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Magnesium citrate is a widely used over the counter drug with little to no safety concerns. This case study describes the development of magnesium toxicity after a single dose of magnesium citrate in a patient with extensive prior gastrointestinal surgery for pancreatic adenocarcinoma. The surgery resulted in extensively altered gastrointestinal physiology and several mechanisms could have influenced the abnormal absorption of magnesium seen in this patient. The patient had normal renal function pointing to a different mechanism than previously reported magnesium toxicities., (Copyright© South Dakota State Medical Association.)

Objectives: Micropapillary urothelial carcinoma of the urinary bladder (MPUC) is a rare variant of urothelial carcinoma which has aggressive clinical characteristics. The objective is to investigate the molecular subtypes of MPUC and the impact to the clinical outcome and determine whether MPUC represents a variant of adenocarcinoma., Materials and Methods: We evaluated surrogate immunohistochemical markers of luminal, basal, and p53-like subtypes and correlated with prognosis and the expression of markers related to bladder adenocarcinoma and glandular differentiation in 56 cases of MPUC (10 cases of transurethral resection and 46 cases of radical cystectomy). Biomarker expression in co-existing conventional urothelial carcinoma was also analyzed. Cox regression analysis was performed to study the impact of molecular subtype on the clinical outcome., Results: Thirty-four cases (61%) met criteria for the luminal subtype. Twenty-two cases (39%) displayed a p53-like subtype. In contrast, 40/56 (71%) cases of coexisting conventional urothelial carcinoma were classified as luminal subtype and 16/56 (29%) cases were designated as p53-like subtype. There was no significant survival difference between luminal subtype and p53-like subtype. CDX2, villin, and cadherin 17 were negative in all cases. MUC1 was strongly and diffusely expressed in the stroma-facing surface of MPUC tumor cells in all the cases., Conclusions: Our findings suggest that MPUC possesses characteristics of luminal and p53-like subtypes, and does not harbor phenotypic features of the basal subtype. There is no significant difference in the prognosis between luminal and p53-like subtype MPUC. MPUC is not a variant of adenocarcinoma and does not represent a form of glandular differentiation, in contrast to other organ sites., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To determine survival and management strategies for high-grade adenocarcinoma of salivary glands (ASG)., Methods: A retrospective analysis of cases diagnosed between 1998 and 2015 from our single tertiary referral center was performed. Multivariable logistic regression was used to determine factors associated with survival., Results: Thirty-eight cases of high-grade ASG were identified. Most patients were men (68.4%) with a median age of 65.5 years (range 23-84 years). Most tumors were T3 and T4 (65.8%). Regional metastases were common (55.2%), and 42.1% developed distant metastases. The mean follow-up was 60.5 months. All patients received surgery as primary treatment, with 84.2% of patients receiving adjuvant radiation therapy or chemoradiotherapy ([C]RT). Cumulative overall survival was 89.1%, 50.9%, and 20.7% after 1, 5, and 10 years, respectively. Disease-specific survival was 94.4%, 69.8%, and 42.8%, and distant-metastases-free survival (DMFS) was 80.5%, 50.1%, and 40.1% after 1, 5, and 10 years. On multivariable analysis, advanced T status correlated with DMFS (hazard ratio 2.75, 95% CI 0.93-8.16). Postsurgical (C)RT reduced the locoregional recurrence rate by 23.9%, and it improved the locoregional-recurrence-free survival by 39% (p = 0.094)., Conclusion: High-grade ASG is considered to have an unfavorable prognosis. Adjuvant (C)RT reduces the rate of locoregional recurrences. Distant metastases are common, and an advanced T stage has increased prognostic value for development of early distant lesions.

