Sam D. Graham

Novel mitochondrial DNA deletion found in a renal cell carcinoma.

Polymerase chain reaction (PCR) was used to analyze a rarely deleted region of mitochondrial DNA (mtDNA) from 39 human renal cell carcinomas (RCC) and matched normal kidney tissue removed during radical nephrectomy. One tumor specimen (E.R.) had a unique PCR product approximately 250 base pairs (bp) smaller than the PCR product found in the normal E.R. kidney. Sequence analysis of the tumor‐specific PCR fragment revealed a 264 bp deletion in the first subunit (NDI) of NADH:ubiquinone oxidoreductase (complex I) of the electron transport chain. Southern analysis of the RCCs demonstrated that approximately 50% of the mtDNA molecules in the primary RCC contained a unique 3.2 kb EcoRV restriction fragment found only in E.R. tumor mtDNA. Northern analysis demonstrated preferential transcription of the truncated NDI mRNA. None of the five metastases or any normal tissue from E.R. contained levels of the NDI deletion detectable by PCR. This is the first reported case of an intragenic NDI mtDNA deletion. Genes Chromosom Cancer 15:95–101 (1996).

Staging of early prostate cancer: A proposed tumor volume-based prognostic index

Current staging of early prostate cancer separates patients into two groups: those with palpable and non-palpable tumors. Such staging relies on digital rectal examination in making this separation, despite the low sensitivity, low specificity, and low positive predictive value of this method. As an alternative, tumor volume may be useful for staging because of its powerful prognostic ability and its potential to be assessed clinically due to recent advances in imaging techniques such as transrectal ultrasound. In this study, we evaluate the utility of tumor volume in predicting progression of early prostate cancer based on the composite published evidence from nine pathologic studies of serially-sectioned prostates. Logistic regression revealed that tumor volume was a good positive predictor of all measures of tumor progression. There was a 10 percent probability of capsular invasion in tumors measuring about 0.5 cm3; 10 percent probability of seminal vesicle invasion in tumors measuring about 4.0 cm3; and 10 percent probability of metastases in tumors measuring about 5.0 cm3. These composite results suggest that tumor volume is a significant predictor of cancer progression. A volume-based prognostic index is proposed as an adjunct to staging for early prostate cancer.

Incidence of granulomatous prostatitis and acid-fast bacilli after intravesical BCG therapy

OBJECTIVESnTo determine the incidence of granulomatous prostatitis and acid-fast bacilli (AFB) after intravesical bacillus Calmette-Guerin (BCG) therapy for superficial bladder transitional cell carcinoma (TCC) or carcinoma in situ (CIS).nnnMETHODSnOne hundred nineteen men underwent radical cystoprostatectomy for invasive bladder cancer from January 1, 1980 through December 31, 1995. Twelve patients had received intravesical BCG therapy before undergoing cystoprostatectomy. Nine men who did not receive intravesical BCG therapy before undergoing cystoprostatectomy served as controls. The surgical specimens were examined with a Ziehl-Neelsen stain for the presence of granulomatous prostatitis and for the presence of AFB.nnnRESULTSnGranulomatous prostatitis was identified in 9 of 12 patients (75%) who had received intravesical BCG therapy. AFB were identified in 7 of 9 patients (77%) with granulomatous prostatitis.nnnCONCLUSIONSnPathologic evidence of granulomatous prostatitis with AFB is a common occurrence after intravesical BCG therapy and its incidence is far greater than the reported incidence of symptomatic granulomatous prostatitis. AFB discovered during the evaluation of either an increased level of prostate-specific antigen or prostate nodule in otherwise asymptomatic men may require no specific therapy.

Renal cell carcinoma with inferior vena caval involvement

Renal cell carcinoma extends into the lumen of the inferior vena cava in approximately 4% of patients at the time of diagnosis. Surgical removal of the intracaval tumor thrombus with radical nephrectomy is the preferred treatment for this malignancy. From January 1977 to June 1990, 31 such patients were examined for combined problems of renal carcinoma and intracaval tumor extension. Twenty-six of these patients underwent radical nephrectomy and vena caval thrombectomy. Ten patients had tumor thrombus confined to the infrahepatic vena cava, 11 had retrohepatic caval involvement, and 5 had extension to the level of the diaphragm or into the right atrium. Surgical approach was dictated by the level of caval involvement. Control of the suprahepatic vena cava plus temporary occlusion of hepatic arterial and portal venous inflow were necessary in some cases; cardiopulmonary bypass was required for transatrial removal of more extensive tumors. Five of the 26 patients had evidence before operation of distant metastatic disease; none of these survived beyond 12 months. The 5-year actuarial survival rate of the 21 patients without known preoperative metastatic disease was 57%. Complete surgical excision of all gross tumor appears to be critical for long-term survival in these patients.

