Urinary biomarkers predict brain tumor presence and response to therapy.

PURPOSE: A major difficulty in treating brain tumors is the lack of effective methods of identifying novel or recurrent disease. In this study, we have evaluated the efficacy of urinary matrix metalloproteinases (MMP) as diagnostic biomarkers for brain tumors. EXPERIMENTAL DESIGN: Urine, cerebrospinal fluid, and tissue specimens were collected from patients with brain tumors. Zymography, ELISA, and immunohistochemistry were used to characterize the presence of MMP-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL), and vascular endothelial growth factor (VEGF). Results were compared between age- and sex-matched controls and subjected to univariate and multivariate statistical analyses. RESULTS: Evaluation of a specific panel of urinary biomarkers by ELISA showed significant elevations of MMP-2, MMP-9, MMP-9/NGAL, and VEGF (all P < 0.001) in samples from brain tumor patients compared with controls. Multiplexing MMP-2 and VEGF provided superior accuracy compared with any other combination or individual biomarker. Receiver-operating characteristics curves for MMP-2 and VEGF showed excellent discrimination. Immunohistochemistry identified these same proteins in the source tumor tissue. A subset of patients with longitudinal follow-up revealed subsequent clearing of biomarkers after tumor resection. CONCLUSION: We report, for the first time, the identification of a panel of urinary biomarkers that predicts the presence of brain tumors. These biomarkers correlate with presence of disease, decrease with treatment, and can be tracked from source tissue to urine. These data support the hypothesis that urinary MMPs and associated proteins are useful predictors of the presence of brain tumors and may provide a basis for a novel, noninvasive method to identify new brain tumors and monitor known tumors after treatment.     

Nuclear morphometry and prognosis in favorable histology Wilms' tumor: A prospective reevaluation.

PURPOSE: This study was designed to evaluate the ability of a previously published nuclear morphometry discriminant function to predict disease-free survival in patients with Wilms' tumor. PATIENTS AND METHODS: We identified 218 patients with stage I-IV Wilms' tumor of favorable histology who were entered onto the National Wilms' Tumor Study (NWTS) between January 1, 1990 and April 15, 1994. The nuclear morphometry score was calculated for each patient as follows: MV(f) = (0.02 x AGE) + (1.17 x SNRF) + (90.6 x LEFD) - 94, with AGE denoting age at diagnosis in months, SNRF the skewness of the nuclear roundness factor, and LEFD the lowest value of nuclear ellipticity as measured by the feret diameter method. Relative risks of relapse were estimated for the total score and for each of its components. Sensitivity and specificity were determined for the criterion of "MV(f) is greater than -0.35" as a predictor of relapse. RESULTS: By contrast with previously published results, neither the SNRF nor the LEFD made any contribution to the prediction of disease-free survival. Sensitivity and specificity of the criterion of "MV(f) is greater than -0.35" were 71% and 56%, respectively. CONCLUSION: Re-evaluation of a published nuclear morphometry score showed that it did not predict disease-free survival in patients with Wilms' tumor. The earlier study very likely overestimated the predictive power of nuclear morphometry by using the same data set both to develop the score and to evaluate its properties. Because of the huge number of combinations of nuclear morphometry measurements that may enter into the multivariate discriminant function, use of appropriate statistical methods is essential to estimate accurately the sensitivity and specificity.     

Current therapy for Wilms' tumor

Wilms' tumor was the first solid malignancy in which the value of adjuvant chemotherapy was established. Multimodality treatment has resulted in a significant improvement in outcome from approximately 30% in the 1930s to more than 85% in the modern era. Although the National Wilms' Tumor Study Group and the International Society of Pediatric Oncology differ philosophically regarding the merits of preoperative chemotherapy, outcomes of patients treated with either up-front nephrectomy or preoperative chemotherapy have been excellent. The goal of current clinical trials is to reduce therapy for children with low-risk tumors, thereby avoiding acute and long-term toxicities. At the same time, current clinical trials seek to augment therapy for patients with high-risk Wilms' tumor, including those with bilateral, anaplastic, and recurrent favorable histology tumors.     

