis (two each ST and ganglioneuroma, one each YST, neuroblastoma and MBS). The urodynamic findings were normal in three children. On spinal and pelvic MRI a presacral lipoma with syringomyelia was discovered in one child with ST. Eight children had bladder dysfunction and two had no neurogenic damage (which was only in sacral tumours); in one child it was related to an upper motor neurone lesion from spinal dysraphism and in the other to a lower motor neurone lesion from surgical injury to the splanchnic nerves. Patients operated for paraspinal tumours had more bladder dysfunction but no signs of neurogenic damage, as did the patient with partial bladder resection. However in Group B, there may have been a transient or incomplete nerve injury in one patient. CONCLUSIONS: Deficits of parasympathetic, sympathetic and somatic innervation of the bladder and the urethra may occur in children after surgery for pelvic neoplasms, related to minor or major surgical trauma. In ST, a tethered cord may be associated with mixed neurogenic damage. Knowledge of bladder dysfunction in anorectal malformations, spinal dysraphism, etc. and the clinical protocol used in these patients also seemed to be useful for understanding the development of voiding dysfunction in patients with neoplasm.

Measures to prevent renal impairment after resection of retroperitoneal neuroblastoma.

Postoperative renal impairment has been reported after kidney-preserving resection of retroperitoneal neuroblastomas (NB). To avoid renal damage, intraoperative procedures include monitoring of central venous pressure (CVP) and diuresis, i.v. administration of electrolyte solutions, mannitol, and furosemide, and local application of lidocaine to the renal vessels. During the first 5 postoperative (p.o.) days, CVP, diuresis, body temperature (T), and lactate dehydrogenase (LDH) levels were monitored; color Doppler ultrasound (CDUS) was also performed on the 7th p.o. day. Simultaneous increases of T (>38.5 degrees ) and LDH (>1,500 IU/l) and/or reduction of urinary flow (< 1.5 ml/kg.h) were indicative of renal damage: in these cases dopamine was administered and CDUS performed. If renal blood flow was normal on CDUS, dopamine was administered for another 2 days; if a vascular thrombosis was detected, fibrinolytic agents (urokinase 4,000 IU/kg bolus and then 4,000 IU/kg.h for 24 h) were utilized. Between May 1997 and June 2000, 29 children (9 F, 20 M, aged) 6-72 months (median 39) affected by grade II inoperable, grade III, and grade IV NB underwent these preventive procedures at the time of surgical excision of the mass after chemotherapy 23 had an uneventful p.o. course. CDUS at 7 days was normal in 22; in 1 (polar resection at operation) it demonstrated a slight reduction of blood flow in the renal cortex. For all 23 patients, the CDUS at 3, 6, and 12 months was negative. Three patients showed a single altered parameter; the CDUS p.o. and during follow-up did not show any alteration. The other 3 patients had two or more altered parameters and were treated with dopamine: in 1 the initial CDUS was normal, but it later showed moderate hypotrophy; in 2 patients a vascular thrombosis was documented. Treatment with urokinase was successful in only 1 patient who had a normalized CDUS after 3 months. The 2nd child developed renal failure and needed hemodyalisis. In our experience, elevation of serum LDH and T and/or oliguria were good indicators of renal impairment. CDUS was also useful in detecting renal blood flow reduction and artery occlusion. These preliminary results show these intra- and postoperative measures to reliably avoid renal impairment in these children. Long-term follow-up could confirm the efficacy of these methods.

[Soft tissue sarcoma in childhood: local treatment in patients under 3 years of age. Analysis of the RMS-88 multicenter study]. / Sarcomi delle Parti Molli (SPM) in età pediatrica: trattamento locale nei pazienti sotto i tre anni di età. Analisi dello studio multicentrico RMS-88.