Normal range prostate-specific antigen versus age-specific prostate-specific antigen in screening prostate adenocarcinoma

OBJECTIVESnProstate-specific antigen (PSA) has become the most useful serum tumor marker in the diagnosis and screening of prostate adenocarcinoma. The currently cited reference range of normal (0 to 4.0 ng/mL monoclonal) lacks both the sensitivity and specificity to be universally accepted as a screening test, and alternatives to serum PSA have been proposed, such as PSA density, PSA velocity, and age-adjusted PSA. Age-adjusted PSA takes into account the facts that as men grow older the prostate enlarges and that screening should have maximum sensitivity in younger men and maximum specificity in older men.nnnMETHODSnA population of 4,710 men with no known history of prostate adenocarcinoma underwent 5,629 examinations by transrectal ultrasound of the prostate (TRUS) from 1987 to 1994. This population consists of Mobile Urology Group, Mobile, Alabama, and Emory University, Atlanta, Georgia, patient databases. We have examined our data to determine the sensitivity, specificity, and positive predictive values for normal range PSA (0 to 4 ng/mL) versus age-specific PSA values.nnnRESULTSnA total of 2040 patients had an abnormal digital rectal examination (DRE) and 3581 procedures were performed for an elevated PSA and a normal DRE. Biopsies were performed in 2,657 patients with 945 (35.6%) positive for cancer. Criteria for biopsy included elevated PSA (more than 4 mg/mL), PSA density more than 0.15 abnormal DRE, or suspicious TRUS. Patients were grouped according to decade: group 1 (ages 40 to 49 years, n = 183), group 2 (ages 50 to 59 years, n = 1018), group 3 (ages 60 to 69 years, n = 2358), and group 4 (ages 70 to 79 years, n = 1687).nnnCONCLUSIONSnUse of the age-specific range for PSA increases the sensitivity in younger men more likely to benefit from treatment, and decreases the biopsy rate in older patients who may not be candidates for aggressive treatment. Age-adjusted PSA is the most valuable for patients over the age of 70 years of whom 22% would be spared TRUS with biopsy.

Oral bropirimine immunotherapy of carcinoma in situ of the bladder: results of a phase II trial.

OBJECTIVESnBropirimine is an orally administered immunostimulant that has been shown to have activity against carcinoma in situ (CIS) of the bladder. To further assess this potential activity, bropirimine was administered to 42 patients for bladder CIS in a Phase II trial.nnnMETHODSnPatients were treated with bropirimine 3.0 g/day by mouth for 3 consecutive days each week up to 1 year. Cystoscopy with biopsies and bladder wash cytology were performed quarterly.nnnRESULTSnTwenty (61%) of 33 evaluable patients converted malignant biopsies and bladder wash cytology to negative, including 6 (50%) of 12 who failed prior bacillus Calmette-Guérin (BCG) immunotherapy, 14 (67%) of 21 who had not received prior BCG therapy, and 12 (80%) of 15 with primary CIS. Median response duration exceeds 21 months. Four of the 20 responders did have a papillary tumor recurrence at 3 to 15 months, all Stage Ta or T1. Mild toxicity (grade I or II) suggestive to interferon induction or administration occurred in one third of patients. Headache, transient hepatic enzyme elevations, skin rash, and arthralgias each occurred in 5% to 14% of the patients, with nausea or emesis in 21%. Grade 1 tachycardia/palpitations or chest pain each were noted in 5%.nnnCONCLUSIONSnOral bropirimine can induce remission of bladder CIS with acceptable toxicity at 3.0 g/day. Bropirimine may be a valuable alternative to cystectomy for some failures of BCG therapy and may have the potential to replace BCG as front-line therapy because of its ease of administration.

Evaluation of staging lymphadenectomy in prostate cancer.

