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BACKGROUND Many patients with low-risk prostate cancer (PC) who are diagnosed with Gleason score 6 at biopsy are ultimately found to harbor higher grade PC (Gleason ≥ 7) at radical prostatectomy. This finding increases risk of recurrence and cancer-specific mortality. Validated clinical tools that are available preoperatively are needed to improve the ability to recognize likelihood of upgrading in patients with low-risk PC. METHODS More than 30 clinicopathologic parameters were assessed in consecutive patients with Gleason 6 PC upon biopsy who underwent radical prostatectomy. A nomogram for predicting upgrading (Gleason ≥ 7) on final pathology was generated using multivariable logistic regression in a development cohort of 431 patients. External validation was performed in 2 separate cohorts consisting of 1151 patients and 392 patients. Nomogram performance was assessed using receiver operating characteristic curves, calibration, and decision analysis. RESULTS On multivariable analysis, variables predicting upgrading were prostate-specific antigen density using ultrasound (odds ratio [OR] = 229, P = .003), obesity (OR = 1.90, P = .05), number of positive cores (OR = 1.23, P = .01), and maximum core involvement (OR = 0.02, P = .01). On internal validation, the bootstrap-corrected predictive accuracy was 0.753. External validation revealed a predictive accuracy of 0.677 and 0.672. The nomogram demonstrated excellent calibration in all 3 cohorts and decision curves demonstrated high net benefit across a wide range of threshold probabilities. The nomogram demonstrated areas under the curve of 0.597 to 0.672 for predicting upgrading in subsets of men with very low-risk PC who meet active surveillance criteria (all P

BACKGROUND Radical prostatectomy and radiotherapy (RT), both radical therapies, are the standard treatments of curative intent for early prostate cancer. However, these therapies are not curative in all patients and, consequently, a substantial proportion of treated patients remain at risk of disease progression and/or cancer-related death. METHODS This article presents contemporary data on the incidence of prostate-specific antigen (PSA) and clinical disease progression after primary therapy of curative intent in relation to commonly assessed pretreatment or pathologic disease characteristics. RESULTS The data highlight the substantial risk of progression for certain patient groups, such as those with Gleason score 8–10, cT3 disease, lymph node metastases, and/or pretreatment PSA levels > 20 ng/mL. CONCLUSIONS Improved and/or additional treatment options are needed for these patient groups. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND One of the goals of a noninvasive test for bladder carcinoma screening would be to reduce surveillance cystoscopies among patients with a history of bladder carcinoma. In addition, an accurate bladder carcinoma marker could be used to screen a high-risk population. The authors examined the efficacy of the hyaluronic acid–hyaluronidase (HA-HAase) and BTA-Stat tests to detect and predict bladder carcinoma recurrence and tested their specificity for bladder carcinoma screening. METHODS Over a four year period, the authors prospectively collected 225 urine specimens from 70 bladder carcinoma patients and analyzed them by the HA-HAase test. Tumors were identified during 178 visits, and in 47 specimens there was no evidence of disease (NED). Twenty six of these 70 patients were randomly selected to have the BTA-Stat test (111 surveillance visits). In a separate study, 401 former Department of Energy (DOE) workers, who are likely to be at a higher risk for bladder carcinoma, were screened by the HA-HAase and BTA-Stat urine tests. RESULTS The HA-HAase test had an approximately 91.0% sensitivity, 70% specificity, 87% accuracy, 92% positive predictive value (PPV), and 67% negative predictive value (NPV) in the 70 bladder carcinoma patients. There were 14 false-positives; however, 6 of these had recurred in approximately 5 months. Only 4 out of 33 NED cases recurred in that time period (chi-square = 5.43; degrees of freedom [DF] = 1; P = 0.0198). Thus, a false-positive HA-HAase test carried a significant risk of recurrence within five months (relative risk [RR] = 3.5; odds ratio [OR] = 5.44). In a direct comparison, the HA-HAase and BTA-Stat had 94% and 61% sensitivity, 63% and 74% specificity, 87% and 64% accuracy, 89% and 88% PPV, and 77% and 38% NPV, respectively. While 6 of the 10 false-positive on the HA-HAase test recurred in 5 months (chi-square = 9.6; DF = 1; P = 0.004), only 1 of the 7 false-positives on the BTA-Stat test recurred in that time period (chi-square = 0.096; DF = 1; P = 0.756). The RR and OR for the HA-HAase test were 10.2 and 24, and for the BTA-Stat, 1.4 and 1.5, respectively. In the DOE worker screening study, the HA-HAase and BTA-Stat had 14% (56 out of 401) and 16.7% (67 out of 401) positive rates, respectively. Sixty three percent of the positives on the BTA-Stat test, but only 25% of the positives on the HA-HAase test, had benign urologic conditions. None of the biomarker positive cases with clinical follow-up (n = 29) had evidence of bladder carcinoma. CONCLUSIONS The HA-HAase test is efficient and superior to the BTA-Stat for detecting and predicting bladder carcinoma recurrence. Noninvasive tests with low false positive rates could be used for bladder carcinoma screening in high-risk populations (e.g., those with occupational exposure to carcinogens or smokers). Cancer 2002;95:61–72. © 2002 American Cancer Society. DOI 10.1002/cncr.10652

