Faculty Bibliography

OBJECTIVES: This pilot study was designed to prospectively assess whether the addition of laparoscopy at the time of interstitial brachytherapy is safe, provides verification and/or guidance of needle placement, and results in a reduction of treatment-related morbidity. METHODS: Between 7/93 and 2/97 15 consecutive eligible patients were entered into this study. All patients received external pelvic radiation to a dose range between 45 and 61.20 Gy using 1.8-Gy fractions. In each patient the minimum prescribed dose for the brachytherapy portion was 20 Gy. Minimum cumulative doses to sites of gross disease ranged from 71.8 to 115.3 Gy. A Syed-Neblett afterloading perineal template was used in all the procedures. Laparoscopy using established guidelines was performed during placement of interstitial needles. During template placement, verification of interstitial needles on laparoscopy and any subsequent changes or needle rearrangement were noted. RESULTS: No acute radiation toxicity greater than Grade 2 was noted during the external beam portion of treatment, and no perioperative complications were encountered. These needles were withdrawn under laparoscopic guidance to just below the peritoneal reflection, avoiding proximity to the bowel and improving tumor coverage. Median follow-up time was 26 months. No late radiation morbidity greater than Grade 2 nor any laparoscopic-related complications were noted. To date, one patient has died of disease; six are alive with disease; and eight are alive free of disease with a mean disease-free survival of 17.3 months. CONCLUSION: Laparoscopy at the time of interstitial brachytherapy appears to be safe. No radiation toxicity greater than Grade 2 has developed. No perioperative complications were seen with the addition of laparoscopy. The addition of laparoscopy to the placement of transperineal interstitial implants impacted needle arrangement and/or loading of sources in 50% of patients

OBJECTIVES: Although a computed tomography (CT) scan of the abdomen and pelvis is often recommended as part of the staging evaluation for newly diagnosed prostate cancer, most scans are negative for metastases. We hypothesized that biopsy Gleason score, serum prostate-specific antigen (PSA) levels, and clinical stage could predict for a positive CT scan and that a low-risk group of patients could be identified in whom CT might be omitted. METHODS: All patients who had both pathologic review of their prostate cancer biopsies and abdominopelvic CT scans at our institution between January 1990 and May 1996 were studied. Gleason score, PSA, and stage were evaluated by univariate (chi-square) and multivariate (logistic regression) analyses for their ability to predict for a positive CT. RESULTS: Of 588 patients, 41 (7%) had a positive CT scan. Multivariate analysis showed Gleason score, PSA, and clinical stage to be significant independent predictors of a positive CT scan, all P <0.001. The odds ratios for a positive CT scan were 6.17 (95% confidence interval [CI] = 1.58 to 24) for Gleason score 8 to 10 versus 2 to 6; 2.25 (CI = 1.24 to 4) for PSA greater than 50 versus 0 to 15 ng/mL; 2.08 (CI = 1.70 to 3.21 ) for Stage T2c-T4 versus T2b or lower. All 244 patients with Gleason score 2 to 7, PSA 1 5 ng/mL or less, and clinical Stage T2b or less had negative CT scans. Of the other 174 patients with a Gleason score of 2 to 7, 8 (5%) had a positive CT scan. Of the 1 26 patients with a Gleason score of 8 to 10, 28 (22%) had a positive CT scan. CONCLUSIONS: Gleason score, PSA, and clinical stage were independent predictors for a positive CT scan of the abdomen and pelvis in patients with newly diagnosed prostate cancer. In this cost-conscious era, we can decrease expenditure by obviating the need for a CT scan in low-risk patients (clinical Stage T2b or less, Gleason score 2 to 7, and PSA 15 ng/mL or less). A CT scan should be considered in all other patients

CGP, 41251, a staurosporine derivative, is a potent inhibitor of protein kinase C (PKC). In recent studies we found that this compound causes growth inhibition and induces apoptosis in human glioblastoma cell lines and also inhibits the growth of xenografts of a human astrocytoma. In this study we investigate its effects on cell cycle control. Treatment of glioblastoma or gliosarcoma cells with CGP 41251 lead to a time and dose dependent increase of the percentage of cells in the G2-M phase of the cell cycle. This correlated with a decrease of CDC2- and CDK2-associated histone H1 kinase activities as well as a decrease in the cellular level of the CDC2 protein. The decrease of CDC2- associated histone H1 kinase activity was detected within 5 hours, and there was complete inhibition after 24 hours. Assays of mixtures of cell extracts obtained from cultures treated with CGP 41251, the inactive analog CGP 42700, or untreated cultures indicated that this decrease was due to a decrease in the CDC2 kinase itself rather than the accumulation of an inhibitor of this kinase. In vitro assays in which CGP 41251 was added directly to the in vitro assay system revealed marked inhibition of both CDC2- and CDK2-associated kinase activity at about 1 microM. Thus CGP 41251 inhibits CDC2- and CDK2-associated kinase activities both in vivo and in vitro. Its biologic effects may, therefore, not be due simply to inhibition of PKC. Since cells in the G2-M phase of the cell cycle are relatively more sensitive to killing by gamma- radiation than cells in other phases of the cell cycle, we carried out radiosensitization studies. We found that CGP 41251 was a radiation sensitizer in two glioblastoma cell lines. Therefore, this compound may be useful in the treatment of glioblastomas, possibly in combination with radiation therapy