The purpose of this report is to describe the treatment and the outcome of patients affected by soft tissue sarcomas and enrolled in the Italian Cooperative Study RMS 88, whose age was less than 36 months. In particular the role of local treatment is discussed, considering that RT was not recommended by the protocol. The 104 patients, 70 affected by RMS and 34 by NR-STS, were grouped according to the Intergroup Rhabdomyosarcoma Staging (IRS) system. The general guidelines of the study for the local treatment included surgery in Gr I, surgery + radiotherapy (40 Gy) in Gr II, surgery (1 or more procedures) + radiotherapy (45-54 Gy) in Gr III, but RT was not recommended for patients < 3 years. RMS: The 5 patients in Gr I did not receive RT: 4/5 are alive NED and 1 is lost at FU. Among the 5 patients in Gr II, 5 did not receive RT and are alive NED; 4 were given RT and 2 of these died of disease. In the 56 patients in Gr III, RT was utilized in 25: 5 died of disease and 6 manifested distant sequelae due to RT. 10/31 patients who were not given RT, did not undergo any other local treatment and died of disease; 4 patients died after surgery only. NRSTS: 7/9 Gr I patients are alive (1 was treated with RT and did not present sequelae); 1/9 died and 1 is lost at FU. 3/6 Gr II patients are alive (1 after RT), 2 died of disease and 1 is lost at FU. 2/19 Gr III patients were given RT and 1 died of disease; 3 of the not irradiated patients died without any local treatment, 4 after surgery only. CONCLUSION: The local treatment was important for patients' outcome: only 28% of the RMS and 36% of the NRSTS patients who were not treated with surgery a/o RT are in CR. Surgery was not particularly aggressive (6 mutilating procedures). RT was utilized in 33/104 patients and sequelae were 7. The difference in overall survival between patients less than 3 and patients more than 3 is not statistically significant.

111 renal neoplasms of childhood: a clinicopathologic study.

PURPOSE: The aim of this study was to perform a clinicopathologic evaluation of a single pediatric institution renal tumor series. Most patients were treated within the frame of 3 consecutive SIOP trials, which included preoperative chemotherapy as their main feature. METHODS: Medical records and diagnoses of 111 patients were reviewed. The association of pathologic features with outcome was investigated by means of the Kaplan-Meier method, the Cox model, and a logistic multivariate analysis. Comparison among different trial results was carried out. RESULTS: In 98 patients (88%), nephroblastoma was diagnosed, followed by 6 adult-type renal tumors, 3 cystic nephromas, 2 mesoblastic nephromas, and 2 clear cell sarcomas. For nephroblastoma, a statistically significant correlation between grade and both disease-free survival rate and 5-year survival rate, and between stage and overall survival rate was shown. Lymph node involvement, local relapse, nephrogenic rests, and older age at presentation appeared to be less important prognostic factors. Tumor spillage was very sensitive to chemo or radiotherapy. No significant difference in outcome was observed among different trials. CONCLUSIONS: Wilms' tumor was the most frequent neoplasm and resulted in a 5-year cure rate of 90%. Clinical course was influenced mainly by diffuse anaplasia and, to a minor extent, by lymph node involvement. Because some tumors followed an unpredictable course, it is likely that also other biological factors played a significant role.

Glutathione transferase P1 polymorphism in neuroblastoma studied by endonuclease restriction mapping.

Several members of the different glutathione transferase (GST) gene classes are polymorphic. Particular interest has been focused on the GSTP class because this gene class is up-regulated during the early stage of oncogenesis and is significantly overexpressed in many human tumors. It has also been shown that high levels of GSTP1 expression are associated directly with tumor drug resistance and with poor patient survival. Our aim was to understand the possible association between GSTP1 polymorphism and cellular response to chemotherapeutic drugs in neuroblastoma. In fact, several antineoplastic drugs used in the neuroblastoma high-risk chemotherapeutic protocol are potential substrates of GSTP1-1 (etoposide, adriamycin and carboplatin). The GSTP1 genotype homozygote *A/*A was identified in 11 patients independent of their response to the chemotherapeutic treatment. Only four patients had a heterozygote genotype A*/B*. Therefore, based on our preliminary data, we were not able to conclude that GSTP1 polymorphism had an impact on patient response to treatment in neuroblastoma.

Importance of local treatment in pediatric soft tissue sarcomas with microscopic residual after primary surgery: results of the Italian Cooperative Study RMS-88.