BACKGROUND Hepatic vein invasion by renal cell carcinoma with inferior vena cava tumor thrombus is relatively uncommon. The Budd–Chiari syndrome that results from obstruction of the suprahepatic venous drainage by the tumor could evolve toward liver fibrosis and death. Early diagnosis and surgical treatment of this condition is of prime importance. Complete mobilization of the liver and rotation of the inferior vena cava enhances exposure of the ostium of the hepatic veins. This maneuver allows for the complete removal of tumor from the hepatic veins and decompression of the liver. METHODS Between May 1997 and April 2000, four patients with renal cell carcinoma and inferior vena cava thrombus with hepatic vein invasion underwent surgery at the study institution.. Three of the patients had Budd–Chiari syndrome. Surgical techniques were developed to handle these difficult tumors safely. RESULTS Three patients presented with the Budd–Chiari syndrome, one of whom was found to have severe liver failure before surgery. The fourth patient presented with a hepatic vein tumor thrombus. A caval atrial thrombus and hepatic vein thrombus in one patient were removed successfully without opening the chest. Three patients required cardiopulmonary bypass. Hypothermic arrest was required in one patient. At the time of last follow-up, 2 patients were alive at 14 months and 30 months after surgery, respectively, without recurrence. One patient died 6 months after surgery due to metastatic renal carcinoma and 1 patient who had prior severe liver failure died of multiple organ failure 2 weeks after undergoing surgery. None of the four patients required reoperation. CONCLUSIONS Prompt surgical treatment should be performed to avoid hepatic failure and disease progression. The surgical technique described in the current study allowed for removal of the tumor from the hepatic veins and the authors believe it can be used with cardiopulmonary bypass to enhance visibility of the hepatic veins. Cancer 2001;92:1836–42. © 2001 American Cancer Society.

BACKGROUND A randomized, multicenter trial, double-blind for antiandrogen therapy, compared the antiandrogens bicalutamide and flutamide, each combined with luteinizing hormone–releasing hormone analogue therapy (LHRH-A) in 813 patients with Stage D2 prostate carcinoma. An analysis of time to progression (median follow-up, 95 weeks) was performed to augment previous analyses of time to treatment failure and time to death. METHODS Patients were randomly assigned 1:1 to double-blind antiandrogen therapy, receiving either bicalutamide (50 mg once daily) or flutamide (250 mg three times daily), and were assigned 2:1 to LHRH-A with goserelin acetate (3.6 mg every 28 days) or leuprolide acetate (7.5 mg every 28 days). The primary endpoint of the trial was time to treatment failure, defined as an adverse event leading to withdrawal of randomized therapy, objective progression, death, or withdrawal from study therapy for any reason. Secondary endpoints were time to death, quality of life, and subjective response. The current analysis of time to progression included progression data collected prospectively for 561 patients (69%) and retrospectively for 252 patients (31%). RESULTS Disease progression occurred for 223 of 404 patients (55%) in the bicalutamide plus LHRH-A group and for 235 of 409 patients (58%) in the flutamide plus LHRH-A group. The hazard ratio for time to progression of bicalutamide plus LHRH-A to that of flutamide plus LHRH-A was 0.9 (two-sided 95% confidence interval [CI], 0.75 to 1.08; P = 0.26). The upper one-sided 95% CI was 1.05, which met the definition of equivalence (

