Kathleen O'Toole

Molecular staging of prostate cancer with the use of an enhanced reverse transcriptase-PCR assay

OBJECTIVE Because up to 40 percent of surgically treated patients with prostate cancer are subsequently found to be clinically understaged, a more sensitive staging modality to identify extraprostatic disease prior to surgery is required. METHODS We describe an enhanced reverse transcriptase [RT] polymerase chain reaction (PCR) assay utilizing oligonucleotide primers specific for the human prostate-specific antigen (PSA). This assay identifies PSA-synthesizing cells from reverse transcribed mRNA. This assay was applied to RNAs extracted from the peripheral blood lymphocytes of 65 patients with clinically localized prostate cancer. In addition, blood from 20 women, 20 young men, 25 age-matched control men under treatment for benign prostatic hyperplasia (BPH), and 18 men with established, untreated metastatic prostate cancer was tested. RESULTS An RT-PCR assay for PSA can recognize one PSA-expressing cell diluted into one hundred thousand lymphocytes. The sensitivity of this assay can be enhanced by the addition of digoxigenin-modified nucleotides to the PCR reaction and this assay was applied to RNAs extracted from the peripheral lymphocyte fraction of 148 prostate cancer patients and controls at this institution. Although no specimen from women or men without cancer was positive in this assay, 14 of 18 metastatic prostate cancer patients were positive (77.8%). Additionally, 25 of 65 (38.5%) patients with clinically localized disease (T1-2b) were positive from blood specimens obtained prior to surgery. Final pathologic results from this group of patients identified a correlation between positivity on this assay and the presence of capsular tumor penetration (sensitivity, 68%; specificity, 84%) as well as strong correlation with the finding of carcinoma at the surgical margin (sensitivity, 87%; specificity, 76%). Logarithmic regression analysis of the results of the RT-PCR assay indicates its remarkable superiority to digital rectal examination, computed tomography scan, endorectal coil magnetic resonance imaging, PSA, prostate-specific antigen density, or Gleason score for predicting the true pathologic stage of prostate cancer in these surgically treated patients. CONCLUSIONS An RT-PCR assay using PSA primers to detect prostate cells in the peripheral circulation of surgical-candidate patients is significantly correlated with capsular penetration and tumor-positive surgical margins. This molecular assay provides a sensitive and specific means to stage correctly apparent localized prostate cancer prior to radical prostatectomy.

Regression of established tumors and metastases by potent vascular endothelial growth factor blockade

Vascular endothelial growth factor (VEGF) is a critical promoter of blood vessel growth during embryonic development and tumorigenesis. To date, studies of VEGF antagonists have primarily focused on halting progression in models of minimal residual cancer. Consistent with this focus, recent clinical trials suggest that blockade of VEGF may impede cancer progression, presumably by preventing neoangiogenesis. However, VEGF is also a key mediator of endothelial–vascular mural cell interactions, a role that may contribute to the integrity of mature vessels in advanced tumors. Here, we report that high-affinity blockade of VEGF, using the recently described VEGF-Trap, abolishes mature, preexisting vasculature in established xenografts. Eradication of vasculature is followed by marked tumor regression, including regression of lung micrometastases. Thus, the contribution of relatively low levels of VEGF to vessel integrity may be critical to maintenance of even very small tumor masses. Potent blockade of VEGF may provide a new therapeutic option for patients with bulky, metastatic cancers.

Expression of PAX8 in normal and neoplastic renal tissues: an immunohistochemical study

Cell-lineage-specific transcription factors are a group of regulatory proteins expressed in embryonic, differentiated, or neoplastic cells of the same lineage and represent a valuable repertoire of tissue-specific markers for the diagnosis of human tumors. Together with PAX2, PAX8 is a nephric-lineage transcription factor and is required for the establishment of renal-lineage cells and the formation of the kidney. In contrast to PAX2, little is known about the expression of PAX8 in adult kidney and renal tumors. In this study, we used immunohistochemistry to investigate the expression of PAX8 in adult human kidney and renal epithelial tumors. We report here that PAX8 was detected in renal epithelial cells in all segments of renal tubules from the proximal tubules to the renal papillae and in the parietal cells of Bowmans capsule in the adult kidney. PAX8 was also present in 98% of clear cell renal cell carcinomas (RCCs), 90% of papillary RCCs, and 95% of oncocytomas, similar to PAX2. In addition, PAX8 was found in 82% of chromophobe RCCs, 71% of sarcomatoid components of RCCs, and 100% (2/2) of renal medullary carcinomas. Overall, PAX8 was detected in 85% of metastatic renal tumors. Interestingly, expression of PAX8 was noted in some urothelial cells in the renal pelvis and ureters and ∼23% of urothelial carcinomas of the renal pelvis, but not in the urothelium or urothelial carcinomas of the urinary bladder; this probably underlines the different embryonic origins of urothelial cells in the upper and lower urinary tracts. As shown in this study, PAX8 is widely expressed in normal and neoplastic renal tissues. PAX8 may be a useful additional marker for renal epithelial tumors; however, its specificity and sensitivity await further investigation.