Background: Primary adenocarcinoma of the urinary bladder is rare. The molecular and cellular events leading to its pathogenesis are not well delineated. The goal of this study was to investigate p53 and p16 expression, as well as HPV status, in a relatively large series of primary bladder adenocarcinomas., Materials and Methods: Thirty six cases of urinary bladder adenocarcinoma were chosen from participating institutions. The diagnosis and available clinical history were reviewed in each case. Immunostains for p53, p16 and HPV and high-risk and low-risk HPV-ISH were performed on all tumors., Results: Patients had an average age of 61 years with a male predominance (1.5 ∶ 1 male ∶ female ratio). The average tumor size in cystectomy specimens was 4.3 cm. Of the cases managed by transurethral resection, 40% were pT2 at the time of diagnosis. In cystectomy specimens, 77% were either pT3 or pT4. Strong nuclear p16 expression was seen in 67% of all cases and p53 expression was present in 58% of the cases. Expression of both markers was seen in 33% of cases. Expression of p16 or p53 alone was present in 12 (33%) and 9 (25%) cases, respectively. Neither marker was expressed in only 3 (8%) of the tumors. No significant correlation between clinical variables and any of the markers we studied was identified. No HPV infection was detected in any case., Conclusions: Expression of p53 and/or p16 is very common in urinary bladder adenocarcinoma. These findings implicate a high likelihood that alterations in these cell cycle proteins contribute to the pathogenesis of these tumors. Despite frequent immunohistochemical labeling for p16, no evidence of HPV infection was found.

The identification of mutations in epidermal growth factor receptor (EGFR) and translocations involving anaplastic lymphoma kinase (ALK) in lung adenocarcinoma has drastically changed understanding of the disease and led to the development of targeted therapies. Adenocarcinoma of the urinary bladder is rare and poorly understood at the molecular level. We undertook this study to determine whether EGFR mutations, increases in EGFR copy number, or ALK translocations are present in these tumors. Twenty-eight cases of primary bladder adenocarcinoma were analyzed. For EGFR mutational analysis, PCR-amplified products were analyzed on the Q24 Pyrosequencer with Qiagen EGFR Pyro Kits. All cases were analyzed via fluorescence in situ hybridization (FISH) using Vysis ALK Break Apart FISH Probes for detection of ALK chromosomal translocation and Vysis Dual Color Probes to assess for increased gene copy number of EGFR. None of the 28 cases examined showed mutational events in EGFR or ALK rearrangements. EGFR polysomy was seen in 10 out of 28 (36%) cases. No correlation with EGFR polysomy was seen in the tumors with respect to age, histologic subtypes, pathologic stage, or lymph node metastasis. In summary, EGFR mutations and ALK rearrangements do not appear to be involved in the development of primary adenocarcinoma of the urinary bladder. A subgroup of cases (36%), however, demonstrated increased gene copy number of EGFR by FISH.

Glandular neoplasms involving the urinary bladder carry a challenging differential diagnosis including primary and secondary processes. We investigated the potential diagnostic utility of cadherin-17 and GATA3 in 25 primary adenocarcinomas of the urinary bladder, as compared with other commonly used markers including β-catenin and p63. Urothelial carcinoma with glandular differentiation (11), colorectal adenocarcinoma secondarily involving the bladder (25), and primary colorectal adenocarcinoma (22) were also analyzed and the results were compared using a Fisher exact test. Cadherin-17 was expressed in 23/25 primary bladder adenocarcinomas (92%), 23/25 colorectal adenocarcinomas involving the bladder (92%), 21/22 primary colorectal adenocarcinomas (95%) and entirely negative (0/11) in both components of urothelial carcinoma with glandular differentiation (P<0.001). In urothelial carcinoma with glandular differentiation, positive nuclear staining for GATA3 was evident in the urothelial component for 18% (2/11) and the glandular component for 9% (1/11) with additional tumors showing only cytoplasmic staining. Nuclear reactivity for GATA3 was not present in primary bladder adenocarcinoma and primary/secondary colorectal adenocarcinoma (P<0.05). Positive nuclear and cytoplasmic immunostaining for β-catenin was evident in 21/22 primary colorectal adenocarcinomas (95%) and 23/25 cases of secondary involvement by colorectal adenocarcinoma (92%). In contrast, positive membranous and cytoplasmic staining for β-catenin was observed in 23/25 primary bladder adenocarcinomas (92%) and 11/11 urothelial carcinomas with glandular differentiation (100%, P<0.001). p63 was expressed only in the urothelial component of urothelial carcinoma with glandular differentiation and not in the glandular component (P<0.001). In summary, cadherin-17 is a relatively specific and sensitive marker for primary adenocarcinoma of the urinary bladder, distinguishing it from urothelial carcinoma with glandular differentiation. However, it does not distinguish primary bladder adenocarcinoma from secondary involvement by colorectal adenocarcinoma. The pattern of reactivity for β-catenin remains the most useful marker for distinguishing these two tumors.

