Hyperfractionated low-dose radiotherapy for high-risk neuroblastoma after intensive chemotherapy and surgery.

PURPOSE: To assess prognostic factors for local control in high-risk neuroblastoma patients treated with hyperfractionated 21-Gy total dose to consolidate remission achieved by dose-intensive chemotherapy and surgery. PATIENTS AND METHODS: Patients with high-risk neuroblastoma in first remission received local radiotherapy (RT) totaling 21 Gy in twice-daily 1.5-Gy fractions. RT to the primary site followed dose-intensive chemotherapy and tumor resection; the target field encompassed the extent of tumor at diagnosis, plus 3-cm margins and regional lymph nodes. RT to distant sites followed radiologic evidence of response. Local failure was correlated with clinical factors (including other consolidative treatments) and biologic findings. RESULTS: Of 99 consecutively irradiated patients followed for a median of 21.1 months from RT, 10 relapsed in or at margins of RT fields at 1 to 27 months (median, 14 months). At 36 months after RT, the probability of primary-site failure was 10.1% +/- 5.3%. No primary-site relapses occurred among the 23 patients whose tumors were excised at diagnosis, but there were three such relapses among the seven patients who were irradiated with evidence of residual disease in the primary site. Four of 18 patients with MYCN-amplified disease and serum lactate dehydrogenase greater than 1,500 U/L had local failures (23.4% +/- 10.7% risk at 18 months). Acute radiotoxicities were insignificant, but three of 35 patients followed for > or = 36 months had short stature from decreased growth of irradiated vertebra. CONCLUSION: Hyperfractionated 21-Gy RT is well tolerated and, together with dose-intensive chemotherapy and surgery, may help in local control of high-risk neuroblastoma. Extending the RT field to definitively encompass regional nodal groups may improve results. Visible residual disease may warrant higher RT dosing. Patients with biologically unfavorable disease may be at increased risk for local failure. RT to the primary site may not be necessary when tumors are excised at diagnosis.

Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase.

PURPOSE: We have synthesized a series of hybrid polar compounds that induce differentiation and/or apoptosis of various transformed cells. These agents are also potent inhibitors of histone deacetylases (HDACs). Pyroxamide (suberoyl-3-aminopyridineamide hydroxamic acid) is a new member of this class of compounds that is currently under development as an anticancer agent. We investigated the activity of pyroxamide as an inducer of differentiation and/or apoptosis in transformed cells. EXPERIMENTAL DESIGN AND RESULTS: Pyroxamide, at micromolar concentrations, induced terminal differentiation in murine erythroleukemia (MEL) cells and caused growth inhibition by cell cycle arrest and/or apoptosis in MEL, prostate carcinoma, bladder carcinoma, and neuroblastoma cells. Administration of pyroxamide (100 or 200 mg/kg/day) to nude mice at doses that caused little evident toxicity significantly suppressed the growth of s.c. CWR22 prostate cancer xenografts. Despite the potent growth-inhibitory effects of pyroxamide in this tumor model, serum prostate-specific antigen levels in control versus pyroxamide-treated mice were not significantly different. Pyroxamide is a potent inhibitor of affinity-purified HDAC1 (ID(50) = 100 nM) and causes the accumulation of acetylated core histones in MEL cells cultured with the agent. Human CWR22 prostate tumor xenografts from mice treated with pyroxamide (100 or 200 mg/kg/day) showed increased levels of histone acetylation and increased expression of the cell cycle regulator p21/WAF1, compared with tumors from vehicle-treated control animals. CONCLUSIONS: The findings suggest that pyroxamide may be a useful agent for the treatment of malignancy and that induction of p21/WAF1 in transformed cells by pyroxamide may contribute to the antitumor effects of this agent.

Histone deacetylase inhibitors and retinoic acids inhibit growth of human neuroblastoma in vitro.

