Helen S. L. Chan

Immunohistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood.

Increased expression of P-glycoprotein is associated with multidrug resistance (MDR) in many cell lines. Significant levels of P-glycoprotein have been detected in a number of human tumors. The purpose of this study was to determine whether P-glycoprotein expression correlates with both response to chemotherapy and prognosis in soft tissue sarcoma of childhood. In a retrospective study, biopsy samples from 30 cases of rhabdomyosarcoma (RMS) and undifferentiated sarcoma (US) treated at The Hospital for Sick Children in Toronto were analyzed using a semiquantitative immunohistochemical procedure. P-glycoprotein was detected in nine patients, four at diagnosis, and five at subsequent biopsy. All nine patients relapsed after a clinical response (complete [CR] 55%, partial [PR] 45%) to chemotherapy. Twenty of 21 patients with consistently P-glycoprotein-negative tumors received chemotherapy and they all responded clinically (CR 80%, PR 20%). Only one of these 20 patients has relapsed. The probability of relapse-free survival was significantly different (P less than .000000012) in chemotherapy-treated patients whose tumors contained detectable levels of P-glycoprotein (n = 9), compared with those whose tumors contained no detectable P-glycoprotein (n = 20). The overall probability of survival was also significantly different in these two groups (P less than .0000267). Both relapse-free and overall survivals remained statistically different in the two groups of patients when analyzed by the log-rank method, after adjustment for differences in stages and sites. The incidence of other adverse prognostic factors in the two groups, for example, younger and older ages, low pretreatment lymphocyte counts, large tumors, and unfavorable histology were not significantly different. Thus, detectable P-glycoprotein appears to be an important adverse prognostic factor in children with soft tissue sarcoma, and consistent absence of the protein is associated with a favorable prognosis.

P-Glycoprotein Expression as a Predictor of the Outcome of Therapy for Neuroblastoma

BACKGROUND AND METHODS Multidrug resistance in chemotherapy for cancer is characterized by increased genetic expression of P-glycoprotein, which acts as an ATP-dependent drug-efflux pump. To determine whether P-glycoprotein levels are of prognostic value in such cases, we measured these levels immunohistochemically in a retrospective study of sequential tumor samples from 67 children with neuroblastoma. RESULTS P-glycoprotein was not detected in pretreatment samples from either of the 2 patients with Stage I disease, any of the 21 with Stage II disease, or any of the 8 with Stage IVS disease, but it was detected in the samples from 1 of the 17 patients with Stage III disease (6 percent) and 12 of the 19 with Stage IV disease (63 percent). Of the 44 patients with nonlocalized neuroblastoma (Stage III, IVS, or IV), 26 of the 31 who were negative for P-glycoprotein had a complete response to primary treatment, as compared with 6 of the 13 who were positive for P-glycoprotein (84 percent vs. 46 percent, P = 0.0232 by Fishers exact test). Log-rank analysis of outcome, with simultaneous stratification according to tumor stage and age, showed that the group that was negative for P-glycoprotein had significantly longer relapse-free survival (P = 0.0011) and overall survival (P = 0.0373) than the group that was positive. CONCLUSIONS Expression of P-glycoprotein before treatment may predict the success or failure of therapy for nonlocalized neuroblastoma. Neuroblastoma may be a promising tumor to treat with anticancer drug therapy combined with a chemosensitizing agent capable of reversing P-glycoprotein-mediated multidrug resistance.

Posterior fossa medulloblastoma in childhood: Treatment results and a proposal for a new staging system

Seventy-two children with posterior fossa medulloblastoma were diagnosed at the Hospital for Sick Children, Toronto, from 1977 to 1987 and treated by standard methods. The 5- and 10-year survival and disease-free survival rates were 71% and 63%, and 64% and 63%, respectively. Total tumor resection, as determined by the surgeon was the most significant favorable prognostic factor. Post-operative meningitis, a residual enhancing mass lesion on the post-operative, pre irradiation CT scan and dissemination to the brain or cord at diagnosis were unfavorable factors. These four easily definable factors were used to define a staging system with prognostic significance. Five-year disease-free survival rates were for Stage I (total resection, no adverse factor) 100%, Stage II (total resection with one or more adverse factor or less than total resection with no other adverse factor) 78%, and Stage III (less than total resection with one or more adverse factor) 18%. Evaluation of treatment results in medulloblastoma requires that these prognostic factors be known.