BACKGROUND: The goal of primary excision in soft tissue sarcomas is the complete removal of the tumor by a nonmutilating procedure. However, microscopic residuals may be left after a conservative procedure because of inadequate preoperative assessment or difficulties during the operation. The purpose of this report is to describe the treatment and the outcome in patients, enrolled in the Italian Cooperative Study RMS-88, with microscopic residuals after primary excision (IRS Group IIa). PROCEDURE: Microscopic residuals were evident at histology in 52 of 90 patients who had a macroscopic complete primary excision: 25 rhabdomyosarcomas (RMS) and 27 nonrhabdo-soft tissue sarcomas (NRSTS). Eighteen patients were treated with primary reexcision (PRE) and chemotherapy (CT) using VA or IVA regimens; 27 patients received radiation therapy (RT; 40 Gy) and IVA; 7 children in whom PRE was not feasible and RT could not be administered for age <3 years were treated with CT (IVA) alone. RESULTS: Of the 18 patients who underwent a successful PRE + CT, the local relapses were 3 (16.6%); of 27 cases who had RT + CT there were 4 local relapses (14.8%); 3 local relapses occurred in those 7 patients in whom CT alone was administered (43%). CONCLUSIONS: Microscopic residuals after primary surgery were difficult to manage because of the absence of a measurable target. PRE represented the treatment of choice for children <3 years of age who cannot receive RT and for paratesticular sites. PRE and RT showed similar results in achieving local control in extremity and trunk sites, but they could not always avoid local recurrence. In particular PRE was not effective in tumors larger than 5 cm. If microscopic residuals could not be avoided and PRE was not possible, adequate RT was effective both for RMS and for NRSTS.

Features and outcome of neuroblastoma detected before birth.

BACKGROUND/PURPOSE: The growing use of routine ultrasonography during pregnancy is leading to an increasing number of prenatally diagnosed neuroblastomas. Optimal strategy has not yet been defined for these patients, because knowledge on this particular neuroblastoma (NB) population is still limited. However, definite guidelines are needed to avoid inadequate treatment. The authors analyzed the cases of antenatally detected NB (ADNB) reported in the Italian Neuroblastoma Registry during the past 6 years to elucidate the features of this subset of NB. METHODS: The Italian Neuroblastoma Registry was reviewed for the period January 1993 to December 1998 to collect clinical, radiographic, surgical, and histopathological data on ADNB cases. NB stage was evaluated according to INSS criteria. All patients had undergone imaging (computed tomography or magnetic resonance imaging) of the primary tumor and bone marrow biopsy before surgical resection. RESULTS: Seventeen patients were identified. Primary tumour site was adrenal glands in 16 cases and retroperitoneal ganglia in 1. Stage distribution was stage I, 13 cases; stage II-A, 1 case; stage II-B, 1 case; stage IV-S, 2 cases. All cases underwent primary tumour resection. Mean age at surgery was 4 weeks. Resection of primary tumor was radical in 16 cases, partial in 1. All tumors were characterised by favourable histology according to Shimada classification. N-myc gene amplification was studied in 14 patients. N-myc amplification was detected only in a newborn with stage II-A NB, who died of massive bleeding 2 days after tumor resection. DNA index and 1p deletion were studied in 11 and 8 patients, respectively. Both diploidy and deletion of 1p were observed in a newborn who subsequently died of disease progression despite surgery, chemotherapy, and radiation therapy. Fourteen of 17 patients currently are alive and free of disease, and one with IV-S NB and short follow-up is alive with disease. CONCLUSIONS: Our data give evidence that in most cases infants with ADNB represent a subset of patients with excellent outcome. Aggressive treatment may not always be necessary. Infants with ADNB with unfavorable features should undergo early surgical excision, whereas patients with favourable features could be observed awaiting spontaneous regression of the mass, reserving delayed surgery for tumors that increase in size or do not regress.

Myofibroblastic tumours: neoplasias with divergent behaviour. Ultrastructural and flow cytometric analysis.

