Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy.

BACKGROUND: Clinical trials in men with biochemically recurrent prostate cancer (BRPC) have been hampered by long survival times, making overall survival (OS) a difficult end point to reach. Intermediate end points are needed in order to conduct such trials within a more feasible time frame. PATIENTS AND METHODS: This is a retrospective analysis of 450 men with BRPC following prostatectomy treated at a single institution between 1981 and 2010, of which 140 developed subsequent metastases. Androgen deprivation therapy (ADT) was deferred until after the development of metastases. Cox regression models were developed to investigate factors influencing OS. RESULTS: Median metastasis-free survival (MFS) was 10.2 years [95% confidence interval (CI) 7.6-14.0 years]; median OS after metastasis was 6.6 years (95%CI 5.8-8.4 years). Multivariable Cox regressions identified four independently prognostic variables for OS: MFS (HR 0.77; 95% CI 0.63-0.94), number of metastases (≤3 versus ≥4; HR 0.50; 95% CI 0.29-0.85), pain (absent versus present; HR 0.43; 95% CI 0.25-0.72), and bisphosphonate use (yes versus no; HR 0.60; 95% CI 0.37-0.98). CONCLUSIONS: MFS emerged as an independent predictor of OS in men with BRPC treated with deferred ADT after the development of metastases. MFS may be a reasonable intermediate end point in future clinical trials. This observation requires prospective validation.

Use of the Prostate Health Index for detection of prostate cancer: results from a large academic practice.

BACKGROUND: The Prostate Health Index (phi) outperforms PSA and other PSA derivatives for the diagnosis of prostate cancer (PCa). The impact of phi testing in the real-world clinical setting has not been previously assessed. METHODS: In a single, large, academic center, phi was tested in 345 patients presenting for diagnostic evaluation for PCa. Findings on prostate biopsy (including Grade Group (GG), defined as GG1: Gleason score (GS) 6, GG2: GS 3+4=7, GG3: GS 4+3=7, GG4: GS 8 and GG5: GS 9-10), magnetic resonance imaging (MRI) and radical prostatectomy (RP) were prospectively recorded. Biopsy rates and outcomes were compared with a contemporary cohort that did not undergo phi testing (n=1318). RESULTS: Overall, 39% of men with phi testing underwent prostate biopsy. No men with phi<19.6 were diagnosed with PCa, and only three men with phi<27 had cancer of GG⩾2. Phi was superior to PSA for the prediction of any PCa (area under the receiver operating characteristic curve (AUC) 0.72 vs 0.47) and GG⩾2 PCa (AUC 0.77 vs 0.53) on prostate biopsy. Among men undergoing MRI and phi, no men with phi<27 and PI-RADS⩽3 had GG⩾2 cancer. For those men proceeding to RP, increasing phi was associated with higher pathologic GG (P=0.002) and stage (P=0.001). Compared with patients who did not undergo phi testing, the use of phi was associated with a 9% reduction in the rate of prostate biopsy (39% vs 48%; P<0.001). Importantly, the reduction in biopsy among the phi population was secondary to decreased incidence of negative (8%) and GG1 (1%) biopsies, whereas the proportion of biopsies detecting GG⩾2 cancers remained unchanged. CONCLUSIONS: In this large, real-time clinical experience, phi outperformed PSA alone, was associated with high-grade PCa, and provided complementary information to MRI. Incorporation of phi into clinical practice reduced the rate of unnecessary biopsies without changing the frequency of detection of higher-grade cancers.

Metastatic potential prediction by a visual grading system of cell motility: prospective validation in the Dunning R-3327 prostatic adenocarcinoma model.

A method for accurate prediction of prognosis in individual patients with prostatic carcinoma does not exist. The limitations of pathological grading systems may result from the failure of standard pathological examination of fixed dead tissue to accurately assess the biological and metastatic behavior of live tumor cells. Many of the sublines of the Dunning R-3327 rat prostatic adenocarcinoma are histologically similar yet differ in metastatic potential. Cells from the Dunning model were grown in culture and filmed by time-lapse videomicroscopy. These cells exhibited characteristic membrane ruffling, pseudopodal extension, and cellular translation that could be graded with 80% reproducibility. Individual cells from sublines with high metastatic potential were separated from cells from sublines of low metastatic potential in 96% of cases. We have applied our cell motility grading system to prospectively classify the metastatic potential of neoplastic cells. The mean motility grades of sublines of high and low metastatic potential differed significantly (Mann-Whitney-Wilcoxon, P less than 0.0005). Among seven sublines in which the grading system was developed, individual cells were correctly classified as high or low metastatic in 71% of cases by ruffling or pseudopodal extension, 73% of cases by translation, and 75% of cases by motility index, an average of the three parameters of motility. Among four newly tested sublines, cells from a low metastatic and high metastatic sublines were perfectly classified. Cells from two other low metastatic sublines were misclassified. When all 88 cells from the 11 sublines were classified, high metastatic cells were detected with 94% sensitivity and 50% specificity. The predictive value of a determination of low metastatic was 93%, whereas the predictive value of an assignment of high metastatic was 52%. The ability to detect and accurately classify most highly metastatic cells while rarely erring in a classification of low metastatic potential suggests that a grading system of cancer cell motility should be evaluated in human prostatic carcinoma. The motility of live prostatic carcinoma cells may predict patient prognosis better than standard pathological grading systems.