BACKGROUND: Neuroblastoma is a common childhood cancer with a poor overall prognosis. Retinoic acids (RAs) have been studied as a potential therapy, showing promise in recurrent disease. The histone deacetylase inhibitor (HDACI) M-carboxycinnamic acid bishydroxamide (CBHA) is another potential therapy, which we recently described. Combinations of RAs and HDACIs currently under investigation display synergy in certain neoplasms. In this study, we evaluate the effect of combinations of RAs and HDACIs on human neuroblastoma cells. PROCEDURE: Established cell lines were cultured in increasing concentrations of HDACIs, RAs, and combinations thereof. Following exposure, viable cell number was quantified by trypan blue dye exclusion on a hemacytometer. Cell cycle analysis was performed by propidium iodide staining and FACS. RESULTS: All assayed HDACIs and RAs decreased viable cell number. Lower concentrations of each agent were effective when the two were combined. The primary reason for decreased cell number appears to be apoptosis following HDACI exposure and G1 arrest following RA exposure. Both effects are seen with cotreatment. Caspase inhibition abrogates the apoptotic response. CONCLUSIONS: CBHA causes apoptosis of human neuroblastoma in vitro, an effect that can add to the effects of RA. HDACIs and RAs inhibit neuroblastoma in significantly lower concentrations when used together than when used individually. Combination therapy may improve the ultimate efficacy while reducing the side effects of these agents in clinical use.

The long-term complications of chemotherapy in childhood genitourinary tumors.

Combination chemotherapy, often in conjunction with surgery and external radiotherapy, is utilized in most children with tumors of the genitourinary tract. These chemotherapeutic agents are capable of causing a variety of delayed toxicities. Common late complications include cardiotoxicity associated with prior exposure to an anthracycline, pulmonary dysfunction, infertility in males due to prior therapy with alkylating agents, and secondary leukemia in individuals treated with epipodophyllotoxins.

Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection.

OBJECTIVE: We sought to establish the outcome and optimal therapeutic sequence for patients with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor of the chest wall. METHODS: Patients 30 years of age or younger with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor of the bone were randomly assigned to receive vincristine, doxorubicin, cyclophosphamide, and dactinomycin or those drugs alternating with ifosfamide and etoposide. Local control was obtained with an operation, radiotherapy, or both. RESULTS: Fifty-three (13.4%) of 393 patients had primary tumors of the chest wall (all rib). Event-free survival at 5 years was 57% for the chest wall compared with 61% for other sites (P >.2). Ifosfamide and etoposide improved outcome in the overall group (5-year event-free survival, 68% vs 54%; P =.002), and a similar trend occurred in chest wall lesions (5-year event-free survival, 64% vs 51%). Patients with chest wall lesions had more attempts at initial surgical resection (30%) than those with other primary tumor sites (8%, P <.01). The attempt at initial resection for chest wall lesions did not correlate with size. Initial resections at other sites were restricted to smaller tumors. Initial resection resulted in negative pathologic margins in 6 of 16 patients, whereas the delayed resection resulted in negative margins in 17 of 24 patients (P =.05). Although there was no difference in survival by timing of the operation in rib lesions, a higher percentage of patients with initial surgical resection received radiation than those with resection after initial chemotherapy (P =. 13). CONCLUSIONS: Although rib primary tumors are significantly larger than tumors found in other sites, their outcome is similar. We favor delayed resection whenever possible to minimize the number of patients requiring radiation therapy.

Pediatric chest wall Ewing's sarcoma.