Salvage therapy in metastatic adult Wilms' tumor

Adult Wilms' tumor is a rare and aggressive malignancy. Despite multimodality therapy for all stages of disease, the majority of patients develop fatal metastases. Little information is available on effective salvage therapy. The current report describes a 38-year-old man who had Stage I disease. Pulmonary metastases developed after radical nephrectomy and tumor bed irradiation while receiving adjuvant chemotherapy. He achieved a complete remission lasting 8 months with a combination chemotherapy regimen of cyclophosphamide, vinblastine, dactinomycin, and cisplatin. After isolated pulmonary relapse, he received whole-lung irradiation and remained disease-free 4.5 years after diagnosis. The previously reported results of therapy in metastatic or unresectable adult Wilms' tumor are reviewed, and the current case of effective salvage therapy is documented.     

The treatment of Wilms' tumor: Results of the national Wilms' tumor study.

The National Wilms' Tumor Study, initiated in 1969, tested competing treatment strategems for patients with tumors ranging from Group (Gp) I (tumors confined to the kidney and totally removed) to Gp IV (remote metastases present at diagnosis). Three hundred and fifty-nine of 606 registered patients were randomized in the trial. Gp I patients under 2 years of age fared well whether postoperative radiation therapy (RT) was or was not added to 15 months' maintenance actinomycin D (AMD). Their prognosis was better than that for older cohorts similarly treated, in whom the difference in relapse rates between treatment groups were suggestive of an RT effect. Combined AMD and vincristine (VCR) gave better results than either agent alone in patients with more advanced tumors (Gps II and III) still confined to the abdomen, all of whom received postoperative RT as well. Preoperative VCR given Gp IV patients in addition to postoperative RT, AMD, and VCR did not improve results. The frequency of mesoblastic nephroma (1%), of bilateral tumors (5%), and of incorrect preoperative diagnosis of Wilms' tumor (5%), the toxicities of the various regimens, and other ancillary data are presented and discussed.     

The role of radiation therapy in the management of Wilms' tumor

Since the early decades of this century, radiation therapy has played an important role in the management of Wilms' tumor. Although in prior years the high radiation doses and eccentric field arrangements used in treatment were responsible for significant late toxicity, examination of long-term survivors and the important information obtained from the National Wilms' Tumor Studies (NWTS) and Societe Internationale d'Oncologie Pediatrique studies have now allowed us to tailor radiation fields and doses to provide high levels of local tumor control with minimal late effects. At present, most patients with NWTS stage III and stage IV tumors are offered radiotherapy as an integral component of their cancer management. Attempts to further refine selection criteria defining those patient groups who will benefit from radiation therapy are ongoing.     

The use of asymmetric-field inversion gel electrophoresis to predict tumor cell radiosensitivity.

The success of a predictive assay for radiotherapy relies on the use of one or more tumor cell traits that equate with tumor radioresistance or radiosensitivity. These traits can be divided into intrinsic (genetic) and extrinsic (epi-genetic) factors. Most probably, a tumor's response to radiotherapy will be influenced by both of these sets of traits. Radiobiological analysis of cultured cells derived from explanted tumors of head and neck patients has shown that in vitro survival of tumor cells is not the only factor affecting tumor radiocurability. Two possible reasons are the high degree of selection involved in growing the cells in vitro and the inability to assess the contribution of the cell-cell contact effect with cultured cells. A possible means of overcoming both of these problems would be an assessment of the radiosensitivity of the cell population immediately after removal from the tumor. Since a good correlation exists between intrinsic cellular radioresistance and DNA double-strand break repair (DSBR) as assayed by the Neutral Elution technique [21], we have investigated the feasibility of using asymmetric field inversion gel electrophoresis (AFIGE) in identifying resistant tumor cells in vitro. AFIGE has several advantages over neutral elution in that it is faster (approximately 60-80 samples can be run on the same agarose gel) and, most importantly, one can visualize DNA damage and repair by staining the DNA with ethidium bromide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Wilms' tumor in adolescence.

Two cases of Wilms' tumor in adolescent males are presented. The clinical and radiographic findings were unusual and both presented atypical gross and microscopic features that could be correlated with the radiographic findings. Histologic examination of both tumors showed evidence of tubular and glomerular maturation, a feature usually associated with Wilms' tumors of early infancy. One of the tumors contained a large amount of cartilage and bone. The other was grossly cystic and incorporated some features of multilocular cystadenoma, a benign metanephric tumor.     