Early cell motility changes associated with an increase in metastatic ability in rat prostatic cancer cells transfected with the v-Harvey-ras oncogene.

The development of metastatic ability by cancer cells is a multifactorial process whose temporal events are complex and poorly understood. One step in the metastatic process may involve cell motility. Previous studies reported correlations between motility and metastatic ability. Whether this correlation, seen in cancer cells maintained for long periods of time, is an epiphenomenon developing late in the growth of the cancer as a selection artifact of continuous passage, or is critically required for the acquisition of metastatic ability is unknown. To investigate the relationship between cell motility and the acquisition of metastatic ability, advantage was taken of recently developed DNA transfection methods for inducing high metastatic ability in initially low metastatic cancer cells. The Dunning AT2.1 cell line, a clonal rat prostatic cancer cell line with low metastatic ability, was transfected with a plasmid containing the neomycin resistance gene alone or in combination with the v-Harvey-ras oncogene. A series of the transfected cells was isolated by limiting dilution. After the first in vitro passage following transfection, cells were inoculated into rats to characterize their metastatic ability. The same transfectants were simultaneously studied using our visual grading system of cell motility to study the early motility changes associated with newly acquired metastatic ability. The data demonstrate increased membrane ruffling, pseudopodal extension, and cell translation (translocation) in the v-H-ras-transfected cell lines with high metastatic potential.

Association of glyceraldehyde-3-phosphate dehydrogenase expression with cell motility and metastatic potential of rat prostatic adenocarcinoma.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression is increased in Dunning R-3327 rat prostatic adenocarcinoma cell lines relative to normal rat ventral prostate tissue. GAPDH expression closely correlates with cell motility of Dunning prostate cancer cell lines and accurately distinguishes cell lines with high metastatic potential from those with low metastatic potential. Increased GAPDH expression in the cancer cell lines is not simply related to increased growth rate, since rapidly proliferating normal prostate tissue did not exhibit elevated GAPDH expression.

Nuclear matrix protein patterns in human benign prostatic hyperplasia and prostate cancer.

The nuclear matrix represents the structural component of the nucleus that determines nuclear shape and higher order DNA organization. We have previously shown tissue specificity in nuclear matrix proteins (NMP), in rat sex accessory tissues, and in a rat model of prostate cancer. This study compares NMP patterns for fresh human normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer for 21 men undergoing surgery for clinically localized prostate cancer or BPH. NMP patterns were compared using high resolution two-dimensional polyacrylamide gel electrophoresis. We identified by molecular weight and isoelectric point 14 different proteins that were consistently present or absent among the various tissues. One protein (PC-1), a M(r) 56,000 protein with an isoelectric point of 6.58, appeared in 14 of 14 different nuclear matrix preparations from prostate cancer and was not detected in normal prostate (0 of 13) or BPH (0 of 14). The NMP patterns are consistent with a model of disease progression in which BPH shares many of the nuclear matrix changes observed in prostate cancer.

Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer.

Vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting gene-transduced cancer vaccines induces tumoricidal immune responses. In a Phase I human gene therapy trial, eight immunocompetent prostate cancer (PCA) patients were treated with autologous, GM-CSF-secreting, irradiated tumor vaccines prepared from ex vivo retroviral transduction of surgically harvested cells. Expansion of primary cultures of autologous vaccine cells was successful to meet trial specifications in 8 of 11 cases (73%); the yields of the primary culture cell limited the number of courses of vaccination. Side effects were pruritus, erythema, and swelling at vaccination sites. Vaccine site biopsies manifested infiltrates of dendritic cells and macrophages among prostate tumor vaccine cells. Vaccination activated new T-cell and B-cell immune responses against PCA antigens. T-cell responses, evaluated by assessing delayed-type hypersensitivity (DTH) reactions against untransduced autologous tumor cells, were evident in two of eight patients before vaccination and in seven of eight patients after treatment. Reactive DTH site biopsies manifested infiltrates of effector cells consisting of CD45RO+ T-cells, and degranulating eosinophils consistent with activation of both Th1 and Th2 T-cell responses. A distinctive eosinophilic vasculitis was evident near autologous tumor cells at vaccine sites, and at DTH sites. B-cell responses were also induced. Sera from three of eight vaccinated men contained new antibodies recognizing polypeptides of 26, 31, and 150 kDa in protein extracts from prostate cells. The 150-kDa polypeptide was expressed by LNCaP and PC-3 PCA cells, as well as by normal prostate epithelial cells, but not by prostate stromal cells. No antibodies against prostate-specific antigen were detected. These data suggest that both T-cell and B-cell immune responses to human PCA can be generated by treatment with irradiated, GM-CSF gene-transduced PCA vaccines.

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.

Expectant management: an option for localized prostate cancer.

Localized prostate cancer demonstrates tremendous heterogeneity in the natural history of the disease. To this end, although prostate cancer may be present histologically in nearly 30% of all men above the age of 50 y, the lifetime risk of developing clinically significant disease is 18% (one in six). Furthermore, the lifetime risk of dying from prostate cancer is less than 4%. Therefore, in order to avoid unnecessarily treating potentially insignificant prostate cancer, the concept of expectant management has been considered for this disease. In this brief review, we discuss the evolution of expectant management for men with localized prostate cancer.

Prediction of progression following radical prostatectomy. A multivariate analysis of 721 men with long-term follow-up.

We studied 721 men with clinically confined disease who underwent radical prostatectomy. No patient received preoperative or postoperative radiotherapy or hormone therapy until progression occurred. For those men without progression, the mean follow-up was 6.5 years with a median of 6 years (range 1 to 12 years). Because patients with lymph node metastases or seminal vesicle invasion had such a high risk of progression, enhanced prognostication was not needed in men with these findings. Thus we focused this analysis on the 617 men without lymph node metastases or seminal vesicle invasion. In the multivariate analysis, Gleason score (P < 0.0001), surgical margins (P = 0.004), and capsular penetration (P = 0.007) were all independent predictors of progression. Tumors with a Gleason score of 2 through 4 were almost invariably cured, with a 10-year progression-free risk of 96%. At the opposite end of the spectrum, the 10-year actuarial progression-free risk for men with a Gleason score of 8 through 9 was 35%. Men with Gleason score 2 through 4 or 8 through 9 tumors could not be stratified into different risks of progression based on the presence or extent of capsular penetration or margin status. For the men with Gleason score 5 through 7 tumors (88.2% of cases), predicting their risk of progression was enhanced by knowledge of their tumor's capsular penetration and margin status. Tumors with a Gleason score of 5 through 6 and 7 were each stratified into three groups with different risks of progression. Using the actuarial curves within this study, physicians will be able to more accurately determine a patient's risk of progression following radical prostatectomy based on a combination of the radical prostatectomy Gleason score, extent of capsular penetration, and status of surgical margins of resection.

The prognostic significance of tertiary Gleason patterns of higher grade in radical prostatectomy specimens: a proposal to modify the Gleason grading system.

The Gleason grading system of prostatic adenocarcinoma does not account for the existence of a tertiary (third most prevalent) pattern, and there are no studies concerning the latter's prognostic influence. The authors analyzed 114 radical prostatectomies with small tertiary components, which mostly occupied less than 5% of whole tumors. These specimens were compared with a prostatectomy database comprised of 2,276 cases without a tertiary component. The pathologic stages of "typical" Gleason score 5 to 6 tumors (Gleason scores 2 + 3 = 5, 3 + 2 = 5, 3 + 3 = 6), which contained tertiary patterns 4 or 5, were significantly higher than those of "typical" Gleason score 5 to 6 tumors without pattern 4 (p = 0.018) but lower than those of "typical" Gleason score 7 tumors (p = 0.021; Gleason scores, 3 + 4 = 7, 4 + 3 = 7). Typical Gleason score 7 tumors with a tertiary pattern 5 showed significantly worse pathologic stages than typical Gleason score 7 tumors (p = 0.008) without pattern 5 and were not different statistically from typical Gleason score 8 (Gleason score, 4 + 4 = 8) tumors. Both typical Gleason score 5 to 6 and 7 tumors with tertiary components revealed significantly higher progression rates than typical Gleason score 5 to 6 tumors (p <0.0001) and Gleason score 7 tumors (p = 0.003) without tertiary components, and progressed like typical Gleason score 7 and 8 tumors respectively. Tertiary high-grade components have an adverse impact on biologic behavior. The authors propose that the Gleason system for radical prostatectomy specimens be modified to take into account small volumes of patterns 4 and 5, which are important prognostically.