BACKGROUND: Chest wall tumors of primitive neuroectodermal origin (PNET, Ewing's sarcoma [ES]) are rare and have a poor prognosis. Multimodality therapy has improved survival results, and long-term survival is possible. Whether adjuvant radiation therapy is uniformly beneficial remains unclear. METHODS: A retrospective analysis of the authors' institutional experience between 1979 and 1998 was performed. RESULTS: Twenty consecutive patients with PNET-ES of the chest wall were identified. The median age was 12 years (range, 2.5 to 21 years). Median follow-up was 3 years (range, 7 months to 19.4 years). Seven patients presented with a mass, 12 with pain, 1 with respiratory distress, and 1 with a neuropathy. Initial therapy consisted of biopsy and neoadjuvant chemotherapy followed by chest wall resection in 12 patients. Of the remaining 8 patients, 6 underwent biopsy, followed by chest wall resection and adjuvant chemotherapy, 1 underwent biopsy, chemotherapy, and resection of a lung nodule, and 1 underwent biopsy, chemotherapy, and a laminectomy and decompression procedure. All 20 patients were included in institutional-based trials using multiagent chemotherapy. Fifteen patients received radiation therapy with a median dose of 3,000 cGy. At last follow-up, 11 patients are alive and disease free, with a median survival of 7.5 years (range, 7 months to 19.4 years). Seven of 11 (64%) survivors had neoadjuvant therapy followed by chest wall resection. Seven of 11 (64%) survivors had radiation therapy. There was no surgical mortality. Twelve patients had treatment-related complications, 3 of which were related to surgical resection. There were no survivors among patients with recurrent disease. Three of the patients who died of disease had both local and distant recurrences, 4 patients had distant recurrence only, and one patient had local recurrence only. Only 4 of 9 (44%) patients who died were treated initially with chemotherapy followed by chest wall resection. All but 1 of those that died (89%) received initial radiation therapy. All 9 patients who did not survive received additional salvage radiotherapy as well. CONCLUSIONS: Long-term survival is possible with ES-PNET after complete chest wall resection. This may be facilitated by neoadjuvant chemotherapy. Long-term survival without radiation therapy is possible, and consideration of radiation therapy should be made on a case-by-case basis.

Clinical categories of neuroblastoma are associated with different patterns of loss of heterozygosity on chromosome arm 1p.

Deletion of the short arm of chromosome 1 is frequently observed in neuroblastoma (NB). We performed loss of heterozygosity (LOH) analysis of 120 well characterized NB to better define specific regions of 1p loss and any association with clinical and biological prognostic features (DNA index, MYCN, age, and stage). All categories of disease were represented including 7 ganglioneuromas, 8 stage 4S, 33 local-regional (stages 1, 2, and 3), and 72 stage 4 NB according to the International Neuroblastoma Staging System. Patients were consistently treated with stage-appropriate protocols at a single institution. Sixteen highly informative, polymorphic loci mapping to chromosome 1 were evaluated using a sensitive, semi-automated, fluorescent detection system. Chromosome arm 1p deletions were detected in all categories of tumor except ganglioneuroma. Frequent LOH was detected at two separate regions of 1p and distinct patterns of losses were associated with individual clinical/biological categories. Clinically aggressive stage 4 tumors were predominantly diploid with extensive LOH frequently detected in the region of 1ptel to 1p35 (55%) and at 1p22 (56%). The shortest region of overlap for LOH at 1p36 was between D1S548 and D1S1592 and for 1p22 was between D1S1618 and D1S2766. Local-regional tumors were mostly hyperdiploid with short regions of loss primarily involving terminal regions of 1p36 (42%). Most spontaneously regressing stage 4S tumors (7/8) were hyperdiploid without loss of 1p36 or 1p22. These findings suggest that genes located on at least two separate regions of chromosome arm 1p play a significant role in the biology of NB and that distinct patterns of 1p LOH occur in individual clinical/biological categories.

Clinically critical impact of molecular genetic studies in pediatric solid tumors.

BACKGROUND: Standard cytogenetic techniques are time-consuming and often not informative with solid tumors. In contrast, the reverse transcriptase-polymerase chain reaction (RT-PCR) is a readily available technique that can rapidly detect tumor-specific chromosomal rearrangements, even in small biopsy specimens. We present cases depicting the importance of including molecular diagnostic studies in the routine evaluation of pediatric solid tumors. PROCEDURE: We used RT-PCR to detect chimeric transcripts specific for major pediatric solid tumors, including peripheral primitive neuroectodermal tumor (pPNET), alveolar rhabdomyosarcoma (ARMS), and desmoplastic small round-cell tumor (DSRCT). We reviewed six recent cases in which the initial diagnosis was changed by the results of RT-PCR. RESULTS: Highly unusual or nonspecific clinical and/or histopathologic findings led to the initial diagnoses of neuroblastoma in three patients and DSRCT, leukemia, and carcinoma in one patient each. The final diagnoses after RT-PCR studies were pPNET in three patients, ARMS in two patients, and DSRCT in one patient. RT-PCR results led to early corrections in the diagnosis in two patients, but four patients received treatment not considered optimal for the neoplasms ultimately diagnosed, including three who, despite presenting with localized tumors that have a >70% cure rate with standard therapy, have died or are dying of disease. CONCLUSIONS: Molecular genetic studies on solid tumors can clarify the diagnosis in seemingly straightforward as well as in overtly problematic cases. These diagnostic distinctions are now critical as disease-specific and risk-directed therapies have emerged.