Improved prognosis in Wilms' tumor due to adjuvant combination drug therapy

78 children with Wilms' tumor stage I--IV diagnosed since 1960 are presented. There were two groups of patients: one group consisting of 35 patients which received adjuvant chemotherapy for 1 year, the other group consisting of 43 patients which received no chemotherapy. Surgical excision and irradiation was identical in both groups. The prognosis was greatly improved by adjuvant chemotherapy: 4-year survival rates increased from 25 to 69%. Late side effects from radiation and chemotherapy were noted: 15/78 patients suffered from scoliosis and all patients treated by chemotherapy had a decreased lymphotoxin activity over years. The following factors appear to be related to prognosis: the extent of disease in patients determined by better techniques, histopathology of the tumor, and the nature of treatment.     

Intraoperative radiation therapy for Wilms' tumor in situ or ex vivo.

Patients with bilateral Wilms' tumor who have local recurrence after undergoing maximum-dose multitechnique therapy are problematic. The role of surgery in the management of these patients is changing from ablation to preservation of renal tissue. Bilateral nephrectomy is reserved as a last resort. Intraoperative radiation therapy (IORT) is advantageous to conservative management, as illustrated by the current cases of two children with recurrent Wilms' tumors in their remaining kidneys. Both children underwent limited surgery and precisely directed IORT. In one patient the nephron-sparing surgery and IORT were performed in situ. In the other the kidney was removed, treated with ex vivo bench surgery and radiation surgery, and then reimplanted. The adjuvant use of IORT, either in situ or ex vivo, in nephron-sparing surgery permits complete obliteration of gross and microscopic disease while maximizing residual renal function.     

Evaluation of nuclear unrest and p53 immunostaining in Wilms' tumor

BackgroundNuclear unrest is a term applied to Wilms’ tumors (WT) that show nuclear abnormalities close to anaplasia but without abnormal mitoses. p53 is claimed to be associated with anaplasia and poor prognosis. This study was undertaken to evaluate the clinical significance of nuclear unrest and p53 immunostaining in Wilms’ tumor.Material and methodsThis is a retrospective study of 63 patients who presented at NCI with Wilms’ tumors, and underwent preoperative chemotherapy followed by nephrectomy. Histopathologic assessment and p53 immunohistochemistry were done.ResultsWT with nuclear unrest grade III closely resembled anaplastic tumors and both of them (group 1) constituted 19% of cases. Group 1 constituted 29% of cases showing blastema dominant morphology compared to 9.4% of cases without blastema dominant morphology with significant statistical difference (p = 0.047). Almost 83% of cases that achieved 1st complete remission were stages I, II and III, while 17% were stages IV and V with significant statistical difference (p < 0.001). Stage affected the 3-year relapse-free-survival (RFS) significantly (p = 0.014) as it was more in stages I, II and III than in stages IV and V (75.4% versus 50%). Blastema dominant morphology and high risk state significantly lowered the 3-year overall survival (OS) into 54.8% in comparison to 80.9% for cases with non-blastema dominant morphology (p = 0.042). Regarding p53 immunohistochemistry, group 1 tumors showed positive p53 more than group 2 with significant statistical difference (p = 0.014). p53 Positive immunostaining was significantly associated with high risk nephroblastoma (p = 0.004).ConclusionTumor stage and blastema dominant morphology are potent prognostic factors. p53 is linked to blastema dominant morphology. WT with nuclear unrest grade III closely resembles anaplastic WT. It may be appropriate to group tumors with nuclear unrest grade III with anaplastic histology regarding treatment stratification.     

High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer.

Vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been reported to be associated with a poor prognosis in primary breast cancer and in several other cancer types. In the present study, we have measured with ELISA the levels of VEGF in cytosolic extracts of 845 primary breast tumors of patients who developed a recurrence during follow-up. All of the patients received tamoxifen (n = 618) or cyclophosphamide, methotrexate, 5-fluorouracil (CMF) or 5-fluorouracil, Adriamycin, cyclophosphamide (FAC) chemotherapy (n = 227) as first-line systemic therapy after diagnosis of advanced disease. VEGF levels were not related to age or menopausal status but were negatively related to the cytosolic levels of estrogen receptor and progesterone receptor (P < 0.0001). In patients who relapsed within 1 year after primary surgery, tumor VEGF levels were higher than in patients who showed a longer disease-free interval (P = 0.0005). In patients with a first relapse in the viscera, VEGF levels were higher compared with those that relapsed to the bone or soft tissue (P = 0.0004). In univariate analysis for response to first-line tamoxifen therapy, patients with high or intermediate levels showed a poor rate of response, compared with patients with low tumor-VEGF levels (P = 0.0001). Similarly, in multivariate analysis for response to tamoxifen treatment, corrected for age, site of relapse, disease-free interval, and estrogen receptor and progesterone receptor status, VEGF status was an independent predictive factor (P = 0.009). In concordance, higher levels of VEGF were associated with a short progression-free survival and postrelapse overall survival (both, P < 0.0001). On first-line chemotherapy, the rate of response decreased with higher tumor levels of VEGF, both in univariate (P = 0.003) and in multivariate analysis (P = 0.004). Furthermore, higher VEGF levels were associated with a short progression-free survival (P = 0.003) and postrelapse overall survival (P = 0.001). In conclusion, the tumor VEGF level is an important independent marker that predicts a poor efficacy of both tamoxifen and chemotherapy in advanced breast cancer. Knowledge of the tumor level of VEGF might be helpful in selecting individual patients who may benefit from treatments with antiangiogenic agents combined with conventionally used drugs.     

The use of gallium-67 scintigraphy to monitor tumor response rates and predict long-term clinical outcome in patients with lymphoma

The aim of this study was to determine whether gallium (Ga)-67 scintigraphy can monitor the treatment response rates and predict the long-term clinical outcome in patients with lymphoma. Gallium-67 scintigraphy was performed upon admission (baseline Ga) in 33 consecutive, newly diagnosed patients. Twenty-eight patients (Hodgkin's disease, n = 18; non-Hodgkin's lymphoma, n = 13) with Ga avid tumors were included in the study. All the patients were treated with induction chemotherapy. Gallium-67 scintigraphy was performed in all patients after the first cycle of chemotherapy (post-cycle 1 Ga) and repeated after the fourth cycle (post-cycle 4 Ga) or after completion of treatment (end-of-chemotherapy Ga). Nineteen patients had a fast response (68%, negative in post-cycle 1 and end-of-chemotherapy Ga), 4 intermediate response (14%, partial positive post-cycle 1 Ga that progressed to negative post-cycle 4 Ga), 3 slow response (11%, partial positive in both post-cycle 1 and post-cycle 4 Ga) and 2 no response (7%, positive in both post-cycle 1 and end-of-chemotherapy Ga). In patients who had either fast or intermediate response, 22 (96%) were free of disease at a median follow-up period of 30 months (range, 11-45 months). All 5 patients (100%) who had slow or no response had progressive disease or residual disease. In conclusion, the findings indicate that Ga could effectively be used to monitor the treatment response rates and predict the long-term clinical outcome in patients with lymphoma and should be used in treatment modifications aimed at reducing toxicity of effective therapy in patients with fast response and replacing treatments early in patients with slow or no response.     

Spinal cord compression in widely metastatic Wilms' tumor. Paraplegia in two children with anaplastic Wilms' tumor.

Spinal cord compression in Wilms' tumor is a rare event, generally caused by invasion of the canal by paraspinal lesions or metastatically involved vertebral bodies. This case report reviews the clinical presentation, radiologic evaluation, and emergent therapy in two cases of spinal cord compromise involving patients with widely metastatic Wilms' tumor. One of these is the only known report of intradural metastasis in a child with this malignancy. Both cases illustrate the importance of anticipating and rapidly responding to neurologic complications that may arise in patients with aggressively metastatic Wilms' tumor.     

Early multimodal therapy in adult Wilms' tumor: case report

Wilms' tumor occurs rarely in adults, especially after the third decade. In adults, the prognosis of Wilms' tumor is worse than in children. In this case report, we present a 48-year old patient who relapsed with advanced stage shortly after primary surgery. A definitive treatment plan has not been established because of the rarity of this tumor in adults. After surgical removal, multimodal therapy should be begun immediately for long-lasting, complete remission.