OBJECTIVESnTo prospectively evaluate a clinical algorithm that predicts nodal status in patients with prostate cancer and to assess the impact on the outcome.nnnMETHODSnBetween September 1988 and December 1994, 192 patients with organ-confined prostate cancer and considered surgical candidates for radical perineal prostatectomy (RPP) were stratified using the algorithm: prostate-specific antigen (PSA) 20 ng/mL or less, Gleason score 7 or lower, and clinical Stage T2a or lower. Patients failing any of these criteria were placed in the high-risk group and underwent a pelvic lymphadenectomy. Patients who satisfied all the criteria were placed in the low-risk group and underwent RPP without evaluation of the pelvic lymph nodes. Another contemporaneous cohort of patients (n = 65) underwent pelvic lymphadenectomy and radical retropubic prostatectomy (RRP) without use of the algorithm and were used as a control group. Patients were monitored for at least 24 months.nnnRESULTSnIn the RPP group, 177 patients were considered low risk according to the algorithm and were not offered staging lymphadenectomy before surgery, whereas 15 patients were categorized as high risk for metastasis and underwent staging lymphadenectomy. In the RRP and lymphadenectomy group, 41 patients were considered at low risk and 24 at high risk of disease spread according to the algorithm. In the RPP group, low-risk patients (no lymphadenectomy) had a PSA recurrence rate (27%) similar to that of low-risk patients in the RRP group with negative lymph nodes (29%), P = 0.8. Similarly, high-risk patients with negative lymph nodes in both groups had a similar recurrence rate (53% for RPP and 50% for RRP). Univariate logistic regression analysis showed that PSA was the most significant predictor for disease recurrence (P = 0.0004) followed by preoperative Gleason scores (P = 0.02) and clinical stages (P = 0.03). Multivariate stepwise analysis demonstrated that Gleason score and clinical stage did not add to the prediction of recurrence over PSA alone.nnnCONCLUSIONSnStaging lymphadenectomy can be omitted in low-risk patients without deleterious effects on the outcome as measured by PSA recurrence.

Suramin Inhibits Growth Factor Binding and Proliferation by Urothelial Carcinoma Cell Cultures

Suramin is a polyanionic compound recently noted to inhibit growth factor action and proliferation of several types of neoplastic cells in vitro. Data from clinical trials show antineoplastic activity against some prostatic and adrenal cortical carcinomas. Suramin is excreted unmetabolized into the urine suggesting possible application in treatment of urothelial carcinoma and prompting us to examine the drugs effect on growth factor binding and cell proliferation by two urothelial carcinoma cell lines. Half-maximal inhibition of 125I-epidermal growth factor (EGF) binding to T24 and HT1376 cells was produced by suramin concentration of approximately 300 and 100 microM, respectively. The corresponding value for 125I-insulin-like growth factor 1 (IGF1) binding was 60 microM for both cell lines. Inhibition of T24 and HT1376 growth was virtually complete at suramin concentrations in the range achievable clinically.

CAMPTOTHECIN ANALOGUES/CISPLASTIN: AN EFFECTIVE TREATMENT OF ADVANCED BLADDER CANCER IN A PRECLINICAL IN VIVO MODEL SYSTEM

OBJECTIVEnTo evaluate the impact of the camptothecin analogs on human TCC xenograft, both as monotherapy and in combination with cisplatin (CDDP).nnnMATERIALS AND METHODSnHuman transitional cell carcinoma (TCC) xenograft tumor line (DU4184) tested by subrenal capsule assay in 112 nude mice(NM-SRCA). CDDP and the camptothecin analogs irinotecan (CPT-11) and 9-aminocamptothecin(9-AC) were evaluated.nnnRESULTSnBoth of the camptothecin analogs showed significant short term tumor inhibition which translated into enhanced survival. Maximal tumor inhibition (>95%) was achieved when either of the camptothecin analogs was combined with CDDP with minimal host toxicity. This translated into 400% increase in median survival. While all controls were dead 39 days following tumor implantation, none of the combination treated animals had died.nnnCONCLUSIONnThe combination of CDDP with these camptothecin analogs is an effective therapy against this model of advanced TCC. These observations suggest potential clinical value.

Significance of lipid-associated sialic acid and CA 19-9 as tumor markers for renal cell carcinoma.

Numerous neoplasms, including colonic, lung, stomach, and prostate, have been found to have increased concentrations of lipid-associated sialic acid (LASA). CA 19-9 is a carbohydrate antigen found on the membrane surface of pancreatic, gastric, and colonic cancers. A prospective study involving 25 patients (15 males, 10 females) with renal cell carcinoma (RCC) was undertaken to examine the clinical value of these two markers. Patients ages ranged from twenty-five to seventy-seven years (mean 56 years). The group consisted of 9 Stage I, 1 Stage II, 5 Stage III, and 10 Stage IV patients. Twenty three of the 25 had known disease present when tested. Eleven patients with no known tumor were used as an age-matched control group. Sixteen of the 23 patients with known disease (70%) had elevated LASA values. Nine of the 11 control patients (82%) had normal LASA values. Three of 7 patients with values obtained pre- and post-nephrectomy showed levels returned to normal after nephrectomy; 3 had persistent LASA elevation and were found to have either metastatic or recurrent disease, and 1 had a persistent elevation of his LASA value without known metastatic or recurrent disease. When the 23 patients with known disease were compared according to stage, 62 percent of Stages I and II, 80 percent of Stage III, and 70 percent of Stage IV had elevated LASA values. There was no statistically significant difference between LASA values and tumor stage. CA 19-9 values obtained in 15 of 25 patients with RCC were within normal range.