Childhood melanoma survival.

BACKGROUND: Melanoma in childhood is uncommon. Some believe that melanoma among children is associated with a better prognosis than among adults. METHODS: The authors reviewed their institutional experience with melanoma in 40 patients younger than 18 years treated between 1950 and 1984. All slides were reviewed by a single dermatopathologist who was blinded to clinical outcomes. Long term follow-up was available for all but three patients. RESULTS: There were 26 girls and 14 boys. The median age at diagnosis was 15 years (range, 3-17 years). Eleven patients (28%) were younger than 12 years. Fifteen patients (38%) had melanoma arise in a congenital nevus (2 had bathing trunk nevi. The most common site was the extremity (n = 23), followed by the trunk (n = 10) and the head and neck (n = 7). Seventeen patients (43%) initially were considered to have benign lesions, and 23 patients (57%) were diagnosed correctly with melanoma at initial presentation. Only 21 of 37 evaluable patients (57%) were alive at last follow-up with a median follow-up of 18 years (range, 2-48 years). Fifteen patients (41%) died of their disease, with a median survival of 12 months (range, 6-60 months). One patient died of breast carcinoma 14 years after treatment for melanoma. Disease free survival was 57% at 5 and 10 years. Of the 15 patients who died of disease, 12 were female (P = 0.09) and 10 had melanoma arising in a congenital nevus (P < 0.05). Five-year overall survival was 78% for patients who presented with localized disease (n = 23) and 30% for patients who presented with regional metastasis (n = 16, P < 0.001). There were no survivors among those who presented with systemic disease (n = 1). CONCLUSIONS: Children with melanoma are at significant risk of dying of their disease. Survival is similar to that seen among adults and depends on stage at presentation. The survival advantage observed for adult females is not seen among children.

Synovial sarcoma mimicking desmoplastic small round-cell tumor: critical role for molecular diagnosis.

BACKGROUND: The identification of recently described nonrandom chromosomal defects specific for various small round-cell and spindle-cell sarcomas can eliminate diagnostic uncertainty arising from the clinical and histopathologic overlap of soft tissue neoplasms. METHODS: A 26-year-old man presented with bulky abdominal-pelvic disease. Immunohistochemical and molecular studies on tumor were performed. Treatment was instituted using cycles of high-dose cyclophosphamide (4,200 mg/m2) with doxorubicin (75 mg/m2). RESULTS: Clinical findings pointed to desmoplastic small round-cell tumor. The tumor was histologically undifferentiated and immunoreactive for vimentin but negative for other markers. Reverse transcriptase-polymerase chain reaction revealed the SYT/SSX2 fusion transcript of the synovial sarcoma t(X;18) chromosomal rearrangement. The high-dose chemotherapy, plus surgery, achieved a complete remission, but recurrent disease emerged 13 months from diagnosis. CONCLUSIONS: This clinically unique case of synovial sarcoma highlights how the use of now readily available molecular techniques will allow more accurate appraisals of the incidence and anatomic distribution of soft tissue neoplasms-information that bears upon pathogenesis and treatment. This case confirms the utility of high-dose alkylator-based therapy for synovial sarcoma. It also demonstrates that with nonlocalized solid tumors, the eradication of minimal residual disease remains an elusive goal. One alternative involves immunologic attack against markers derived from tumor-specific chromosomal defects such as those found in our patient.

Clinical, pathologic, and molecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants.