Dyslipidemia and prostate cancer are two of the most common medical conditions affecting adult males in the USA. In recent years, a large volume of research has focused on investigating the relationship between these two disease processes as well as the effect of the cholesterol-lowering medications, such as 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors (better known as 'statins'), on the development and progression of prostate cancer. While there is a paucity of prospective research, encouraging results have been reported in several retrospective clinical studies. Additionally, basic science research has identified interactions between lipids and prostate cancer cells in several key areas. This article will discuss recent clinical and basic science research examining the relationship between dyslipidemia, statins and prostate cancer.

Background: Proliferating cell nuclear antigen (PCNA) plays an important role in DNA replication and repair. The expression and potential utility of this marker in prostatic neoplasia is uncertain. With the development of this new caPCNA selective antibody, we explored the potential utility of this marker in prostate cancer., Methods: Using a traditional primary Fab2' rabbit anti-caPCNA antibody-HRP conjugated secondary anti-Fab2' antibody format, the expression of the caPCNA was analyzed in prostate tissue from 89 radical prostatectomy specimens. The caPCNA expression was correlated with clinicopathologic characteristics., Results: The fraction of cells staining positively with caPCNA antibody in prostatic adenocarcinoma (mean, 23%) was significantly higher than that in benign prostatic epithelium (mean, 2%; P < 0.001) or high-grade prostatic intraepithelial neoplasia (PIN) (mean, 6%; P < 0.05). Moreover, the intensity of caPCNA expression in prostatic adenocarcinoma (mean, 2.9) was significantly higher than that in benign prostatic tissue (mean, 0.7; P < 0.001) or high-grade PIN (mean, 2.0; P < 0.001). Benign prostatic epithelium showed only minimal or negative reactivity. There was significant correlation between the percentage of caPCNA expression and primary Gleason grade (P = 0.01), and with Gleason score (P = 0.02). Adenocarcinomas with positive vascular invasion had a significantly higher percentage of cells staining with caPCNA antibody (P < 0.0001) and a higher intensity of caPCNA expression (P = 0.04)., Conclusions: Our data indicate that increased expression of the cancer-associated isoform of PCNA is common in prostatic adenocarcinoma and its precursor and may be a useful biomarker., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Morphologic and clinical heterogeneity within tumor grades is well recognized in prostate cancer. The objective of the current study was to determine whether the combined percentage of Gleason patterns 4 and 5 in radical prostatectomy specimens is an independent predictor of cancer-specific survival in prostate cancer patients., Methods: The radical prostatectomy specimens were analyzed from 504 consecutive prostate cancer patients who were treated at Indiana University Medical Center between 1990 and 1998. Various clinical and pathologic characteristics were analyzed., Results: A higher combined percentage of Gleason patterns 4 and 5 was associated with older age, higher preoperative serum prostate-specific antigen level, higher pathologic stage, positive surgical margins, extraprostatic extension of tumor, higher Gleason score, perineural invasion, and lymph node metastasis. In the multivariate Cox regression model, the combined percentage of Gleason patterns 4 and 5 was found to be an independent predictor of cancer-specific survival (P = .04)., Conclusions: The combined percentage of Gleason patterns 4 and 5 is a powerful predictor of prostate cancer-specific survival. Assessment of high-grade cancer amounts may allow for better stratification of patients into appropriate prognostic groups and treatment protocols.