Enhanced reverse transcriptase-polymerase chain reaction for prostate specific antigen as an indicator of true pathologic stage in patients with prostate cancer

Background. As up to 50% of all patients with prostate cancer who have undergone radical prostatectomy are found to be understaged subsequent to surgery, a more sensitive early staging modality currently is needed. A molecular assay that detects prostate specific antigen (PSA)‐synthesizing cells in the peripheral circulation of patients with prostate cancer is described.

The Incidence of Multifocal Renal Cell Carcinoma in Patients Who are Candidates for Partial Nephrectomy

PURPOSE A prospective study was performed to determine the incidence of multifocal renal cell carcinoma in patients who are candidates for partial nephrectomy. MATERIALS AND METHODS Preoperative imaging studies and surgical specimens in 44 patients suitable for partial nephrectomy but undergoing radical nephrectomy were prospectively reviewed. RESULTS Of 44 renal cell cancers 11 (25%) demonstrated pathological multifocality, while 10 of 11 multifocal tumors (91%) occurred in the face of a primary tumor 5 cm. or smaller. Tumor multifocality was independent of the size of the primary renal tumor but occurred with a slightly higher frequency in tumors of stage T3A or greater even if the primary tumor was small. CONCLUSIONS Partial nephrectomy in patients with unilateral renal cancer should be approached with caution and should not be performed simply because it is technically feasible.

Increasing incidence and excellent survival of patients with early gastric cancer: experience in a United States medical center.

PURPOSE In Japan, early gastric cancer has an excellent survival rate. In the United States, the disease is less well understood, and it is viewed more pessimistically, although we have previously shown in a small series of patients good short-term survival rates in early gastric cancer as compared with advanced gastric cancer. Our purpose in this study was to determine if the incidence of early gastric cancer and the associated survival rate has changed over a 24-year period. PATIENTS AND METHODS From the records at the Columbia Presbyterian Medical Center, 549 patients were identified who underwent gastric resection for cancer between 1960 and 1984, 69 of whom had early gastric cancer. Survival data were obtained in 63 patients. A comparison of survival rates was conducted between patients with early gastric cancer and the 1980 census figures. RESULTS Over the 24-year period, the total number of resections for gastric cancer at our institution declined. However, the percentage of gastric resections that satisfied the Japanese criteria for early gastric cancer increased from 9 percent between 1960 to 1974 to 17 percent between 1975 to 1984 (p less than 0.05). Of the 69 early gastric cancers, 35 percent involved the mucosa, whereas in 65 percent the malignancy invaded the submucosa. Twenty-eight percent had lymph node involvement. For the patients for whom survival data were available, survival was better than the 1980 census (p less than 0.05). The adjusted five-year survival rate was 97 percent. Neither submucosal invasion nor lymph node involvement altered survival. Patients with type III early cancers (ulcerated), however, had a significantly greater survival rate than patients with type I (polypoid) early cancers (p less than 0.05). CONCLUSION Early gastric cancer is being diagnosed with increasing frequency and has an excellent survival rate. These findings are similar to the Japanese experience and argue for an ongoing aggressive approach to endoscopic biopsy of gastric lesions.

Preoperative Reverse Transcriptase Polymerase Chain Reaction for Prostate Specific Antigen Predicts Treatment Failure Following Radical Prostatectomy