The Small Molecule GMX1778 Is a Potent Inhibitor of NAD+ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors

ABSTRACT GMX1777 is a prodrug of the small molecule GMX1778, currently in phase I clinical trials for the treatment of cancer. We describe findings indicating that GMX1778 is a potent and specific inhibitor of the NAD+ biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Cancer cells have a very high rate of NAD+ turnover, which makes NAD+ modulation an attractive target for anticancer therapy. Selective inhibition by GMX1778 of NAMPT blocks the production of NAD+ and results in tumor cell death. Furthermore, GMX1778 is phosphoribosylated by NAMPT, which increases its cellular retention. The cytotoxicity of GMX1778 can be bypassed with exogenous nicotinic acid (NA), which permits NAD+ repletion via NA phosphoribosyltransferase 1 (NAPRT1). The cytotoxicity of GMX1778 in cells with NAPRT1 deficiency, however, cannot be rescued by NA. Analyses of NAPRT1 mRNA and protein levels in cell lines and primary tumor tissue indicate that high frequencies of glioblastomas, neuroblastomas, and sarcomas are deficient in NAPRT1 and not susceptible to rescue with NA. As a result, the therapeutic index of GMX1777 can be widended in the treatment animals bearing NAPRT1-deficient tumors by coadministration with NA. This provides the rationale for a novel therapeutic approach for the use of GMX1777 in the treatment of human cancers.

Optic glioma in children : surveillance, resection, or irradiation ?

Eighty-seven consecutive children with newly diagnosed optic glioma were managed at University of Toronto hospitals 1958-1990. Overall the 10-year survival, relapse-free survival and freedom from second relapse rates were 84%, 68% and 85%. Twenty-seven patients relapsed or progressed, of whom 40% were free of a second relapse 10 years after the first relapse. Fourteen patients had a second relapse. Thirteen are dead. None survived 5 years after second relapse. Patients with anteriorly located tumors (N = 35), which involved the optic nerve, or chiasm and optic nerves, fared better than those with posteriorly located tumors (N = 52) with spread beyond the chiasm, 10-year survival 95% versus 76%, (p = .02), 10-year relapse-free survival 80% versus 59% (p = .02), respectively. For posterior tumors primary irradiation was more effective than primary subtotal resection for prevention of subsequent relapse, 10-year relapse-free survival 75% versus 41% (p = .02), but salvage therapy was, in part, successful and multivariate analysis of prognostic factors influencing survival for posterior tumors indicated that neither primary resection nor primary irradiation were significant factors. For first relapse, primary irradiation and the presence of neurofibromatosis were the significant favorable factors. Since 1977 and for posterior optic glioma subtotal resection or surveillance were used in 21/29 (72%) patients compared with 4/23 (17%) previously. Ten-year survival rates before and after 1977 were 78% and 67% and 10-year relapse-free survival 64% and 56%, respectively.

Ocular Involvement in Neuroblastoma: Prognostic Implications

Neuroblastoma is one of the commonest childhood malignancies. The most important prognostic factor is age at diagnosis; early diagnosis, when the tumor is still localized and surgically resectable, is second in importance. On retrospective review of children seen at the Hospital for Sick Children, ophthalmic involvement was seen in 80 of 405 (20%). The three major eye signs of neuroblastoma, proptosis, Horners syndrome and opsoclonus, are closely related to the site, stage of tumor, and outcome of the patient. Proptosis or periorbital ecchymosis due to orbital metastases was present in 60 of 80 children (bilaterally in 33). The 3-year survival rate was 11.2%. In 53 of 60 cases with orbital metastases the neuroblastoma originated in the abdomen. Unilateral Horners syndrome occurred in 14 children, as the presenting sign in 9, related to localized disease in 11 and in a favorable location (cervical or thoracic neuroblastoma) in 8. The 3-year survival rate was 78.6%. Opsoclonus-myoclonus was the presenting sign of occult, localized neuroblastoma in all 9 children in whom it occurred. The 3-year survival rate was 100%. For all presentations, girls had a significantly better survival rate than boys (48.7% vs. 22.4%). Children presenting with any of these ophthalmological signs should undergo thorough and repeated investigations searching for neuroblastoma.

