James L. Mohler

Selection of men at high risk for disease recurrence for experimental adjuvant therapy following radical prostatectomy

OBJECTIVESnFollowing surgery, men with recurrent prostate cancer have an isolated elevation in serum prostate-specific antigen (PSA) well in advance of measurable metastatic disease. Rational patient selection for new forms of adjuvant therapy, for example, gene therapy, is imperative.nnnMETHODSnIn a retrospective study of two cohorts, we used proportional hazards regression analysis to develop and validate a multifactor model for identifying men who are at high risk of cancer recurrence. The model cohort consisted of 216 men with clinical Stage T2b and T2c treated by 1 urologist. The validation cohort consisted of 214 men with Stage T2b and T2c disease.nnnRESULTSnA model for log relative risk, Rw, used serum PSA with a sigmoidal transformation (PSAST), radical prostatectomy Gleason score (GS), and pathologic stage (PS) as specimen confined or nonspecimen confined: Rw = (PSAST x 0.06) + (GS x 0.54) + (PS x 1.87). Recurrence risk categories were determined as low risk if Rw is less than 4.0, intermediate risk if it is 4.0 to less than 5.75, and high risk if Rw is more than 5.75. The observed Kaplan-Meier actuarial analysis of the three risk groups correlated well with the predictions determined for the model cohort. We then validated this model independently using a second cohort of 214 men with similar age, stage, and grade treated by 3 different urologists at two different institutions.nnnCONCLUSIONSnThe recurrence rates for men in the high-risk group are similar to those for men with positive lymph nodes and justifies exploration of experimental adjuvant therapy within this group using this model of patient selection.

A Comparison of Nuclear Morphometry and Gleason Grade as a Predictor of Prognosis in Stage A2 Prostate Cancer: A Critical Analysis

The natural history of stage A2 prostate cancer is unknown. Previous studies from this institution have shown that, without treatment, a third of the men with clinically localized stage A2 prostatic adenocarcinoma will have disease progression within 4 years. Presently, most patients who present with stage A2 prostate cancer receive surgical or radiation therapy. The degree of differentiation of the tumor (Gleason score) presently is used to predict the prognosis among patients with clinically localized prostate cancer. The Gleason score does well to predict the prognosis for patients with scores of 2 to 4 and 8 to 10. Unfortunately, the majority of patients fall within the range of Gleason scores of 5 to 7. Better methods are needed to predict which patients diagnosed with stage A2 prostate cancer have a high probability of disease progression. Several studies have reported that morphometrically determined nuclear shape descriptors provided accurate separation of these patients that was superior to Gleason grading methods. To evaluate critically the usefulness of nuclear morphometry for prediction of prognosis we developed a system. The Hopkins Morphometry System, that calculated and compared 15 different shape descriptors that were analyzed by 17 different statistical tests. We tested this system on 18 untreated patients with stage A2 prostate cancer with an average followup of 10.5 years (range 5 to 18 years). For each patient 17 statistical analyses of the 15 shape descriptors (255 total) were evaluated and 50 analyses (50 of 255, 19.6%), including average nuclear roundness factor, provided significant separation (p less than 0.01) of the patients on the basis of outcome, whereas the Gleason score (p equals 0.076) did not. The best separation (p less than 0.01) was provided by the lower quartile analysis of the ellipticity shape descriptor.

Nuclear Roundness Factor Measurement for Assessment of Prognosis of Patients With Prostatic Carcinoma. I. Testing Of A Digitization System

Standard pathological grading systems for prostatic carcinoma based upon glandular architectural pattern or nuclear anaplasia have failed to predict the prognosis of individual patients. Quantitative morphometric analysis of nuclear shape has predicted the outcome of patients with prostatic carcinoma when evaluated by some but not all reported studies. Calculation of nuclear roundness factor by different investigators was complicated by equipment differences and lack of standardized methods for acquiring and reporting data. We have improved our system for nuclear contour digitization and determined its theoretical limitations by digitizing standardized objects. Measurement errors were independent of orientation or location of an object within a microscopic or digitizer tablet field, speed of digitization and introduction of a microscope extension tube and light emitting diode cursor. Perimeters and areas of circles and squares of actual or digitizer-projected diameter or sidelength greater than five mm. were measured with a reproducibility and accuracy of greater than or equal to 90%. When a microscopic circle of diameter similar to prostatic carcinoma nuclei was digitized at a magnification of 2580 X, perimeter and area measurements differed within or between observers by less than 5% and were more than 95% accurate. In order to calculate accurately and evaluate NRF for use in assessing the prognosis of patients with prostatic carcinoma investigators must precisely describe their digitization system, standardization method and observer reproducibility and accuracy when measuring circles that approximate the projected size of prostatic carcinoma nuclei.

Nuclear Roundness Factor Measurement for Assessment of Prognosis of Patients with Prostatic Carcinoma. II. Standardization of Methodology for Histologic Sections

A nuclear shape descriptor, nuclear roundness factor, predicted outcome in patients with prostatic carcinoma whereas standard pathological grading by Gleasons architectural pattern did not. The inability of others to duplicate those successes warranted a reevaluation of the technique for NRF measurement. We previously described our digitization system and measured the perimeter and area of a microscopic circle similar in size to prostatic carcinoma nuclei with a reproducibility and accuracy of greater than 95%. We have applied our improved system to nuclear contour digitization and standardized our method for NRF measurement. In order to calculate accurately the NRF for prostatic carcinoma, the histologic section must have been reviewed by a pathologist and 150 nuclei traced after random selection. NRF measurement reproducibility within and between observers exceeded 90%. This system for NRF measurement successfully predicted outcome in 13 of 15 patients with stages A2, B1, and B2 prostatic carcinoma. Our success with a carefully tested and improved system for NRF determination warrants further evaluation of NRF for assessment of prognosis of patients with prostatic carcinoma.

