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Journal of Indian Association of Pediatric Surgeons, Vol. 10, No. 4, October-December, 2005, pp. 259-263 Selected Summaries Selected summaries Agarwal GautamS, Jindal Bibekanand, Gazula Suhasini Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi Code Number: ip05063 Profiling of nuclear extract proteins from human neuroblastoma cell lines: The search for fingerprints. Mauricio A. Escobar, Derek J. Hoelz, John A. Sandoval, Robert J. Hickey, Jay L. Grosfeld, Linda H. Malkas. Journal of Pediatric Surgery (2005) 40 Most children with neuroblastoma present with advanced, often unresectable metastatic disease. Current screening techniques, urinary markers, continues to miss interval cancers in children who screen negative. Because implementation of routine cancer screening and early treatment are paramount to decreasing cancer mortality rates, the need to explore other methods of NB detection is needed to identify early presence of this malignancy. Traditional markers for diagnosis, prognosis and monitoring in NB include - ferretin, LDH, Trk-A, CD-44, neuron specific enolase, GD2, neuronal peptide Y, chromagranin A, etc. Researchers have found several problems including significant heterogenecity and inadequate reporting of clinical and statistical factors and argued for further studies to validate the value of existing biomarkers. The non-specific nature of several markers in NB hampers their clinical use. The search to find additional biomarkers that yield specific identifiable "fingerprints" for each group of NB is justifiable. One systemic method is investigating the proteins that constitute the tumor cell. The common tool used is 2D-PAGE, proteins are seperated and then identified using mass spectrometry. Researchers now analyze distinct cell compartments. Because nucleus has not been evaluated for biomarkers-authors have focused in this compartment. 20 positively identified spots were differentially expressed in 3 NB cell lines. All these proteins comprise a wide array of functions within a cell. From these authors chose a few individual proteins to serve as potential biomarker for NB tissue. The requirements for this were that the proteins must have diverse functions and have been previously linked to cancer. Authors chose 3 proteins-SET, grp94, stathmin. SET is a nuclear protein that was initially discovered in a patient with acute leukemia. It is expressed in diverse cell types,it has been posulated to have a major role in developing nervous system; as levels decline after birth. Persistent activation may play role in neural based tumors. grp94 is an endoplasmic reticulum protein that migrate to nucleus during period of intracellular stress. These proteins have been posulated to provide stability to other proteins and involved in cell immortalization. Stathmin functions as a cell signaling regulating factors and play an important role in microtubule instability. It has been described being overabundant in many human cancer cells including NB. This report is an initial investigation into NB nucleus proteome, the abundance of oncoproteins found in this compartment suggests that the nucleus is a good source of potential biomarkers. Future work will attempt to validate these proteins as biomarkers in NB. The implications of this work include the identification of promising diagnostic and therapeutic targets for NB that may eventually change the outcome of this childhood malignancy with dismal outcome. Profile of neuroblastoma detected by mass screening, resected after observation without treatment: Results of wait and see pilot study. Takaharu Oue,Masami Inoue, Akihiro Yoneda, Akio Kubota, Hiroomi Okuyama, Hisayoshi Kawahara, Masanori Nishikawa, Masahiro Nakayama, Keisei Kawa. Journal of Pediatric Surgery (2005) 40 The prognosis of Neuroblastoma in younger than 1 year is much better than that older than 1 year. In 1985, Japanese Nationwide mass screening using urinary VMA, HVA for 6 months old infants was started to improve the prognosis of this tumor. More than 2000 patients with NB were discovered and treated. Their prognosis was extremely good. Recent reports have suggested that NB detected by MS regress spontaneously and that it has detected tumors that otherwise may have regressed spontaneously. Thus an observation programme in limited cases, to avoid over-treatment and to estimate how frequently regression occurs was started in 1994. In this study, authors analyzed the profile of NB, resected after observation to elucidate the nature of NB detected by MS. The entry criteria were- Stage 1 and 2, less than 5cms in size, no involvement of large vessels and surgical excision not difficult, parents informed consent. The patients were strictly followed up without receiving any treatment. If increase in size, elevation of tumor markers, or evidence of metastasis was observed, the tumor was resected immediately. Biological features of the tumor were identified- Shimada histological features, amplification of N-myc, 1p deletion, expression of Trk-A. Between June 1994 to March 2004, 43 patients with NB were admitted detected by MS, 22(51%) of them matched the criteria which included 11 boys and 11 girls. Age ranged from 7-11 months. Origin was adrenal in 15 and retroperitoneal paraganglia in 7. 