Pineal region germinomas in childhood treatment considerations

From 1967-1986, 21 children were treated for pineal germinoma, including 16 biopsy-proven, 2 biopsy non-diagnostic, and 3 metastatic unbiopsied (marker negative) patients. Ten of 18 (56%) biopsied patients underwent partial or sub-total tumor resection. Twenty patients were irradiated, 19 of whom are alive. No irradiated patient died of progressive germinoma, but two patients relapsed in the spinal cord and required treatment intensification for salvage. Long-term survivors have significant morbidity. Determination of the minimum effective treatment remains the chief therapeutic challenge.

Extracranial metastases in childhood primary intracranial tumors. A report of 21 cases and review of the literature

A clinical and pathologic review of primary intracranial tumors (917 cases in a 62‐year period) at The Hospital for Sick Children, Toronto, identified 21 cases with systemic metastases (2.3%). This included 15 cases of medulloblastoma and 1 case each of astrocytoma, meningeal sarcoma, malignant melanoma, ependymoblastoma, teratoma, and endodermal sinus tumor, adding to the pediatric literature of 94 previously reported cases (72 medulloblastoma and 22 cases of other brain tumors). Like adults, children with medulloblastoma tend to develop bone and bone marrow metastases, while those with other brain tumors frequently invade adjacent tissues, and then spread to regional lymph nodes and the lungs. The prognosis is almost uniformly fatal, although prolonged palliation could be achieved with radiation and/or chemotherapy. The pathogenesis of systemic metastases is related to breakage of the blood‐brain barrier, whether at surgery, or with tumor invasion into vascular channels, and especially with preoperative systemic‐cerebrospinal fluid shunting. Thirteen of 16 patients who developed systemic metastases, including 5 with peritoneal involvement, had ineffective or no millipore filters within their shunts, suggesting their possible prophylactic role against tumor dissemination. A greater understanding of the pathogenesis of systemic metastases may aid the design of future effective preventive measures.

Juvenile chronic myelogenous leukemia

Juvenile chronic myelogenous leukemia (JCML) is a malignant hematopoietic disorder of monocyte-histiocyte lineage that affects children less than 4 years of age. Since the disease represents only 2% of all childhood leukemias, experience with it has been limited even in large centers. This review summarizes our 10 year institutional study of JCML as well as a comprehensive literature survey. The goal of the article is to underscore the cardinal features of juvenile chronic myelogenous leukemia that are useful for diagnosis, and to highlight recent advances in the understanding of the biology and treatment of the disease.

Congenital mesoblastic nephroma: a clinicoradiologic study of 17 cases representing the pathologic spectrum of the disease.

Congenital mesoblastic nephroma (CMN) is a rare infantile renal tumor with a generally excellent prognosis. We describe 17 tumors that fit into the pathologic spectrum of CMN proposed by Beckwith, which ranges from benign renal tumors, through atypical “gray zone” lesions of more aggressive potential, to “crossover” tumors akin to clear cell sarcoma of kidney. Nine patients with histologically typical CMN were significantly younger and had smaller tumors than did eight patients with atypical CMN. Clinical features did not differ in the two groups of patients. A distinctive “ring sign” on renal sonography was commonly seen in patients with typical intrarenal CMN. All 17 patients were alive with no evidence of disease at a mean follow-up of 10 years. Nephrectomy was adequate therapy for younger infants and for those with typical CMN. Nephrectomy was probably also adequate therapy for infants 3 months of age or younger with atypical CMN, even if the tumor extended to the surgical resection margins and into the perinephric connective tissues. Adjuvant chemotherapy or radiation or both should be reserved for patients older than 3 months who have grossly unresected tumors and for those patients whose fumors have an unequivocally malignant histologic appearance or evidence of aggressive biologic behavior.