PURPOSE: Intense investigation has reshaped concepts about undifferentiated tumors occurring in young people (small round-cell tumors). Tumors associated with t(11;22)(p13;q12) and descriptively designated desmoplastic small round-cell tumor (DSRCT) are a distinctive, rare, poorly understood member of this family. We reviewed 109 cases of DSRCT to further characterize this entity better. METHODS: Clinical information and histology were reviewed. Immunohistochemistry and immunoblotting were performed using standard techniques. Chimeric EWS-WT1 RNA and DNA were detected by polymerase chain reaction (PCR) and genomic translocation breakpoints mapped in a subset of cases. RESULTS: There were 90 males and 19 females from 6 to 49 years of age (mean, 22 years). A total of 103 had tumor in the abdominal cavity, four in the thoracic region, one in the posterior cranial fossa, and one in the hand. Typical histologic and immunohistochemical features were usually evident in well-sampled tumors, but variations in cellularity, stromal components, cytology, architecture, and immunoreactivity occurred. Tumor cells were usually reactive with antibodies to keratin (67 of 78 cases, 86%), epithelial membrane antigen (50 of 54, 93%), vimentin (64 of 66, 97%), desmin (70 of 78, 90%), neuron-specific enolase (60 of 74, 81%), and the EWS-WT1 chimeric protein (25 of 27, 93%); typically nonreactive for muscle common actin (one of 58, 2%), myogenin (zero of eight, 0%), and chromogranin (one of 46, 2%); and variably reactive for MIC2 (nine of 47, 20%) and p53 (five of 17 with > 20% tumor cells reactive). Functional EWS-WT1 gene fusion was evident in 25 of 26 cases with genomic breakpoints in WT1 intron 7, and EWS introns 7, 8, and 9. Prognosis in general is poor, but tumors are responsive to aggressive therapy. CONCLUSION: This large review identifies a greater degree of clinical, pathologic, and molecular variation than originally appreciated for tumors associated with t(11;22)(p13;q12). Translocation and functional fusion of the EWS and WT1 genes appears to be a consistent feature of this unique tumor.

High-dose induction chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy in rhabdomyosarcoma, extraosseous Ewing's sarcoma, and undifferentiated sarcoma.

PURPOSE: To improve response and survival rates in patients with high-risk rhabdomyosarcoma (RMS), extraosseous Ewing's sarcoma, and undifferentiated sarcoma, we used a short course of induction with multi-agent chemotherapy, hyperfractionated radiotherapy, and surgery when possible. Consolidation was with intensive chemotherapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Twenty-six patients (21 with RMS, three with undifferentiated sarcoma, and two with extraosseous Ewing's sarcoma) were entered onto the protocol between June 1990 and March 1994. Induction consisted of ifosfamide, etoposide, doxorubicin, dactinomycin, cyclophosphomide, and vincristine, and a split course of hyperfractionated radiotherapy. Patients who attained a complete response (CR) or good partial response (GPR) received consolidation with high-dose melphalan and etoposide followed by ABMT. RESULTS: Of 26 previously untreated patients 19 (73%) achieved a CR (n=13) or GPR (n=6) at the completion of induction and underwent ABMT. Two-year overall survival (OS) was 56% (95% confidence interval [CI], 36% to 76%) and progression-free survival (PFS) was 53% for the whole group (95% CI, 33% to 73%). CONCLUSION: Consolidation of response by myeloablative chemotherapy was well tolerated. Split-course hyperfractionated radiotherapy did not increase the rate of local control. The results of this short-course therapy were comparable to previous therapies of 1 to 2 years' duration. Induction and consolidation chemotherapy, as well as radiation dose, could be further intensified, since no death due to toxicity occurred among these patients.

Neovascularity and clinical outcome in high-grade extremity soft tissue sarcomas.