Neuroendocrine differentiation in prostate cancer: enhanced prediction of progression after radical prostatectomy.

It is controversial whether neuroendocrine (NE) differentiation in adenocarcinoma of the prostate is associated with more aggressive behavior. Most studies included patients with tumors of a wide range of grades and stages and an end point of disease-specific survival, a relatively insensitive marker of progression. The authors studied completely embedded radical prostatectomy specimens from 104 patients with clinically organ-confined carcinoma and no history of adjuvant or neoadjuvant therapy. Progression was marked by a serum prostate-specific antigen (PSA) concentration greater than or equal to 0.2 ng/mL. Seventy-six men did not progress, with a mean follow-up period of 8.0 years (range = 7 to 10 years). Forty-eight men progressed at a mean time after surgery of 3.6 years (range = 1 to 8 years). Twenty-one percent of the tumors were organ confined: 79% had capsular penetration. Seminal vesicles and lymph nodes were negative in all cases. A representative section through the main tumor mass was stained for chromogranin A. Reactive neoplastic cells were counted subjectively as well as individually enumerated. Gleason grade, pathological stage, and degree of NE differentiation all correlated with progression. Only grade and extent of NE differentiation predicted progression in a multivariate analysis. NE differentiation did not correlate with stage or grade. Extent of NE differentiation separated patients (59 cases) with tumors of Gleason sum less than or equal to 6 into groups with high and low risks for progression (P < .008) independent of Gleason sum. Extent of NE differentiation provides prognostic information in addition to that provided by grade in cases of early prostate cancer treated by radical prostatectomy.

OA-519 (fatty acid synthase) as an independent predictor of pathologic state in adenocarcinoma of the prostate.

OBJECTIVES: To improve the prediction of pathologic stage beyond that provided by Gleason score. METHODS: We investigated the tissue expression in prostate cancer of a relatively new marker, oncoantigen 519 (OA-519). Because Gleason score is one of the most powerful predictors in prostate cancer, we restricted our evaluation to 66 radical prostatectomy specimens of varying pathologic stages which were either Gleason score 6 or 7. Immunohistochemical staining of OA-519 was assessed with a combined staining score from 0 to 8, taking into account both the intensity and percentage of tissue staining. In addition, an intensity score was derived based on whether any intense staining was present in case. RESULTS: OA-519 staining of the primary prostate cancer was highly predictive in separating cases with organ-confined disease or capsular penetration versus cases with seminal vesicle invasion or lymph node metastases; Gleason score 6 or 7 was also predictive. In a logistic multivariate regression analysis, both OA-519 and Gleason score were strong independent predictors of pathologic stage (P = 0.0004). CONCLUSIONS: OA-519 predicted pathologic stage well when analyzing primary prostate cancer in radical prostatectomy specimens and is presently being investigated on preoperative biopsy material to assess its ultimate clinical applicability. OA-519 has significant promise as a prognostic marker for prostate cancer and is one of the few markers that provides additional predictive information beyond that of the Gleason score.

Anatomic approach for placement of surgical drains after radical retropubic prostatectomy: long-term effects on postoperative pain.

OBJECTIVES: The placement of drains following radical retropubic prostatectomy (RRP) may potentially damage neural and vascular structures within the abdominal wall, leading to postoperative pain and morbidity. In this study, we compare postoperative pain in two groups of men who underwent RRP. The Davol drains were either placed lateral to the rectus muscle (n = 100) or in the medial two thirds of the rectus muscle (n = 100). METHODS: We investigated postoperative pain for an average of 5 months after RRP. Detailed responses were obtained from 89.5% (179 of 200) of the men. The average age was 57 years and the average follow-up 20 weeks. RESULTS: Overall, 33.5% (60 of 179) of the men reported postoperative pain associated with either the incision or drain site. Rated on a scale of 0 to 10 (with 10 representing the most pain), the average pain scale assessment was 1.3 +/- 2.6 (range 0 to 6). Pain was attributable to the incision site only in 9% (16 of 179) and at the drain site only in 24% (42 of 179). We found more pain overall (41%) where the drains were placed lateral to the rectus muscle as compared with men in whom the drains were placed in the medial two thirds of the rectus muscle (26%) (P = 0.03). CONCLUSIONS: Placement of drains in the medial two thirds of the rectus muscles avoids injury to intercostal nerves and results in less pain at the drain sites.