17 in stage 1; 3 in stage 2; 2 patients in stage 4 were also included as parents refused any treatment 13(59%) of 22 cases showed spontaneous regression and continued on observation. Urinary markers normalized in all but one, within 18 months. In the remaining 9(41%) cases tumor resection was performed. In 2 cases as parents desired surgery, remaining 7 because of increase in size and/or elevation of tumor markers. In 2 cases lymph node metastasis at surgery resulted in upgrading of tumor from stage 1 to 2 and 1 to 3, in one case tumor growth resulted in the upgrading from stage 1 to3. According to Shimada - 7 were favorable and 2 unfavorable, DNA content was aneuploid in 7 and diploid in 2, Trk-A expression was low in 4, no tumor showed N-myc amplification. 4(44%) had atleast one unfavorable biologic factor and 3 of them had more than 2 features. Post-operative chemotherapy was given in 4 cases, who had stage 3 tumor and/or unfavorable factors. All patients survived without recurrence. 29% tumors detected by MS had spontaneous regression. 5 of the 9 resected tumors had favorable features- possibility of regression. Authors argue that observation program is most effective to avoid unnecessary treatment. Several reports have proven that MS did not improve the overall mortality rate of NB. MS detects a number of spontaneously regressing NB. The optimal time for MS should be the point at which regressing NB can no longer be detected but more aggressive tumors can be found. Urinary markers normalized by 18 months in most regressing NB so the authors suggest that screening in age around 18 months may be more effective. Thoracic neuroblastoma: Outcome of incomplete resection. A. Horiuchi, T. Muraji, C. Tsugawa, E. Nishijima, S. Satho, S. Takamizawa, H. Misu, O. Mabuchi, K. Kangawa, M. Fujita. Pediatric Surgery International 2004;20:714-8 Neuroblastoma is a highly malignant tumor that demonstrates unusual clinical behavior. The prognosis for thoracic neuroblastoma has been documented as good. The importance of gross total resection in the management of neuroblastoma in improving disease free survival has been stressed earlier. Attempts at complete resection of thoaracic neuroblastoma extending to intervertebral foramina may lead to complication (hemorrhage, cerebrospinal fluid leakage). The author studied 102 patients of Neuroblastoma, of which 20 had thoracic neuroblastoma and compared the tumor characterstic and survival between thoracic and nonthoracic neuroblastoma and analyzed the outcome of incomplete resection on prognosis between the two group. Among the patients aged less than 1 year there was no significant difference in overall survival between the two group. Among those aged more than 1 year old the overall 5 year survival rate was 100% in thoracic neurblastoma as compared to their nonthoracic counterpart (44.4%) with a significant difference (p = 0.015). This difference is because, thoracic neuroblastoma was detected at an earlier stage (p = 0.003) and the incidence of ganglioneuroblastoma was significantly higher (p = 0.003) in thoracic neuroblastoma as compared to their nonthoracic counterpart. The 5-year survival rate without disease was compared between complete and incomplete resection group. Among the patients less than 1 year old, there was no significant difference in the prognosis between the two groups regardless of the surgical margin. Among the patients aged >1 year from thoracic neuroblastoma, the 5-year survival rate was 100% in both the groups regardless of the surgical margin. In contrast, in the non-thoracic neuroblastoma group the 5-year survival rate was significantly lower (p = 0.02) among the patients who had incomplete resection. Based on these findings the authors recommended that there is no need to perform aggressive complete resection of thoracic neuroblastoma at any age. The reason for better outcome in thoracic neuroblastoma seems to be early stage at diagnosis, histologic differentiation, higher incidence of favourable histology and lower serum NSE level. In addition a tendency for maturation of thoracic neuroblastoma to ganglioneuroma may be responsible for better prognosis. Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: An inter-group study. D. Billimire. Journal of Pediatric Surgery 2004;39:3 The purpose of this study was to perform an evaluation of outcome and the role of surgical staging components in malignant germ cell tumors of the ovary in children and adolescents. Malignant GCT account for 20% of ovarian masses in children and adolescents. Historically, these children had a poor outcome with surgery alone. Early regimens combining radiation + VAC and doxorubicin brought survival to 60%. Further improvement in survival rate was accomplished with introduction of platinum based regimens. Two intergroup studies from extra cranial malignant GCT in children were taken by POG and CCSG from 1990-1996. Children with stage I and stage II ovarian tumors were entered into POG 9048/CCG8891 and were treated in non-randomized fashion with tumor resection followed with 4 cycles of chemotherapy. The chemo-regimen included cisplatin - 100mg/m2x5dys and Bleomycin 15mg/m2 x 1 day. Children with stage III and stage IV were entered into POG 9049/CCG8892. This high risk group was treated with surgical resection at diagnosis, if possible, followed by 4 cycles of PEB. The patients were randomly selected to either standard PEB or high dose cisplatin at 200mg/m2 .If tumor was not resected at diagnosis, second look surgery with attempted resection after 4 cycles of chemotherapy was done. Surgical guide lines recommended complete evaluation of disease at diagnosis with safe resection. The main components of staging procedure included- A detailed review of operative notes and pathology reports was focused on compliances with staging laprotomy. There were 131girls with MGCT ; stage I-41, stage II-16, stage III-58, stage IV-16. Age ranged from 1.4-20yrs. Information on clinical presentation was available in 82 of them. 9 presented with acute abdomen, 4 presented with precocious puberty. Tumor ranged from 5-37cms in size. 75 of 131 had a grossly cystic component including 27 that had no teratoma elements. Histology of tumors showed mixed tumors in most patients with teratoma elements in 60. Patients with pure germinoma (n=23) were only eligible for enrollment in high risk group (stages III & IV). Management of primary tumor in stage I and II included USO-40, UO-14; TAH + BSO-1, BO-1, enucleation -1. Management in stage III and IV included UO-6; TAH + BSO-5, BSO-3, BO-1 enucleation-1, biopsy only-6. The recommended surgical guidelines were seldom followed completely.
6 year event free survival was stage I 95%, stage II-87.5%, stage III-96.6%, stage IV-86.7%. Events on follow up included AML, peritoneal implants, myelodysplasia, Tumor relapse, local relapse and lung metastasis. Survival rate with MGCT were excellent in this study with only 3% (4 of 131) tumor related mortality. Previous recommendation of extensive surgical resection have been abandoned without compromise in outcome. Because there are no gross tumor characteristics that define malignancy and risk is significant, these should always be managed and completely staged with assumption that malignancy is present. In this study incidence of capsular breach was significant; this suggests that surgeons assessment of capsular integrity is frequently in error and so the pathologist must receive an intact specimen. Although several patients underwent radical resections, survival was excellent in girls treated with separation of adherent plane or initial biopsy only with delayed resection. These support initial conservative surgery limited to tumor excision for straight forward cases and biopsy only for densely adherent or extensive tumor. Yield of ascitic fluid was high confirming its important role in staging. 5 girls were staged upto stage III based on this alone. Visual inspection was reliable for assessment of peritoneum, omentum and fallopian tube. Bilateral lymph node sampling at 4 sites was recommended but followed only in 2% of cases so cannot be commented upon but yield of malignancy is grossly abnormal nodes was 41% and no positive specimens in grossly normal nodes. The revised guidelines include Surgical view of the treatment of patients with hepatoblastoma: Results from the first prospective trial of the international society of pediatric oncology liver tumor study group (SIOPEL-1). J. M. Schnater, D. C. Aronson, J. Plaschkes, G. Perilongo, J. Brown, J. B. Otte, L. Brugieres, P. Czauderna, G. MacKinlay, A. Vos. Pediatric Surgical Center Amsterdam (EKZ-AMC/VUmc), Amsterdam, The Netherlands. Cancer. 2002;94:1111-20 The Society of Pediatric Oncology Liver Tumor Study Group launched its first prospective trial with the intention to treat all patients of hepatoblastoma with preoperative chemotherapy and delayed surgical resection. One of the primary objectives was to assess whether the assumed surgical advantages of primary chemotherapy stand up to more detailed scrutiny. Between 1990 and 1994, 91 centres in 33 different countries registered 154 patients of less than 16 years age with hepatoblastoma. The pretreatment extent of disease (PRETEXT stage) was assessed and biopsy was recommended in face of unequivocal clinical findings and mandatory in patients < 6 months and > 3 years because of increased prevalence of other tumour types in these age groups. Patients were treated with cisplatin 80 mg/m2 intravenously over 24 hours and doxorubicin 60 mg/m2 intravenously over 48 hours by continuous infusion (PLADO). Tumours were resected after four of a total of six courses of PLADO. Ease and safety of surgery were defined