BACKGROUND: Increased tumor neovascularity has been shown to correlate with poor prognosis in solid tumors. METHODS: Microvessels were identified by factor VIII immunohistochemical staining. Analysis of microvessel counts, tumor characteristics, and resection details was performed on 119 primary, high-grade extremity soft tissue sarcomas (STS) and correlated with clinical outcome. RESULTS: Tumor characteristics and resection details were analyzed and patient outcome was examined with respect to local recurrence, distant metastasis, and disease-specific survival. Factors found to be significant on univariate analysis for all outcome variables were positive microscopic margin and tumor size. A positive microscopic margin was found to be a significant risk factor for local recurrence (P = .03), distant metastasis (P = .006), and disease-specific survival (P = .004). A primary tumor greater than 10 cm in diameter was a poor prognostic factor for distant metastasis (P = .03) and disease-specific survival (P = .006) when compared to tumors smaller than 10 cm. Microvessel count did not correlate with survival nor did it predict distant metastasis or local recurrence. Histologic subtypes of STS that have a prominent vascular pattern as a diagnostic criterion (i.e., angiosarcoma, liposarcoma, hemangiopericytoma) form a subgroup of all STS. Neovascularity in these subtypes showed no relationship to clinical outcome. CONCLUSIONS: These data confirm the prognostic importance of microscopic margin and tumor size in high-grade extremity STS. Neovascularity measured by factor VIII staining had no prognostic significance in these mesenchymal tumors, in contradistinction to carcinomas. Alternatively, microvessel counts may not accurately represent the angiogenic capacity of STS. Therefore, patients with STS who are eligible for anti-angiogenesis clinical trials cannot be identified solely by microvessel count.

Pediatric rhabdomyosarcoma of the head and neck.

PURPOSE: Survival for pediatric rhabdomyosarcoma has improved with the use of multidrug chemotherapy and external beam radiotherapy. This study was performed to determine survival in a cohort of patients treated on one of three multidrug treatment protocols for head and neck rhabdomyosarcoma and to identify factors that place patients at risk for treatment failure. METHODS: Pertinent prognostic variables including age, sex, subsite of origin, resectability, and TNM stage were analyzed by the Kaplan-Meier methods with comparisons between variables performed using the Prentice-Wilcoxon test statistic. RESULTS: Overall 5-year survival was 74% (95% confidence interval 64% to 84%). Local failure accounted for the cause of death in 10 patients, and 8 died of disseminated disease. On univariate analysis, each variable contributing to the TNM staging system was significant in determining survival; invasiveness (P = 0.01), size (P = 0.02), nodal metastases (P <0.01), and distant disease (P <0.01). CONCLUSION: Survival has improved for head and neck rhabdomyosarcoma treated with multimodality therapy. Patients with advanced-stage disease are at greatest risk for treatment failure and require the most aggressive therapy.

Chest wall rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma is the most common soft tissue sarcoma in the pediatric age group. The primary tumor site is an important prognostic determinant. Axial lesions are associated with decreased survival and provide a clinical challenge. METHODS: A retrospective analysis of the authors' institutional experience between 1972 and 1996 was performed. Patients were from a data base of 302 consecutive cases. RESULTS: Fifteen consecutive patients with chest wall rhabdomyosarcoma were identified. The median age was 16 years (range, 6 months-25 years). Median follow-up was 6.6 years (range, 10 months-18.5 years). Nine patients presented with a mass, six with pain, two with respiratory distress, and one with ulnar neuropathy. The median lesion size was 7 cm (range, 3-16 cm). A surgical procedure was the initial therapy for 13 of 15 patients. Fourteen patients received radiation therapy with a median dose of 4400 cGy. All but one were included in institutional-based trials using multiagent chemotherapy. At last follow-up, 10 patients were alive and disease free, with a median survival of 123 months (range, 51-221 months). Seven of ten survivors underwent a complete resection as their initial therapy. There was no surgical mortality, and only two patients had treatment-related complications. Of the five patients who died, two underwent complete resection as their initial therapy. All five patients had invasive tumors. Four were > 10 cm, 3 were of alveolar subtype, and 2 were embryonal. CONCLUSIONS: Complete resection of chest wall rhabdomyosarcoma is recommended. However, survival is possible for patients with microscopically positive surgical margins with the addition of chemotherapy and radiation.

The application of minimal access procedures in infants, children, and young adults with pediatric malignancies.