BACKGROUND Human papillomaviruses (HPVs) commonly cause proliferative lesions of squamous epithelia, and infection with certain HPV types carries a high risk of malignant transformation, especially in the uterine cervix but also at other sites, including the esophagus. We used molecular techniques to detect and type HPV in an in situ squamous cell carcinoma in the esophagus of a 39-year-old woman. METHODS DNA was extracted from paraffin sections of the esophageal lesion and of the uterine cervix (which was removed several years earlier), and analyzed for HPV by polymerase chain reaction (PCR). Primers complementary to highly conserved regions of the open reading frame of most genital HPVs were used to amplify a ∼450 base pair product that contained both conserved and divergent regions. The PCR products were hybridized with probes specific for HPV-6, HPV-11, HPV-16, and HPV-18, and with a consensus probe. A conspicuous band in the esophageal sample failed to hybridize with any of the probes. The amplimer was subcloned and sequenced. The sequence was compared with other known HPVs. RESULTS The intraepithelial neoplasia in the patient's cervical cone biopsy contained HPV-16. The esophageal lesion contained HPV that did not hybridize with probes for types 6, 11, 16, or 18, but exhibited 98.3% homology with HPV-73. CONCLUSIONS Squamous cell carcinoma in situ of the esophagus may be associated with infection by HPV-73. Cancer 1996;77:2440-4.

Background. Gallbladder cancer has an unusual geographic and demographic distribution, suggesting many possible etiologies. Methods. A case-control study was undertaken at four hospitals in La Paz, Bolivia, and at one hospital in Mexico City, Mexico. Eighty-four patients with newly diagnosed, histologically confirmed gallbladder cancer were compared with 126 control subjects without stones and with 264 control subjects with cholelithiasis or choledocholithiasis without cancer. All study subjects underwent abdominal surgery. Study subjects were interviewed regarding demographic characteristics, medical history, family history, diet, and exposure to agents presumed to be risk factors for biliary cancer. Results. Virtually all subjects in Mexico were judged to be mestizos (i.e., persons of mixed ancestry). In contrast, race was a very strong risk factor for gallbladder cancer in Bolivia. Relative to mestizos who spoke neither language, the odds ratio (95% confidence interval [CI]) for cases versus control subjects without stones for those who spoke Aymara well was 15.9 (CI, 1.9–179), whereas it was 1.4 (CI, 0.2–8.2) for those who spoke Quechua well. An increased risk was also noted for elevated maximum body mass index (P = 0.03), family history of gallstones (odds ratio [OR] = 3.6 [CI, 1.3–11.4]), and physician-diagnosed typhoid (OR = 12.7 [CI, 1.5-598]). An increased risk was also seen with elevated maximum body mass index; compared with those with a body mass index less than 24 kg/m2, those with an index of 24–25 kg/m2, 26–28 kg/m2, and greater than 28 kg/m2 had odds ratios of 1.6 (CI, 0.4–7.6), 1.3 (CI, 0.3–5.6), and 2.6 (CI, 0.5–18.6), respectively (asymptotic test for trend, P = 0.03). Finally, a number of associations were noted with certain dietary and cooking habits. Conclusions. Patients with gallbladder cancer differed from control subjects in race, body mass, physician-diagnosed typhoid, and certain dietary patterns. These findings may provide useful clues to the pathogenesis of gallbladder cancer, but given the number of analyses performed, additional cases need to be studied. Cancer 1995:76:1747–56.

Background. Leuprolide, an agonist of luteinizing hormone-releasing hormone (LH-RH), and flutamide, an antiandrogen, increasingly are being used in the treatment of clinically localized prostate cancer. Only two small series (of 23 and 12 patients) have been published on the distinctive pathologic changes induced in the prostate by androgen deprivation therapy with discrepancies on the presence of squamous metaplasia, necrosis, and possible tumor destruction by combined androgen deprivation therapy. Methods. One hundred and thirteen radical prostatectomy specimens obtained after at least 3 months of leuprolide-flutamide androgen inhibition therapy and 60 nonhormonally treated prostates in randomly selected clinical Stage T2 prostate adenocarcinoma patients were entirely sectioned. Distinctive histologic findings were tabulated and their statistical value determined. Results. Resection margins of excision were involved by tumor in 43% of untreated and in 19% of androgen-deprived patients. Characteristic changes in androgen-inhibited nontumor glands included atrophy, basal cell prominence, vacuolated luminal cell layer, and squamous and transitional cell metaplasia. Prostatic intraepithelial neoplasia (PIN) was observed in 35% of treated patients. The presence of small tumor glands separated by stroma was the most frequently noted effect of androgen deprivation on prostate adenocarcinoma; pyknosis and branching empty spaces were less frequent. Large clear tumor cells within an inflammatory response was a third histologic pattern. Apparently unaltered tumor areas were observed in 43% of prostates exposed to androgen deprivation therapy. Conclusions. Androgen deprivation therapy result in histologically distinctive changes that can be recognized in both nonneoplastic and neoplastic prostate tissue. Residual tumor was present in all 113 treated radical prostatectomy specimens. In addition to glandular shrinkage, therapy was associated with statistically significant reductions in the frequency of high grade PIN and extension of cancer to prostate specimen margins of excisions. Cancer 1995;75:1634-41.