Myofibroblasts are spindle cells having ultrastructural features in common with smooth muscle cells and fibroblasts. In the last few years, tumours have been described in which myofibroblasts represent not only a reactive mechanism but also a true neoplastic component. They constitute new nosologic entities which might be termed "myofibroblastic tumours". Tumours with benign and, rarely, malignant behaviour are reported to belong to this group of lesions. Recently, a third tumour type with borderline biological course, named "inflammatory myofibroblastic tumour" (IMT), has been identified, a condition that has been regarded as a benign and reactive disorder for a long time. Only in recent reports has been demonstrated that, in spite of an apparently benign morphological pattern, some cases of IMT have a malignant course. In this connection, DNA analysis by flow cytometry is a valuable diagnostic tool, because it allows identification of the ploidy status, a procedure that is often useful for predicting the nature and the biological behaviour of the lesion. In this study, 11 cases of myofibroblastic tumours were examined retrospectively by evaluating clinicopathological features and DNA ploidy status by flow cytometry. The diagnosis of myofibroblastic tumour was confirmed by performing histology, immunohistochemistry, and electron microscopy in all patients. In detail, these 11 cases were composed of 1 benign myofibroblastoma, 1 myofibrosarcoma and 9 IMTs. Among these myofibroblastic tumours, all those with local recurrence or distant metastases (one myofibrosarcoma and three IMT) showed an aneuploid cell population demonstrable by flow cytometric analysis, whereas the other cases with benign course (one benign myofibroblastoma and six IMT) exhibited an euploid DNA content. These data suggest the following: a) Besides the rare myofibroblastomas and myofibrosarcomas, IMTs represent a larger group of lesions with potentially different biological and clinical course. b) DNA flow cytometric analysis is a reliable tool that support histopathological examination in characterizing those cases of IMT that, though being malignant, mimic benign lesions. Consequently, it establishes the basis for a different therapeutic approach according to the euploid or aneuploid DNA content.

Spinal cord vascular injuries following surgery of advanced thoracic neuroblastoma: an unusual catastrophic complication.

BACKGROUND: Spinal cord injury is a possible complication associated with removal of thoracic dumbbell neuroblastomas. Our experience with two children whose postsurgical course was complicated by midthoracic spinal cord ischemia is reported there. Permanent paraplegia resulted in both. PROCEDURE AND RESULTS: Preoperative awareness of the origin and distribution of the Adamkiewicz artery (arteria radiculomedullaris magna, ARMM) and of the possible collateral pathways for spinal cord blood supply may be helpful in the planning of operations that involve dissection in the midthoracic posterior mediastinum. Otherwise, a flaccid paraplegia may result. CONCLUSIONS: The syndrome is presumed to be triggered by a spasm, an embolism, or a iatrogenic interruption of the ARMM.

[Peripheral neuroectodermal tumors of the chest wall. Description of a case]. / Tumori neuroectodermici periferici della parete toracica. Descrizione di un caso.

The authors discuss a case of malignant small round cell tumor of the thoracopulmonary region (Askin tumor) in which the initial pathological diagnosis was "sarcoma". Only a review of the histological specimens and the clinical features and evolution revealed the correct diagnosis of "Askin tumor". A 15 year old girl with fever, dyspnoea, cough underwent thoracentesis, which revealed hemothorax. At surgery, a large mass not involving the lung, with pleural thickening, was found in the left hemithorax and excised, without rib resection. No metastasis was observed at that time. Histological findings revealed features of malignant small round cell tumors, with occasional pseudo-rosettes. Chemotherapy was performed. 16 months after clinical presentation the girl died with abdomino-thoracic metastatic disease.

[Recurrent abdominal pain caused by nodular focal hyperplasia of the liver. A case report]. / Dolori addominali ricorrenti da iperplasia focale nodulare del fegato. Descrizione di un caso clinico.

A case of focal nodular hyperplasia of the liver in childhood (FNH or NRC) is reported; a conservative approach is usually preferred in this disease when the diagnosis is surely identified, and a follow-up for some years is recommended. Despite the increased accuracy of modern imaging methods none of them, singly or together, is able to differentiate a malignant lesion with certainty and histological confirmation is mandatory. In the case described a laparotomy frozen section was performed but it was not possible to make a diagnosis and the liver mass was removed. The patient had a complete relief of symptoms with no evidence of recurrence in the follow-up. A review of the literature has been made, trying to point out this disease and its treatment.

Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course?