PURPOSE We previously demonstrated than an enhanced reverse transcriptase-polymerase chain reaction assay for prostate specific antigen (PSA) can predict final pathological stage in radical prostatectomy patients. The potential role of the assay in predicting serum PSA recurrence after radical prostatectomy was explored. MATERIALS AND METHODS We evaluated 100 radical prostatectomy candidates by reverse transcriptase polymerase chain reaction preoperatively, and status was compared to serum PSA, Gleason score and final pathological results. Potential surgical failure was defined as tumor at the surgical margin or extending into the seminal vesicle. Patients were monitored postoperatively by serum PSA every 4 months. Kaplan-Meier analysis was used to evaluate the correlation between reverse transcriptase polymerase chain reaction and disease recurrence, defined as a PSA of 0.2 ng/ml. or greater. RESULTS Enhanced reverse transcriptase polymerase chain reaction for PSA had a stronger correlation with potential surgical failure than preoperative serum PSA or Gleason score (relative risks 15.2, 5.9 and 3.2, respectively). The correlation between these modalities and PSA recurrence was evaluated during a mean followup of 13.6 months (range 5 to 26). Of 36 patients with positive reverse transcriptase polymerase chain reactions 9 had failure by PSA compared to 3 of 64 (4.7%) with negative polymerase chain reactions (p<0.0286). The relative risk for failure by reverse transcriptase polymerase chain reaction was 3.6. Gleason score and serum PSA had higher correlations with postoperative PSA elevations (relative risk 13.2 and 7.6, respectively). A Cox regression analysis model demonstrated that reverse transcriptase polymerase chain reaction for PSA can be used in conjunction with Gleason score and provides statistically significant risk information. CONCLUSIONS Enhanced reverse transcriptase polymerase chain reaction for PSA is a statistically significant predictor of potential failure by pathological analysis and of disease recurrence by PSA. Longer followup data are required to define further the role of the assay in the management of patients with prostate cancer.

Leiomyoma of bladder: Report of case and review of literature

We recently treated a patient with leiomyoma of the bladder and reviewed the 37 most recent cases in the English language literature. Mean patient age was forty-four years. Women made up 76 percent of the patients. Patients presented most commonly with obstructive urinary symptoms (49%), irritative symptoms (38%), hematuria (11%), or flank pain (13%); 19 percent were asymptomatic. Almost all patients had cystoscopy (87%) and intravenous urograms (IVU) (81%), but fewer had masses on bimanual examination (57%), ultrasound (49%), or computed tomography (CT) scan (35%). Most patients were treated with open resection (62%), while 30 percent were treated with transurethral resection (TUR). Almost all patients were cured with a single procedure (89%). Leiomyoma of the bladder is rare and readily cured with excision.

Early Gastric Cancer

We found 28 cases (13%) of early gastric cancer from among 213 cases of gastric cancer resected over a 10-yr period. The incidence was higher in the second 5 yr than the first. The lesions were classified into type I (polypoid, 29%), type II (superficial, 21%). Type III (ulcerated, 32%), and mixed (18%) according to the Japanese classification. Twenty-nine percent had lymph node metastases. In only 50% of the early cases had endoscopy or radiology suggested that the lesions were malignant. Biopsy diagnosis of carcinoma was made in 20 cases preoperatively and was negative for carcinoma in 4 others. Adequate numbers of endoscopic biopsy specimens must be taken to ensure a diagnosis in early gastric cancer. Follow-ups were obtained in all early, and 70% of the advanced cancer patients. Life table survival curves revealed 5-yr survival rates for 68% for the early gastric cancer and 27% for the advanced cancer cases (p less than 0.01). None of the patients in the first group died of gastric cancer. The early gastric cancer patients had a 32% incidence of other, nongastric malignancies compared to 7.7% in the advanced cancer group. Gastric cancer is being diagnosed at an early stage and the survival rates for these patients are significantly greater than those with advanced gastric cancer.

CAN PERINEURAL INVASION ON PROSTATE NEEDLE BIOPSY PREDICT PROSTATE SPECIFIC ANTIGEN RECURRENCE AFTER RADICAL PROSTATECTOMY

PURPOSE We evaluated the role of perineural invasion identified on prostate needle biopsy as a predictor of prostate specific antigen (PSA) recurrence after radical prostatectomy. MATERIALS AND METHODS Between 1993 and 1998 radical prostatectomy was performed in 319 consecutive patients. Prostate needle biopsies were reviewed in all cases. We compared perineural invasion with other preoperative parameters, including digital rectal examination, PSA and biopsy Gleason score, for the ability to predict PSA recurrence with recurrence defined as any serum PSA level greater than 0.2 ng./ml. RESULTS Perineural invasion was identified on 77 of 319 preoperative prostate biopsies (24%). There was PSA recurrence in 46 patients (14.4%) at a mean followup of 25.4 months (range 0.2 to 62.1). Perineural invasion statistically correlated with PSA recurrence. Kaplan-Meier analysis revealed disease-free survival rates of 24 versus 64% when perineural invasion was and was not present in the prostate biopsy (p = 0.0003, log rank 12.92). Multivariate analysis demonstrated that perineural invasion (p = 0.012) and PSA (p = 0.005) were independent preoperative predictive factors of PSA recurrence. When perineural invasion was compared with postoperative parameters, including disease stage, surgical margins and seminal vesicle invasion, it was not an independent predictor because it closely correlated with tumor stage. CONCLUSIONS Perineural invasion on preoperative prostate needle biopsy is a strong independent predictor of PSA recurrence in patients in whom prostate cancer was treated with radical prostatectomy.