Background. Radical cystectomy continues to be one of the primary modalities of treatment for locally advanced bladder cancer. However, long-term survival after cystectomy has improved only marginally in the last decade, and still, nearly half of the patients die from the disease within 5 years. Adjuvant treatments such as radiation therapy and chemotherapy have been used, but a clear advantage has not been demonstrated. Methods. The authors reviewed 130 patients who underwent radical cystectomy by the same surgeon as treatment for transitional cell carcinoma of the bladder. Morbidity, postoperative mortality, overall survival time, and accuracy of clinical staging as well as the effect of perioperative chemotherapy were evaluated. Results. The overall actuarial survival rate at 2, 5, and 10 years was 80%, 53%, and 45%, respectively. The survival rate based on T-classification at 5 years was 82%, 65%, and 28% for less than pT2, pT2, and greater than pT2, respectively. Regional lymph node status had a significant effect on survival. The 5-year survival rate for all patients with negative nodes was 65%, whereas patients with positive nodes had a 18% 5-year survival rate. The overall clinical staging error was 61.5%, with 41.5% of the cancers understaged. Of the patients with cTis, 60% were found to be of greater extent than pT1 tumors. No apparent survival advantage was noted for those patients who received perioperative chemotherapy when compared with patients who were followed conservatively or received chemotherapy upon relapse. These results, however, are not conclusive because this was an observation study and the number of patients was limited. Conclusions. Only a modest improvement in survival time after radical cystectomy has been observed in the last decade, despite the use of adjuvant treatments such as radiation and chemotherapy. The pathologic (pT) classification is the most accurate prognostic indicator. Clinical errors in classification are common and impair the evaluation of neoadjuvant treatments. A high incidence of invasive tumors of greater extent than pT1 was found among patients with clinical cTis; this supports an aggressive approach when these patients do not respond promptly to intravesical chemotherapy. Prospective randomized studies are needed to evaluate objectively the benefit of perioperative adjuvant treatment in locally advanced transitional cell carcinoma of the bladder.

BACKGROUND: Several nomograms have been developed for the purpose of predicting the likelihood of an increase in Gleason sum (GS) from biopsy information compared with the GS determined after examination of the “entire prostate” in patients with prostate cancer. In this study, the authors evaluated and compared the ability of 4 nomograms (published by Capitanio et al, Chun et al, Kulkarni et al, and Moussa et al) to predict GS upgrades for patients with biopsy GS ≤6 prostate cancer who underwent radical prostatectomy (RP) at their center. METHODS: The entire study cohort included 942 patients with a biopsy GS ≤6. Predictive performances of the nomograms were compared using area under the receiver operating characteristic curve (AUC-ROC) analysis, calibration plots, and decision curve analysis (DCA) in the entire cohort, in patients with low-risk prostate cancer (LRPC), and a subgroup of those patients who underwent extended biopsy with ≥10 cores. RESULTS: Patients with a GS ≥7 at prostatectomy included 319 of 942 patients (33.9%) in the entire study cohort, 263 of 814 patients (32.2%) with LRPC, and 84 of 301 patients (27.9%) with LRPC who underwent extended biopsy. With an AUC-ROC of 0.637 to 0.647 in the different subgroups of patients with low-risk cancer, the Kulkarni et al nomogram demonstrated significantly higher discriminative ability compared with the other nomograms. The same nomogram provided a small clinical benefit at DCA. All nomograms were poorly calibrated. CONCLUSIONS: The available prognostic tools had limited ability to predict clinically significant upgrading in patients with biopsy GS ≤6 and, thus, the authors concluded that these tools are not ready for clinical application. Cancer 2011;. © 2011 American Cancer Society.