PURPOSE: The optimal definition of biochemical recurrence of prostate cancer after definitive radiotherapy remains elusive. Different institutions have developed their own definitions, and a consensus conference (CC) sponsored by the American Society for Therapeutic Radiology and Oncology has recently proposed another definition. This study compares the definition previously used at our institution with the definition proposed by the CC. METHODS: Two hundred and eight patients were treated for localized prostate cancer with conformal external-beam radiotherapy between 1989-1993 at our institution and followed for at least 24 months. Patients were categorized as failures according to our institutional definition and the CC definition. Our definition (CPMC) required two increases in serum prostate specific antigen (PSA) over at least a 3-month period with a final value of at least 1 ng/ml or a single value resulting in clinical intervention. The CC definition required three consecutive increases in PSA. This was modified to also consider those patients with one or two increases leading to clinical intervention as failures. Differences in the failure rates between the two definitions were evaluated and factors influencing these differences were explored. In an additional analysis, CC was modified such that patients with one or two PSA increases were censored at the time of the PSA prior to the increases (CC-II), rather than at the last PSA (CC). The median follow-up time was 31 months. RESULTS: There were 36 fewer failures according to CC (n = 96) compared with CPMC (n = 132) (p < 0.001). Twenty cases called failures by CPMC subsequently had a decrease in PSA ('false failures'). The other 16 patients have had two increases in PSA, but are awaiting their next follow-up visit to obtain a third PSA ('pending failures'). Analysis of factors predicting 'pending failures' showed Gleason score to be the sole predictor of this change in status in multivariate analysis (p = 0.03) with patients with lower-grade tumors being more likely to change status (Gleason 2-6: 15% vs. Gleason 7-10: 1%). On the other hand, 'false failures,' compared to true failures, had a lower mean PSA nadir (1.7 ng/ml vs. 7.0 ng/ml, p < 0.001) and significantly smaller mean increases in PSA (1st increase: 0.6 ng/ml vs. 3.4 ng/ml, p = 0.006; 2nd increase: 0.4 ng/ml vs. 4.8 ng/ml, p = 0.002). In 85% (17 of 20) of these patients, at least one of the increases was < or = 0.3 ng/ml compared with 44% (42 of 96) of the true failures (p = 0.0008). CC-II resulted in a small decrease in BDFS rates compared with CC, but did not affect the overall difference between CC and CPMC. A modified definition that defines failure as two consecutive increases in PSA over 3 months, with a final value greater than 1.0 ng/ml and each increase being at least 0.3 ng/ml, or three consecutive increases would result in a 'false' failure rate of only 3% (3 of 99) and identify 56% (54 of 96) of the true failures after only two PSA increases. CONCLUSION: The CPMC definition of two PSA increases can falsely identify patients as failures, particularly if the increases in PSA are small (i.e., < or = 0.3 ng/ml). The CC definition requiring three increases in PSA can falsely identify patients as disease-free when the time to failure is long relative to the follow-up time. We propose a that a definition that combines aspects of both definitions (two consecutive increases in PSA over 3 months, with a final value greater than 1.0 ng/ml and each increase being at least 0.3 ng/ml, or three consecutive increases) may be a better definition of biochemical failure

PURPOSE: To investigate whether a significant proportion of prostate cancer patients who have late sequelae after high-dose external-beam conformal radiation therapy are radio-sensitive because they are carriers of ataxia-telangiectasia, that is, are heterozygous for mutations in the ATM gene. PATIENTS AND METHODS: A group of prostate cancer patients were selected who experienced severe late sequelae, specifically proctitis or cystitis, after high-dose external-beam conformal radiation therapy, together with a control group of patients treated in the same way but who did not have severe late effects. Blood samples were taken from these patients, genomic DNA extracted, and mutations sought in the ATM gene. RESULTS: Of 17 late-effect patients in whom most or all of the ATM gene has been examined, significant mutations (17.6%) were identified in three. No significant mutations were found in the control group. The incidence of ataxia- telangiectasia heterozygotes in the United States population is 1% to 2%. DISCUSSION: These preliminary data suggest that a disproportionate number, but by no means all, of prostate cancer radiotherapy patients who experience severe late effects are ataxia-telangiectasia heterozygotes. If this conclusion is confirmed, these individuals could be identified prospectively and, with dose de-escalation, spared a great deal of discomfort and suffering. As a corollary, if most of the small late-effects population were prospectively identifiable, the dose to the remaining population could potentially be escalated. Present methods of identifying mutations in a large gene, such as ATM, are cumbersome and expensive, but the technology is evolving rapidly, so that rapid screening of the ATM gene is imminent