using the following surrogates: 1) complications of biopsies, which are prerequisite for preoperative chemotherapy; 2) resectability rate at first attempt; 3) microscopic residual disease; 4) local recurrence rate; and 5) local and systemic complications at surgery and within the first postoperative month. One hundred twenty eight patients underwent surgical resection (13 patients underwent primary surgery, and 115 patients underwent delayed surgery after PLADO). A pretreatment surgical biopsy was performed in 96 of 128 patients (75%). Biopsy caused complications (minor bleeding, abdominal pain, wound infection) in 7 of 96 patients (7%). Of the 22 patients who showed pulmonary metastases at the time of diagnosis, 7 underwent thoracotomy. Operative morbidity and mortality were 18% and 5% respectively. Complete macroscopic surgical resection was achieved in 106 patients (92%), including 6 patients who underwent orthotopic liver transplantation. Disease recurrence was seen in 10 patients (8%). The actuarial 5-year event free survival (EFS) rate and the overall survival (OS) rate for the 115 patients that followed the exact protocol were 75% and 85%, respectively. Hence, the authors conclude that biopsy is a safe procedure and should be performed routinely to exclude other liver tumors and assign tumors with unfavourable histologic features directly to a high-risk regimen. Preoperative chemotherapy seems to make tumour resection easier. Reresection of a positive resection margin does not necessarily have to be performed, because postoperative chemotherapy showed good results. Though patients with lung metastases have an overall worse prognosis, resection of lung metastases can be curative if there is local control of the primary tumour. Pretreatment prognostic factors and treatment results in children with hepatoblastoma: A report from the German cooperative pediatric liver tumor study HB 94. J. Fuchs, J. Rydzynski, Von D. Schweinitz, U. Bode, H. Hecker, P. Weinel, D. Burger, D. Harms, R. Erttmann, K. Oldhafer, H. Mildenberger. Study Committee of the Cooperative Pediatric Liver Tumor Study Hb 94 for the German Society for Pediatric Oncology and Hematology. Department of Pediatric Surgery, University of Tuebingen, Tuebingen, Germany. Cancer 2002;95:172-82. A worldwide, unsolved problem remains the treatment of patients with advanced or metastatic hepatoblastoma (HB). The German Cooperative Pediatric Liver Tumor Study HB 94 was a prospective, multicenter, single-arm study from January 1994 to December 1998 with an objective to evaluate some new treatment modalities. First, the intensity of postoperative chemotherapy in patients with Stage I HB or Stage II HB was reduced to two or three courses of chemotherapy, respectively. Second, a maximum of four courses of conventional cisplatinum, ifosfamide, doxorubicin (CDDP/IFO/DOXO) chemotherapy was allowed, and a new treatment arm for patients with advanced or recurrent HB who received etoposide and carboplatin (VP16/CARBO) was evaluated. Third, children age 6 months to 3 years with significantly elevated serum alpha-fetoprotein levels and/or tumor in both liver lobes, with or without distant metastases, were treated without a prior histologic diagnosis. Possible clinical and pathologic prognostic factors were also analyzed and compared with the experience of other groups. Sixty-nine children with HB were treated in this study. The median follow-up of survivors was 58 months (range, 32-93 months). Fifty-three of 69 patients (77%) remained alive, and 16 of 69 patients (23%) died. Long-term disease-free survival was as follows: 96% in Stage I HB, 100% in Stage II HB, 76% in Stage III HB and 36% in Stage IV HB. Twenty-two tumors were resected primarily (32%), and 41 children (59%) underwent surgery after initial chemotherapy. Six children (8%) had no surgical treatment. A complete resection of the primary tumour was achieved in 54 of 63 patients (86%). Two children underwent liver transplantation. There was no perioperative death. Of the 48 children who received primary chemotherapy with CDDP/IFO/DOXO, 41 achieved partial remission (85%). Eighteen children with advanced or recurrent HB underwent VP16/CARBO chemotherapy, with a 66% response rate. The relevant pretreatment prognostic factors were growth pattern of the liver tumour (p = 0.0135), vascular tumour invasion (p = 0.0039), occurrence of distant metastases (p = 0.0001), initial alpha-fetoprotein level (p = 0.0034) and surgical radicality (p < 0.0001). These results underline the necessity of preoperative chemotherapy in all children with HB. The certainty of the diagnosis of HB without biopsy in children age 6 months to 3 year with liver tumors and elevated alpha-fetoprotein is high. Chemotherapy using CDDP/IFO/DOXO and VP16/CARBO is effective. Complete tumor resection and occurrence of distant metastasis are two main prognostic factors. Copyright 2005 - Journal of Indian Association of Pediatric Surgeons |
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