Androgen deprivation therapy is the initial treatment choice for metastatic disease. When enrolling patients into androgen deprivation trials, it is important to consider stratification of enrollees based on prognostic factors that have been identified as important in determining the likelihood of response. Prognostic factors are also helpful in identifying which patients are less likely to respond to treatment; this information also would help to counsel patients. Performance status is an important prognostic factor; however, its impact is minimal because the great majority of men who receive treatment for advanced disease have a normal performance status

Pure antiandrogens have a quality-of-life advantage over other androgen ablation methods in the treatment of patients with prostatic cancer because they do not reduce the serum testosterone and therefore do not have a marked inhibitory effect on libido and potency. The long half-life of two of the three currently studied pure antiandrogens permits once-a-day administration, which should enhance patient compliance. With continued administration, there is a gradual rise in serum testosterone, and the clinical impact of this requires additional study using randomized Phase III trials. Proper stratification of patients at entry into such studies with documentation of various prognostic factors will add statistical value and enable physicians to draw better conclusion on the relative efficacy of these agents.

BACKGROUND: Cancer biomarkers are the backbone for the implementation of individualized approaches to bladder cancer (BCa). Hyaluronic acid (HA) and all 7 members of the HA family, that is, HA synthases (HA1, HA2, HA3), HYAL-1 hyaluronidase, and HA receptors (CD44s, CD44v, and RHAMM), function in tumor growth and progression. However, the diagnostic and prognostic potential of these 7 HA family members has not been compared simultaneously in any cancer. We evaluated the diagnostic and prognostic potential of HA family members in BCa. METHODS: Using quantitative PCR and immunohistochemistry, expression of HA family members was evaluated in prospectively collected bladder tissues (n = 72); mean and median follow-up were 29.6 ± 5.3 and 24 months, respectively. Transcript levels were also measured in exfoliated urothelial cells from urine specimens (n = 148). RESULTS: Among the HA family members, transcript levels of the HA synthases, HYAL-1, CD44v, and RHAMM were 4- to 16-fold higher in BCa tissues than in normal tissues (P < .0001); however, CD44s levels were lower. In univariate and multivariate analyses, tumor stage (P = .003), lymph node invasion (P = .033), HYAL-1 (P = .019), and HAS1 (P = .027) transcript levels, and HYAL-1 staining (P = .021) were independently associated with metastasis. Tumor stage (P = .019) and HYAL-1 (P = .046) transcript levels were also associated with disease-specific mortality. Although HA synthase and HYAL-1 transcript levels were elevated in exfoliated urothelial cells from BCa patients, the combined HAS2–HYAL-1 expression detected BCa with an overall sensitivity of 85.4% and a specificity of 79.5% and predicted BCa recurrence within 6 months (P = .004; RR = 6.7). CONCLUSIONS: HYAL-1 and HAS1 expression predicted BCa metastasis, and HYAL-1 expression also predicted disease-specific survival. Furthermore, the combined HAS2–HYAL-1 biomarker detected BCa and significantly predicted its recurrence. Cancer 2011. © 2010 American Cancer Society.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10 (10B), is irradiated with low-energy thermal neutrons (nth) to yield (4He) alpha-particles and 7Li nuclei (10B+nth-->[11B]-->4He+7Li+2.31 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of 10B and nth to individual cancer cells to sustain a lethal 10B(n, alpha) 7Li reaction. The current review covered the radiobiologic considerations on which BNCT is based, including a brief discussion of microdosimetry and normal tissue tolerance. The development of tumor-localizing boron compounds was discussed, including the sulfhydryl-containing polyhedral borane, sodium borocaptate (Na2B12H11SH), and boronophenylalanine (BPA), both of which are currently being used clinically in Japan as capture agents for malignant brain tumors and melanomas, respectively. Compounds currently under evaluation, such as boronated porphyrins, nucleosides, liposomes, and monoclonal antibodies (MoAbs), were also considered. Nuclear reactors have been used as the exclusive source of neutrons for BNCT. The use of low-energy (0.025 eV) thermal neutrons and higher-energy (1-10,000 eV) epithermal beams, beam optimization, and possible alternative neutron sources (accelerators) were also discussed. Clinical studies performed in the United States during the 1950s and 1960s for the treatment of malignant brain tumors were reviewed. Current studies in Japan and future studies in Europe and the United States concerning the treatment of glioblastomas and melanomas by BNCT were discussed, as were critical issues that must be addressed if BNCT is ever to be a useful therapeutic modality.