OBJECTIVES: The prognostic significance of clinical stage in patients with prostate cancer who are treated with external beam radiotherapy is unclear. This study evaluates multiple pretreatment factors, including clinical stage, to determine which are the best prognostic factors, and develops a classification system based on these factors. METHODS: All 249 evaluable patients with clinically localized adenocarcinoma of the prostate treated with definitive conformal external beam radiotherapy without androgen deprivation at our institution between 1989 and 1993 were analyzed. Clinical stage, serum PSA level, Gleason score, race, and history of transurethral resection of the prostate (TURP) were evaluated for their ability to predict biochemical disease-free survival (BDFS). Factors predictive of BDFS were then used to construct a classification system. The classification system was then analyzed for its ability to predict BDFS, distant metastases, local recurrence, and clinical disease free survival in univariate and multivariate analyses. Median follow-up was 27 months. RESULTS: Gleason score and PSA predicted BDFS in multivariate analysis (both P <0.0001), whereas clinical stage, race, and history of a TURP did not. These two biologic factors were combined into a four-level classification system. This classification system was analyzed together with Gleason score and PSA and was found to be the only predictor of BDFS on multivariate analysis (P <0.0001). In addition, this classification system was the only predictor of distant metastases in multivariate analysis (P <0.0001). CONCLUSIONS: The classification system derived herein based on the biologic factors of Gleason score and serum PSA levels is the sole predictor of distant metastases and biochemical recurrence for patients treated with definitive conformal external beam radiotherapy for clinically localized prostate cancer. This classification system may be useful when comparing competing therapies and stratifying patients in clinical trials, but requires validation from other institutions and other therapies prior to its widespread use

Protein kinase C (PKC) is a central component in signal transduction and growth control and might be an appropriate target for the chemotherapy of human brain tumors. This study demonstrates that the staurosporine derivative Ro 31-8220, a potent PKC inhibitor, inhibited the growth of 7 human brain tumor cell lines with an IC50 of about 2 microM. Calphostin C, a structurally unrelated PKC inhibitor, inhibited the growth of two of these cell lines with an IC50 of about 100 to 300 nM. Drug withdrawal and clonogenicity assays indicated that the growth inhibition by both of these compounds was irreversible. Morphologic studies, DNA fragmentation studies and flow cytometric assays showed that the treated glioblastoma cells underwent apoptosis. Treatment of glioblastoma cells with Ro 31-8220 lead to a rapid decline in the level of the anti-apoptosis protein bcl-2. At least three of the glioblastoma cell lines carried mutant p53 alleles with missense mutations in the DNA binding domain of p53. Therefore, the induction of apoptosis in these cell lines occurred through a p53-independent mechanism. Furthermore treatment of these glioblastoma cell lines with Ro 31-8220 or calphostin C led to an increase of cells in the G2-M phase of the cell cycle. This correlated with a decrease in CDC2-associated histone H1 kinase activity, as well as a decrease in the level of the CDC2 protein as shown by immunoblotting. When added to subcellular assays Ro 31-8220 markedly inhibited CDC2 histone H1 kinase activity with an IC50 of 100 nM, but calphostin C directly inhibited this kinase activity only at very high concentrations (above 100 microM). Thus these compounds inhibit the growth of glioblastoma cells through novel mechanisms. Ro 31-8220, in particular, might be a useful agent for the treatment of human brain tumors

BACKGROUND: Circulating prostate cells can be detected in the venous blood of patients with clinically localized prostate carcinoma by applying reverse transcriptase-polymerase chain reaction (RT-PCR) techniques using primers specific for the prostate specific antigen (PSA) gene. This study evaluates whether the detection of circulating cells correlates with established prognostic factors, treatment, and pathologic stage. METHODS: Two hundred and twenty-seven patients with clinically localized adenocarcinoma of the prostate had an RT-PCR assay performed as part of their staging evaluation. No treatment decisions were made on the basis of the RT-PCR results. Of these, 156 patients were treated with radical prostatectomy (RP) and 71 with radical external beam radiotherapy (EBRT). Forty-eight patients were treated with hormonal therapy prior to RP (n = 39) or EBRT (n = 9). The prognostic factors analyzed for their relationship to RT-PCR were clinical stage, pretreatment serum PSA levels, Gleason score of the biopsy specimen, and Gleason score of the surgical specimen. An analysis of the relationship between treatment and RT-PCR results was also performed. Multivariate logistic regression analysis of predictors of RT-PCR positivity was performed as well. In addition, univariate and multivariate analyses of predictors of pathologic stage, including RT-PCR, were performed. RESULTS: Sixty-one patients (26.9%) had a positive RT-PCR assay. There was no relationship between clinical stage, pretreatment PSA, biopsy Gleason score, or surgical Gleason score and RT-PCR positivity. In univariate analysis, patients treated with RP had a higher rate of RT-PCR positivity than patients treated with EBRT (P = 0.054). However, in multivariate logistic regression analysis no factor, including treatment with RP, was a significant predictor of RT-PCR positivity. RT-PCR and pretreatment PSA predicted pathologic stage in univariate and multivariate analyses (P < 0.0001 and P = 0.002, respectively). CONCLUSIONS: The detection of circulating prostate cells using RT-PCR occurs in approximately 25% of early stage prostate carcinoma patients and is independent of other established prognostic factors. In addition, a positive RT-PCR assay is a strong predictor of pathologic upstaging in patients with clinically organ-confined disease