Prediction of metastatic potential by a new grading system of cell motility: Validation in the Dunning R-3327 prostatic adenocarcinoma model

Many grading systems for prostatic carcinoma exist; however, none allows pathologists to accurately predict the prognosis of individual patients. Examination of dead fixed histological sections of malignancies may not be the best way to predict the biological behavior of living dynamic tumors. We have developed a grading system that reproducibly characterized the motility of living cancer cells. In the Dunning R3327 rat prostatic adenocarcinoma model, three sublines of high metastatic potential (greater than 90%) were distinguished from four sublines of low metastatic potential (less than 10%). Individual cells from these sublines were correctly identified as high or low metastatic in 96% of cases by grading membrane ruffling, pseudopodal extension, and vectoral translation.

Time Lapse Videomicroscopic Identification of Dunning R-3327 Adenocarcinoma and Normal Rat Prostate Cells

A method for accurate prediction of prognosis in human prostatic cancer does not exist. The limitations of pathologic grading systems may result from the failure of standard pathological examination of fixed dead tissue to accurately assess the biological behavior of live tumor cells. Many of the sublines of the Dunning R-3327 rat adenocarcinoma are histologically similar yet differ widely in their metastatic potential. The nonmetastatic G, occasionally metastatic AT-1 and AT-2, and highly metastatic AT-3 and MAT-Lu Dunning sublines, and normal dorsal prostate were grown in culture and filmed by time-lapse videomicroscopy. Cell membrane ruffling, undulation and pseudopodal extension, vectoral translation, irregularity of pathway, and overall subjective motility (gestalt) were visually graded. Intra-assay, intra-observer, and inter-observer reproducibility were 75, 80 and 75% respectively. The combination of ruffling, pseudopodal extension and vectoral translation was most successful in identifying the six sublines. To validate this technique prospectively, five tumor sublines and two normal prostates were graded by 10 observers unfamiliar with the technique. Fifty-nine percent of unknowns were correctly identified when motility profiles were compared to previously developed standards by least sum of squares analysis. We devised a new technique for characterizing the motility of living prostate cells which was more accurate in identifying normal rat prostate and the Dunning sublines than standard pathological examination. Prostatic cancer cell motility may reflect biological behavior and metastatic potential and thus contribute to the assessment of an individual patients prognosis.

Unusual urological presentations of acquired immune deficiency syndrome: large cell lymphoma.

We describe 2 patients with unrecognized acquired immunodeficiency syndrome who presented with acute urological conditions. One patient had inapparent obstructive anuric renal failure and the other had a testicular mass. The etiology in each case was large cell lymphoma. Recognition of the acquired immunodeficiency syndrome by urologists requires an awareness of its many unusual presentations.

Metabolic acidosis after bladder replacement: comparison of severity and reversibility in ileal and colonic reservoirs.

Metabolic acidosis developed frequently after ureterosigmoidostomy and rectosigmoid bladder construction but has been reported rarely after the newer methods of continent urinary diversion which also employ intestinal reservoirs. We created an animal model in which to compare the metabolic effects of bladder replacement with segments of ileum or colon and the potential for reversing these derangements with nicotinic acid and chlorpromazine. One year after six dogs bladders were replaced by colon (three) or ileum (three), all dogs appeared in excellent health and were free of urinary tract obstruction and clinical infection. Both groups of dogs were severely acidotic with diminished arterial pH and arterial and venous total CO2 concentrations although normal serum electrolytes and creatinine concentrations were maintained. Both groups of dogs absorbed approximately one half the urinary sodium, chloride and urea presented to their intestinal reservoirs. After treatment with nicotinic acid and chlorpromazine, the metabolic status of both groups of animals improved. Although nicotinic acid reduced urinary excretion of electrolytes more effectively than chlorpromazine, nicotinic acid was not more effective for reversing metabolic acidosis. When nicotinic acid was provided as an adjunct to sodium bicarbonate therapy in two animals acidosis was corrected at reduced doses of sodium bicarbonate. Based upon this work in an animal model, there does not appear to be a metabolic advantage to intestinal reservoirs which incorporate ileum versus colon. However, asymptomatic patients with normal serum electrolytes and creatinine concentrations may be acidotic. The effects of long term mild acidosis are unknown. However, if therapy is required to prevent diminution of whole body buffers or changes in bone density specific therapy with nicotinic acid or chlorpromazine may reduce the requirement for alkali for correction of metabolic acidosis.

Creatinine Clearance Prediction in Spinal Cord Injury Patients: Comparison of 6 Prediction Equations

The renal function of spinal cord injury patients frequently is overestimated by 3 commonly used equations to predict creatinine clearance. Overestimation of creatinine clearance may result in aminoglycoside overdosage and resultant nephrotoxicity. Three newer prediction equations have been developed from creatinine clearances measured in neurologically abnormal patients. These 6 equations were tested in 77 male and 9 female spinal cord injury patients (48 quadriplegics and 38 paraplegics, including 38 with acute and 48 with chronic injuries). The equation developed by Sawyer and Hutchins was superior to 2 other equations developed in spinal cord injury patients and 3 equations developed in neurologically normal patients. However, creatinine clearances predicted by this equation were within 30 ml. per minute of measured creatinine clearances in only two-thirds of the spinal cord injury patients. Errors ranged from overestimation by 95 ml. per minute (151 per cent) to underestimation by 106 ml. per minute (45 per cent). The potential for large errors in creatinine clearance prediction necessitates measurement of creatinine clearance as soon as possible when renal excreted and toxic pharmaceuticals are administered to spinal cord injury patients.