Prostate glands exposed to androgen deprivation with leuprolide -+ flutamide were evaluated for pathologic changes which might be related to therapy. Comparing pretreatment and posttreatment tissue by visual discrimination using light microscopic study revealed treatment-related alterations in the size and distribution of neoplastic glands in 60% of cases. Quantitative measurements documented glandular changes in an even greater percentage of cases. Although distinctive, the histologic pattern was not specific for leuprolide/flutamide. The absence of appreciable degeneration and necrosis in tumor cells suggests that this type of androgen deprivation may act through suppression rather than ablation of prostatic cancers. The relationship between treatment-related histologic effects and initial tumor grade and clinical stage as well as expression of prostate-specific antigen was studied. Accurate histologic assessment of leuprolide/flutamide-treated prostate glands should not be a problem so long as specimens are thoroughly examined and drug-related variations in tumor morphologic features are appreciated. Cancer 68:821-828,1991.

Three factors were identified in a multivariate analysis of prognostic factors in men with metastatic prostate cancer as significantly associated with their progression-free survival: 1) extent of disease on the bone scan, 2) pretreatment serum testosterone, and 3) performance status. Men with less than six bone metastases, a pretreatment testosterone greater than 300 ng/100 ml, and an excellent performance status will have a progression-free survival much longer than a man with more extensive bone metastases, a low testosterone prior to androgen deprivation, and a poor performance status. This information should be used to ensure proper stratification in randomized trials. It may also be helpful in identifying the patient unlikely to be helped by our current treatment. Such patients should be considered for alternative approaches with the aim of improving survival.

BACKGROUND Hispanics are the largest minority group in the U.S. Most studies assessing race as a predictor of biochemical disease recurrence after radical retropubic prostatectomy (RRP) have focused on African-American patients. To the authors' knowledge, little has been published to date regarding radical prostatectomy in Hispanic patients. Hispanics represent 29% of the patients in the current study. The authors analyzed the presentation and outcome of Hispanic males managed with radical prostatectomy. METHODS In the current study, 1163 RRPs were performed. Patients were categorized by ethnicity as Hispanics, white non-Hispanics, African-Americans, and other ethnicities. African-American and other minority group patients were excluded from the analysis because of the small number in the current series. A comparative analysis of Hispanics and white non-Hispanics was performed. RESULTS RRP was performed in 1163 patients. Two hundred seven Hispanic and 518 white non-Hispanic patients met the study criteria. The mean follow-up was 46.9 months. Twenty-three percent of the Hispanic patients received neoadjuvant therapy. RRP Gleason scores of 2–6, 7, and 8–10 were found in 45% of patients, 38% of patients, and in 17% of patients, respectively. Lymph node metastases were present in 3%, seminal vesicle invasion in 13%, and extraprostatic extension in 23% of Hispanic patients. Adjuvant hormonal therapy was administered to 6% of the Hispanic patients. The biochemical disease recurrence rate was 12%. The mean time to biochemical disease recurrence was 29.7 months. A comparison between the Hispanic and the white non-Hispanic groups showed no significant differences in the analyzed variables. CONCLUSIONS Hispanic patients managed with radical prostatectomy for prostate carcinoma were found to have similar presentation, pathologic findings, and outcome as the white non-Hispanic patients. Cancer 2004. © 2004 American Cancer Society.

The workgroup discussed the use of prostate specific antigen (PSA) in monitoring and managing patients with benign prostatic hyperplasia (BPH) and prostate cancer. Periodic monitoring provides an opportunity for more timely diagnosis and treatment of prostate cancer with the potential to decrease morbidity and mortality from this disease. The workgroup agreed on several basic principles and recommendations for specified patient groups.

Human papillomaviruses (HPVs) commonly cause proliferative lesions of squamous epithelia, and infection with certain HPV types carries a high risk of malignant transformation, especially in the uterine cervix but also at other sites, including the esophagus. We used molecular techniques to detect and type HPV in an in situ squamous cell carcinoma in the esophagus of a 39-year old woman.DNA was extracted from paraffin sections of the esophageal lesion and of the uterine cervix (which was removed several years earlier), and analyzed for HPV by polymerase chain reaction (PCR). Primers complementary to highly conserved regions of the open reading frame of most genital HPVs were used to amplify a approximately 450 base pair product that contained both conserved and divergent regions. The PCR products were hybridized with probes specific for HPV-6, HPV-11, HPV-16, and HPV-18, and with a consensus probe. A conspicuous band in the esophageal sample failed to hybridize with any of the probes. The amplimer was subcloned and sequenced. The sequence was compared with other known HPVs.The intraepithelial neoplasia in the patient's cervical cone biopsy contained HPV-16. The esophageal lesion contained HPV that did not hybridize with probes for types 6, 11, 16, or 18, but exhibited 98.3% homology with HPV-73.Squamous cell carcinoma in situ of the esophagus may be associated with infection by HPV-73.