PURPOSE: To determine whether resection of primary tumor has a favorable influence on outcome of infants (age 0 to 11 months) with stage IV-S neuroblastoma. PATIENTS AND METHODS: Between March 1976 and December 1993, 97 infants with previously untreated neuroblastoma diagnosed in 21 Italian institutions were classified as having stage IV-S disease. Seventy percent were younger than 4 months. Adrenal was the primary tumor site in 64 of 85 patients with a recognizable primary tumor. Liver was the organ most often infiltrated by the tumor (82 patients), followed by bone marrow and skin. RESULTS: The overall survival (OS) rate at 5 years in 80% and event-free survival (EFS) rate 68%. In 24 infants, the effect of resection of primary tumor could not be evaluated because of rapidly fatal disease progression (n = 8), absence of a primary tumor (n = 12), or partial resection (n = 4). Of 73 assessable patients, 26 underwent primary tumor resection at diagnosis: one died of surgical complications, one relapsed locally and died, and two others relapsed (one of these two locally) and survived, for a 5-year OS rate of 92% and EFS rate of 84%. Of the remaining 47 patients who did not undergo primary tumor resection at diagnosis 11 suffered unfavorable events, of whom five died, for an OS rate of 89% and EFS rate of 75% (no significant difference from previous group). Disease recurred at the primary tumor site in only one five who died, and in only one of six survivors of progression or relapse; in these patients, the primary tumor, located in the mediastinum, was successfully resected. CONCLUSION: Infants who underwent resection of the primary tumor at diagnosis had no better outcome than those in whom the decision was made not to operate.

[Accidents in childhood. Experiences at the Emergency Department of the Bambino Gesù Hospital of Rome]. / Gli infortuni in età pediatrica. L'esperienza del Servizio di Accettazione e Soccorso dell'Ospedale "Bambino Gesù" di Roma.

Considering the clinical and statistical data about injured children coming to the emergency department in the years between 1990 and 1995, the Authors hope better information, identification of risks, use of safety devices in order to successfully implement precautionary measures and the assistance in accidents which still are the first reason for death in children.

D-CECaT as preoperative chemotherapy for unresectable neuroblastoma in children over one year of age.

The role of intensive pre- and postoperative chemotherapy in unresectable nonmetastatic neuroblastoma is still controversial. A preoperative regimen that included deferoxamine, cyclophosphamide, etoposide, carboplatin and thiotepa (D-CECaT) was evaluated in 10 children over one year of age at diagnosis, and this was followed by surgery and postoperative chemotherapy. After four courses of D-CECaT, the response rate was 9/10 with 3 complete responses, 6 partial responses and 1 minor response. Severe but transitory myelosuppression was the major toxic effect. Complete remission by combined D-CECaT chemotherapy and surgery was obtained in 9/10 patients, while 1 case achieved complete remission only with postoperative chemotherapy. All children are disease-free with a median follow-up of 30.5 months (range: 1+ to 50+). This intensive treatment was effective in both standard- and high-risk unresectable NB. However, whether a less intensive approach and fewer courses can also give similar results in standard-risk cases warrants further study.

[Echinococcosis/hydatidosis in children: combined medical and surgical treatment]. / Echinococcosi/idatidosi in età pediatrica: trattamento combinato medico-chirurgico.

The outcome of 5 children with visceral hydatid cysts treated with Albendazole and surgical therapy is reviewed. The diagnoses were confirmed by immunological tests, X-ray, ultrasound scanner (US) and computer tomography. The therapeutic approach was correlated to the type of infection pictures. Immunological tests, X-ray and US were performed with the aim to evaluate the response to the therapeutic protocol. Combination of pharmacological and surgical treatment resulted in a complete resolution for all patients without any recurrence and further dissemination of infection.

[Treatment of parapneumonic empyema in children]. / Trattamento dell'empiema parapneumonico in età pediatrica.

A 31 case series of pleuropneumonia is presented, in a 7 year period. All patients were treated following same standards consisting of a pleural catheter insertion. Results support conservative treatment: short hospitalization and absence of psychological or physical traumas was achieved. Follow up is very good for all patients and none had invalidating consequences.

[Intrapancreatic lipoma: a case report]. / Lipoma intrapancreatico: descrizione di un caso.

A rare case of asymptomatic pancreatic lipoma in an eleven-month-old child is presented. The abdominal mass was discovered occasionally during a grip episode. Preoperative tests proved the presence of a neoformation arising from the pancreas. It was multilobed, capsulated and located between colon transversus, spleen and stomach without infiltration of surrounding structures. The histological picture was that of a mature lipoma. The authors discuss the differential diagnosis versus other fat tumors.