The presence of positive surgical margins is a negative prognostic indicator in patients undergoing prostatectomy for prostate cancer; whether the extent of the positive margins affects the clinical outcome with regards to prostate-specific antigen (PSA) recurrence remains uncertain. We evaluated the linear extent of margin positivity as a prognostic indicator in a series of radical prostatectomy specimens. One hundred seventy-four consecutive margin-positive prostatectomy specimens were evaluated. The linear extent of margin positivity was measured with an ocular micrometer and ranged from 0.05 to 75.0 mm (mean, 8.94; median, 5.0). The linear extent of margin positivity was associated with tumor volume (P = .03) but was not associated with patients' age at surgery, preoperative PSA level, prostate weight, pathologic stage, Gleason score, extraprostatic extension, seminal vesicle invasion, perineural invasion, high-grade prostatic intraepithelial neoplasia, or PSA recurrence. In the full model multiple Cox regression, significant predictors for PSA recurrence were Gleason score (P = .001) and preoperative PSA (P = .01); extent of margin positivity was not predictive of PSA recurrence (hazard ratio, 1.00; 95% confidence interval, 0.98-1.02; P = .97) nor was tumor volume a significant factor when adjusted for other covariates (P = .27). Preoperative PSA, tumor stage, and Gleason score remained significant prognostic factors in evaluating the likelihood of PSA recurrence in patients with positive surgical margins; the extent of margin positivity, however, is not a prognostic factor for PSA recurrence and should, therefore, not necessarily be included in the final report for radical prostatectomy specimens.

Tumor volume has been considered an important variable in determining the probability of prostate-specific antigen (PSA) recurrence in prostatic adenocarcinoma. There have been many studies that have tried to determine an appropriate method of calculating tumor volume, but no single methodology has been agreed upon. We tested the hypothesis that the ratio of tumor positive tissue blocks to the total number of blocks submitted (positive-block ratio) can be used as an independent prognostic indicator for PSA recurrence. We analyzed 504 patients who underwent total radical retropubic prostatectomy between 1990 and 1998. None of the patients had preoperative radiation or androgen-deprivation therapy. Clinical records were reviewed. The mean positive-block ratio was 0.44 (median, 0.43; range, 0.05 to 1.0). The positive block-ratio was significantly associated with Gleason score, pathologic stage, surgical margin status, extraprostatic extension, seminal vesical invasion, lymph node metastasis, perineural invasion, and preoperative serum PSA level (all P<0.001). Using a multivariate Cox regression model, controlling for pathologic stage, Gleason score, lymph node metastasis, and surgical margin status, positive-block ratio was an independent predictor of PSA recurrence (hazard ratio, 2.3; 95% confidence interval, 1.06-4.83; P=0.03). Five-year PSA recurrence-free survival was 67% for those patients with positive-block ratio 0.43 (P<0.001). Positive-block ratio is an independent predictor of PSA recurrence and this simple method of tumor measurement seems to be promising for quantifying tumor volume if our findings are validated by subsequent reports.

Extraprostatic extension is an unfavorable prognostic factor for prostate cancer. Consequently, it has been assigned to pT3a in the current 2002 tumor, lymph node, metastasis staging system. The aim of our study is to analyze the extent of extraprostatic extension by 8 quantitative methods and to determine which is best for substaging of pT3a tumors. We studied 83 patients with extraprostatic extension after radical prostatectomy for clinically localized prostatic adenocarcinoma. The extent of extraprostatic extension was evaluated using 8 quantitative methods. Univariate and multivariate analyses were performed to determine which measurement best predicts prostate-specific antigen (PSA) recurrence. In the univariate analysis, the radial distance of extraprostatic tumor measured by ocular micrometer was associated with PSA recurrence (P = 0.02). No significant association was observed between PSA recurrence and other measurements of extraprostatic extension, including focal versus established extraprostatic extension using Epstein's criterion, focal versus established extraprostatic extension using Wheeler's modified criterion, the number of extraprostatic neoplastic glands, unilateral versus bilateral involvement, circumferential length of extraprostatic tumor, unifocal versus multifocal involvement, and volume of extraprostatic tumor. In the multivariate analysis, radial distance remained an independent predictor of PSA recurrence (hazard ratio, 2.4; 95% confidence interval, 1.12-5.01; P=0.02). The radial distance of the extraprostatic extension measured by ocular micrometer is an independent prognostic factor for pT3 prostate cancer. Two-year and 4-year PSA recurrence-free survival was 62% and 35%, respectively, for those patients with radial distance <0.75 mm, as compared with 35% and 18%, respectively, for those with radial distance > or =0.75 mm. We recommend reporting this parameter routinely for radical prostatectomy specimens. The strength of its prognostic value for PSA recurrence makes it a potential criterion for incorporation into a future tumor, lymph node, metastasis staging system.