Gallbladder cancer has an unusual geographic and demographic distribution, suggesting many possible etiologies.A case-control study was undertaken at four hospitals in La Paz, Bolivia, and at one hospital in Mexico City, Mexico. Eighty-four patients with newly diagnosed, histologically confirmed gallbladder cancer were compared with 126 control subjects without stones and with 264 control subjects with cholelithiasis or choledocholithiasis without cancer. All study subjects underwent abdominal surgery. Study subjects were interviewed regarding demographic characteristics, medical history, family history, diet, and exposure to agents presumed to be risk factors for biliary cancer.Virtually all subjects in Mexico were judged to be mestizos (i.e., persons of mixed ancestry) In contrast, race was a very strong risk factor for gallbladder cancer in Bolivia. Relative to mestizos who spoke neither language, the odds ratio (95% confidence interval [CI]) for cases versus control subjects without stones for those who spoke Aymara well was 15.9 (CI, 1.9-179), whereas it was 1.4 (CI, 0.2-8.2) for those who spoke Quechua well. An increased risk was also noted for elevated maximum body mass index (P = 0.03), family history of gallstones (odds ratio [OR] = 3.6 [CI, 1.3-11.4]), and physician-diagnosed typhoid (OR = 12.7 [CI, 1.5-598]). An increased risk was also seen with elevated maximum body mass index; compared with those with a body mass index less than 24 kg/m2, those with an index of 24-25 kg/m2, 26-28 kg/m2, and greater than 28 kg/m2 had odds ratios of 1.6 (CI, 0.4-7.6), 1.3 (CI, 0.3-5.6), and 2.6 (CI, 0.5-18.6), respectively (asymptotic test for trend, P = 0.03). Finally, a number of associations were noted with certain dietary and cooking habits.Patients with gallbladder cancer differed from control subjects in race, body mass, physician-diagnosed typhoid, and certain dietary patterns. These findings may provide useful clues to the pathogenesis of gallbladder cancer, but given the number of analyses performed, additional cases need to be studied.

Leuprolide, an agonist of luteinizing hormone-releasing hormone (LH-RH), and flutamide, an antiandrogen, increasingly are being used in the treatment of clinically localized prostate cancer. Only two small series (of 23 and 12 patients) have been published on the distinctive pathologic changes induced in the prostate by androgen deprivation therapy with discrepancies on the presence of squamous metaplasia, necrosis, and possible tumor destruction by combined androgen deprivation therapy.One hundred and thirteen radical prostatectomy specimens obtained after at least 3 months of leuprolide-flutamide androgen inhibition therapy and 60 nonhormonally treated prostates in randomly selected clinical Stage T2 prostate adenocarcinoma patients were entirely sectioned. Distinctive histologic findings were tabulated and their statistical value determined.Resection margins of excision were involved by tumor in 43% of untreated and in 19% of androgen-deprived patients. Characteristic changes in androgen-inhibited nontumor glands included atrophy, basal cell prominence, vacuolated luminal cell layer, and squamous and transitional cell metaplasia. Prostatic intraepithelial neoplasia (PIN) was observed in 35% of treated patients. The presence of small tumor glands separated by stroma was the most frequently noted effect of androgen deprivation on prostate adenocarcinoma; pyknosis and branching empty spaces were less frequent. Large clear tumor cells within an inflammatory response was a third histologic pattern. Apparently unaltered tumor areas were observed in 43% of prostates exposed to androgen deprivation therapy.Androgen deprivation therapy results in histologically distinctive changes that can be recognized in both nonneoplastic and neoplastic prostate tissue. Residual tumor was present in all 113 treated radical prostatectomy specimens. In addition to glandular shrinkage, therapy was associated with statistically significant reductions in the frequency of high grade PIN and extension of cancer to prostate specimen margins of excisions.