OBJECTIVE: In this study, we sought analysis of minimal access procedures in pediatric and young adult oncology patients. METHODS: Between 1990 and 1997, 84 patients underwent 93 minimal access procedures. Clinical, pathological, and operative details were analyzed. RESULTS: There were 32 females and 52 males with a median age of 14 years (range 3 months to 31 years). The median body weight was 50 kg (range 6-94 kg). There were 47 thoracoscopic procedures and 46 laparoscopic procedures. Laparoscopic procedures included liver biopsy (21), diagnostic tumor biopsy (13), lymph node biopsy (4), cholecystectomy (4), oophoropexy (3), and kidney biopsy (1). Median hospital stay was 2 days (range 1-14 days). Six patients had their procedure converted to an open procedure (13%). Thoracoscopic procedures included diagnostic lung biopsy (22), mediastinal mass biopsy or resection (4), pleural biopsy (5), and pleurodesis (4). Eleven were converted to open thoracotomy (23%). Median hospital stay was 4 days (range 2-35 days). There were two complications after laparoscopy (4%) and three disease-related deaths. There were six complications after thoracoscopy (13%), and three disease-related deaths. Adequate tissue was obtained in all biopsy procedures. CONCLUSIONS: Children with cancer require operations for diagnosis and staging. Minimal access procedures are safe and effective and allow adjuvant therapy to begin earlier.

Survival from non-stage 4 neuroblastoma without cytotoxic therapy: an analysis of clinical and biological markers.

The clinical characteristics of 43 patients (pts) and the biological features of their non-stage 4 neuroblastoma (11, 3, 15, 7 and 7 with stages 1, 2A, 2B, 3 and 4S, respectively) all managed initially without cytotoxic therapy at Memorial Sloan-Kettering Cancer Center are summarised. We staged patients by the International Neuroblastoma Staging System and measured their urine and serum tumour markers. Tumour MYCN copy number, chromosomal ploidy, chromosome 1p deletion, Shimada histopathology, trk-A and CD44 expression were analysed. Among patients with localised tumour (n = 36), 13 had residual disease after initial surgery, 19 had regional lymph node invasion and 6 had epidural involvement (2 of 6 being paraplegic). All 7 stage 4S patients had liver tumours, 3 had bone marrow involvement and 3 had lymph node involvement. The most common adverse biological markers were unfavourable histopathology (9/40 evaluable tumours) and diploidy (7/39 tumours tested). At a median follow-up of 50+ months, 42 patients are alive and well (5 with evidence of disease), and 1 patient in remission died of encephalopathy. Progressive/recurrent disease occurred in 12 patients, 1 stage 2A, 2 stage 2B, 4 stage 3 and 5 stage 4S. Chemotherapy was eventually used in 4 patients: a 3-year-old stage 2B patient who developed stage 4; a 2-year-old whose recurrent tumour had poor-risk biological markers; a 1-year-old whose recurrent stage 3 disease infiltrated a vertebral body and a stage 4S infant with respiratory impairment from progressive hepatomegaly. Three of the treated patients had diploid tumours. We conclude that non-stage 4 is of itself a strong predictor of a favourable outcome. Diploidy, unfavourable histopathology and unresectable tumours were associated with disease progression. However, evolution of local-regional tumour into distant metastatic stage 4 disease is not typical of neuroblastoma.

A cDNA encoding a putative 37 kDa leucine-rich repeat (LRR) protein, p37NB, isolated from S-type neuroblastoma cell has a differential tissue distribution.

In human neuroblastoma cells in culture, three morphologically distinct types of cells are observed: neuroblastic N-type cells, Schwannian S-type cells, and intermediate I-type cells. To investigate the differences in gene expression between N-type LA1-55N and S-type LA1-5S cells of the human neuroblastoma cell line LA-N-1, we constructed a subtractive cDNA library from LA1-5S cells. One of the genes that are expressed more in S-type cells than in N-type cells was identified as previously undescribed and is the focus of this report. We cloned a full-length cDNA of this gene, p37NB, and determined its sequence. A homology search against the GenBank database showed that this was from a novel gene encoding a putative 37 kDa leucine-rich repeat (LRR) protein. Northern blot hybridization and RT-PCR showed that the p37NB gene was differentially expressed in S-type compared to N-type cells of a few neuroblastoma cell lines.