Can aggressive prostatic carcinomas be identified and can their natural history be altered by treatment?

The factors that determine tumor aggressiveness are multifactorial: age, stage, and grade. Even a well differentiated tumor in a young patient may be aggressive someday because of genetic drift and tumor heterogeneity. In a recent review of 826 favorably selected cases managed with conservative therapy, metastatic disease had developed in 19% with grade I tumors, 42% with grade II, and 74% with grade III at 10 years. Recognizing that < 20% of men present with grade I disease, most prostate cancers are a threat to life in men who are going to live longer than 10 years. On the other hand, some tumors at presentation are too far advanced to cure. To improve the accuracy of preoperative staging in identifying these cases, we have developed nomograms based upon clinical stage, grade, and serum prostate-specific antigen (PSA). Traditionally, patients with high-grade tumors (Gleason 8-10) were never considered candidates for radical prostatectomy because of their poor expectancy for long-term survival. However, with improvements in the staging of prostate cancer and with a reduction in the morbidity of radical prostatectomy, a subset of these patients are potential candidates for curative therapy. We have recently studied the clinical outcome of 72 men with Gleason scores of 8-10 on needle biopsies who presented with clinically localized disease (9 T1c, 22 T2a, 17 T2b, 13 T2c, and 11 T3a). Of the 63 men who underwent radical prostatectomy, 46 (68%) had negative lymph nodes; nine did not undergo surgery because of positive lymph nodes identified from frozen section. The actuarial likelihood of an undetectable serum PSA at 5 years was 43% for men with negative lymph nodes and 45% for men with organ-confined disease. Thus, with proper evaluation, some men with even the most aggressive tumors can be cured by surgery if their pelvic lymph nodes are negative.

Influence of age and prostate-specific antigen on the chance of curable prostate cancer among men with nonpalpable disease.

OBJECTIVES: To evaluate the relation between age, prostate-specific antigen (PSA) level, and the probability of detecting curable prostate cancer. METHODS: A consecutive surgical series of radical prostatectomies was performed in 492 men with nonpalpable (Stage T1c) disease, who formed the study cohort (mean age 58 years). The cohort was systematically classified into three age groups ([1] 40 to 50 years [n = 69]; [2] 51 to 60 years [n = 227]; [3] 61 to 73 years [n = 196]) and five pretreatment PSA groups ([1] 2.5 to 4.0 ng/mL [n = 36]; [2] 4.1 to 6.0 ng/mL [n = 100]; [3] 6.1 to 8.0 ng/mL [n = 122]; [4] 8.1 to 10.0 ng/mL [n = 76]; [5] greater than 10.0 ng/mL [n = 135]). The percent probability of curable cancer was determined by logistic regression analysis. Curable cancer was defined as organ-confined tumor or a tumor with capsular penetration of low grade (Gleason score less than 7), with negative margins and no involvement of seminal vesicles or lymph nodes. RESULTS: A comparison within age groups and within PSA groups revealed that the probability of curable cancer was more closely associated with age than PSA level. Although the probability of curable cancer was closely related to PSA level across a wide range of PSA values (0.4 to 52 ng/mL), there was only minimal difference (2% to 4%) in the probability of curable cancer within the range of PSA values from 2.5 to 6.0 ng/mL for all ages. CONCLUSIONS: Age is a strong predictor of the probability of curable cancer. Thus, early detection efforts in younger men are more likely to lead to a decrease in prostate cancer mortality. These data suggest that the use of PSA thresholds below 4.0 ng/mL as an indicator of prostate cancer is unlikely to improve the probability of detecting curable cancer.

An algorithm combining age, total prostate-specific antigen (PSA), and percent free PSA to predict prostate cancer: results on 4298 cases.