Radical cystectomy continues to be one of the primary modalities of treatment for locally advanced bladder cancer. However, long-term survival after cystectomy has improved only marginally in the last decade, and still, nearly half of the patients die from the disease within 5 years. Adjuvant treatments such as radiation therapy and chemotherapy have been used, but a clear advantage has not been demonstrated.The authors reviewed 130 patients who underwent radical cystectomy by the same surgeon as treatment for transitional cell carcinoma of the bladder. Morbidity, postoperative mortality, overall survival time, and accuracy of clinical staging as well as the effect of perioperative chemotherapy were evaluated.The overall actuarial survival rate at 2, 5, and 10 years was 80%, 53%, and 45%, respectively. The survival rate based on T-classification at 5 years was 82%, 65%, and 28% for less than pT2, pT2, and greater than pT2, respectively. Regional lymph node status had a significant effect on survival. The 5-year survival rate for all patients with negative nodes was 65%, whereas patients with positive nodes had a 18% 5-year survival rate. The overall clinical staging error was 61.5%, with 41.5% of the cancers understaged. Of the patients with cTis, 60% were found to be of greater extent than pT1 tumors. No apparent survival advantage was noted for those patients who received perioperative chemotherapy when compared with patients who were followed conservatively or received chemotherapy upon relapse. These results, however, are not conclusive because this was an observation study and the number of patients was limited.Only a modest improvement in survival time after radical cystectomy has been observed in the last decade, despite the use of adjuvant treatments such as radiation and chemotherapy. The pathologic (pT) classification is the most accurate prognostic indicator. Clinical errors in classification are common and impair the evaluation of neoadjuvant treatments. A high incidence of invasive tumors of greater extent than pT1 was found among patients with clinical cTis; this supports an aggressive approach when these patients do not respond promptly to intravesical chemotherapy. Prospective randomized studies are needed to evaluate objectively the benefit of perioperative adjuvant treatment in locally advanced transitional cell carcinoma of the bladder.

Androgen deprivation therapy is the initial treatment choice for metastatic disease. When enrolling patients into androgen deprivation trials, it is important to consider stratification of enrollees based on prognostic factors that have been identified as important in determining the likelihood of response. Prognostic factors are also helpful in identifying which patients are less likely to respond to treatment; this information also would help to counsel patients. Performance status is an important prognostic factor; however, its impact is minimal because the great majority of men who receive treatment for advanced disease have a normal performance status. Hemoglobin, alkaline phosphatase, and a semiquantitative grading scale for the number of metastatic foci on the bone scan are useful prognostic factors. The pretreatment serum testosterone level is a powerful prognostic factor. Patients with a low serum testosterone level have a shorter progression-free survival than men whose pretreatment serum testosterone level is above normal. The prognostic importance of pretreatment serum testosterone level has been evaluated in studies using treatment methods that lower this level to castrate levels. Recently, we found that serum testosterone level was not a prognostic factor for men taking the nonsteroidal antiandrogen, Casodex (Zeneca, Wilmington, DE), which does not alter the serum testosterone level. The pretreatment serum prostatic-specific antigen also is a prognostic factor. This antigen may be the best single method for monitoring patients in regard to response to or progression following therapy. The return of the prostatic-specific antigen level to normal (4 ng/ml), or the decline in the prostatic-specific antigen level of90% indicates a prolonged progression-free survival. In the future, it will be interesting to incorporate both the initial prognostic factors as well as monitor the prostatic-specific antigen into a multivariate analysis, which will be highly predictive of a man's response to treatment.

Prognostic factors have been shown to be important when stratifying patients with prostate cancer into randomized trials and counseling the individual patient regarding his chances of response to treatment. However, there are no reports on prognostic factors in patients with Stage D2 prostate cancer treated with a pure antiandrogen as monotherapy.The authors studied a variety of possible prognostic factors among 150 patients with metastatic prostate cancer treated with an antiandrogen (Casodex, Imperial Chemical Industries, Wilmington, DE).In a univariate analysis, performance status; extent of disease (EOD); pretreatment hemoglobin, alkaline phosphatase, prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP) levels; and extent of disease (EOD) on bone scan all were found to be significant prognostic factors (P0.05). Pretreatment serum testosterone levels, identified as one of the most important prognostic factors, was not identified as significant in the current study.Although the pretreatment testosterone level was shown to be an important prognostic factor in previous studies, using other modes of androgen ablation (reducing testosterone to below castrate levels), the current study suggest it may not be a helpful factor if the therapy used is antiandrogens as monotherapy. This may relate to the different mode of action of antiandrogens, which do not reduce serum testosterone levels.

Pure antiandrogens have a quality-of-life advantage over other androgen ablation methods in the treatment of patients with prostatic cancer because they do not reduce the serum testosterone and therefore do not have a marked inhibitory effect on libido and potency. The long half-life of two of the three currently studied pure antiandrogens permits once-a-day administration, which should enhance patient compliance. With continued administration, there is a gradual rise in serum testosterone, and the clinical impact of this requires additional study using randomized Phase III trials. Proper stratification of patients at entry into such studies with documentation of various prognostic factors will add statistical value and enable physicians to draw better conclusion on the relative efficacy of these agents.