OBJECTIVES: To (1) determine if patient age and total prostate-specific antigen (PSA) levels could enhance the ability of percent free PSA to distinguish prostate cancer from benign prostate disease within the 4.0 to 20 ng/mL total PSA range; (2) define the probability of prostate cancer based on patient age, total PSA, and percent free PSA; and (3) define a probability cutoff that distinguishes benign from malignant prostate disease. METHODS: The 3773 urologically referred patients with serum PSA values between 4.0 and 20 ng/mL had a sextant biopsy diagnosed as either prostatic carcinoma (1234) or benign prostatic disease (2539) within 60 days of serum specimen collection. We created a logistic regression model, using patient age, total PSA, and percent free PSA, to assign a probability of prostate cancer, and tested the model on an additional data set (525 patients) to calculate sensitivity and specificity. RESULTS: An 18% probability cutoff detected 95% of malignant biopsies and identified 34% of negative biopsies in the validation set. This approach yielded an 11% percentage point increase in specificity over percent free PSA alone. A 20% probability cutoff detected 90% of malignant cases and identified 42% of negative biopsies. CONCLUSIONS: A prostate cancer probability based on age, total PSA, and percent free PSA is more effective than percent free PSA alone in differentiating benign prostate disease from prostate cancer. This model may assist physicians and patients regarding the need for biopsy.

Ureteral bladder augmentation using the lower pole ureter of a duplicated system.

Megaureters of nonfunctioning renal segments in a duplex system are commonly available for use in reconstructive procedures secondary to high-grade reflux, ectopic ureter, ectopic ureterocele, or obstructive megaureter. The use of megaureters subtending a nonfunctioning lower pole renal segment for bladder augmentation in 2 patients is reported.

Nuclear morphometric analysis of metastasis in Wilms' tumor after multimodal therapy: comparison with primary tumor.

OBJECTIVES: The outlook for children with Wilms' tumor has improved with the use of multimodal therapy, and survival rates now exceed 85%. Yet, 15% of children with tumors with favorable histologic findings continue to recur unpredictably. We previously reported that nuclear morphometry (the distribution of nuclear roundness factor [NRF], lowest values for ellipticity, and age) when combined in a multivariate analysis accurately predicted response to therapy for patients with histologically favorable Wilms' tumors. METHODS: To investigate further the nuclear shape changes associated with disease recurrence, we analyzed histologic sections taken from primary tumors and postmultimodal therapy metastatic lesions for 7 children who had a recurrence with initially histologically favorable primary tumors. RESULTS: Mean NRF was significantly lower (P = 0.0001) in the metastatic lesion (35 +/- 5) group when compared with the primary tumor group (50 +/- 5). The percent coefficient of variation for NRF was also significantly lower (P = 0.006) in the metastatic lesion when compared with the primary tumor. Nuclear area was increased (P = 0.02), although the nuclear perimeter was unchanged (P = 0.1). CONCLUSIONS: (1) Nuclei in metastatic lesions from Wilms' tumors with favorable histologic findings after multimodal therapy are more round and exhibit less variable distribution, suggesting clonal homogeneity within the metastatic lesion. (2) Nuclei in the metastatic lesions have greater area than in the primary tumors yet have an unchanged perimeter, which may be due to internal nuclear expansion secondary to increased cellular deoxyribonucleic acid (DNA) ploidy. Although the results of this study are promising, we are currently extending this hypothesis to a larger group of patients.

Nuclear morphometry accurately predicts recurrence in clinically localized renal cell carcinoma.

Despite careful clinical staging, as many as 30 percent of patients with pathologically, specimen-confined renal cell carcinoma (RCC) have unpredictable recurrence following surgery. Present pathologic and clinical staging systems cannot accurately predict those patients with high risk of disease recurrence from those who are cured by surgery alone. Advances in immunotherapy including gene therapy for RCC have dictated the need to identify RCC patients for adjuvant therapy protocols who have a high probability of recurrence following nephrectomy. Nuclear morphometric techniques developed at our institution have predicted prognosis for a variety of genitourinary tumors; it was used to predict recurrence among patients undergoing nephrectomy for localized RCC. This report is a retrospective study of 26 patients with RCC of similar age, stage (pT1-pT3), and grade. Fifteen were free of disease at a mean of 75.2 months, and 11 had distant disease recurrence at a mean of 27.1 months. Statistical analysis of a variety of nuclear shape descriptors accurately separated this group of patients based on disease recurrence. No nuclear shape descriptor predicted disease recurrence when nuclei within the region of the tumor with the highest grade were analyzed. However, the range of nuclear ellipticity (p = 0.007) best predicted disease recurrence when nuclei were selected in a random fashion. Multivariate analysis of the four best shape descriptors better predicted disease recurrence (p = 0.002) with a sensitivity of 73 percent and specificity of 100 percent. These results are encouraging and suggest that this technique might be used in identifying patients for adjuvant gene therapy.