Purpose: In radical prostatectomy specimens Gleason score 7 is among the most commonly assigned scores for prostate carcinoma accounting for 30% to 50% of cases. Gleason score 7 is different from other more differentiated prostate carcinomas (tumors of Gleason scores 5 and 6) with a significantly worse outcome and higher rate of recurrence. Nonetheless, Gleason score 7 tumors are heterogeneous. In this study we examined the differences in clinical outcome between primary Gleason grade 3 and 4 tumors in patients who underwent radical prostatectomy, and determined the influence of tertiary Gleason pattern 5 on patient outcome., Materials and Methods: A total of 504 patients underwent radical prostatectomy for prostate cancer and 228 of the patients (45%) had a Gleason score of 7. Cases were analyzed for a variety of clinical and pathological parameters. The influence of primary Gleason pattern and tertiary Gleason pattern 5 on patient outcome was assessed in the Cox regression model., Results: Among 228 patients with Gleason score 7 prostatic adenocarcinoma, 91 (40%) had a primary Gleason pattern 4 and 137 (60%) had primary Gleason pattern 3. Patients of the former group were more likely to have a higher pathological stage (p = 0.003), more likely to have PSA recurrence (p = 0.02) and more likely to have a tertiary Gleason pattern 5 (p <0.0001). A total of 37 (41%) patients with primary Gleason 4 had a tertiary Gleason pattern 5, whereas only 13 (9%) patients with primary Gleason 3 had a tertiary Gleason pattern 5. In the Cox regression model controlling for tumor stage and surgical margin status, the primary Gleason pattern was not an independent predictor of PSA recurrence (p = 0.80), whereas the presence of tertiary Gleason pattern 5 was a significant predictor of PSA recurrence (hazard ratio 2.10, 95% CI 1.24-3.55, p = 0.006). Five-year PSA recurrence-free survival was 70% for patients without a tertiary Gleason pattern 5 compared to 19% for those patients with a tertiary Gleason pattern 5., Conclusions: Among patients with Gleason score 7, primary Gleason grade 4 indicates a likelihood of higher tumor stage and higher probability of PSA recurrence than does primary pattern 3. However, it does not independently predict a worse outcome after controlling for other known prognostic parameters associated with disease progression. Regardless of whether the primary Gleason pattern is 3 or 4, a tertiary Gleason pattern 5 is the strongest predictor of a worse outcome in patients with Gleason grade 7 prostatic adenocarcinoma. Therefore, tertiary pattern 5 should be reported in radical prostatectomy specimens.

Purpose: Gleason grade and tumor stage are well established prognostic factors in prostate cancer. Histological demonstration of tumor in lymphovascular spaces has been associated with poor prognosis in many tumor types but it is not included in current prostate cancer grading and staging schemes. Whether lymphovascular invasion is an independent prognostic factor for disease progression in prostate cancer is uncertain. We retrospectively investigated lymphovascular invasion as a predictive factor for biochemical failure and cancer specific survival following radical prostatectomy., Materials and Methods: The records of 504 patients with prostatic adenocarcinoma undergoing radical prostatectomy were reviewed for lymphovascular invasion. Clinical followup data were available on 459 cases. Mean followup was 44 months (range 1.5 to 144). Multivariate analysis was performed using the Cox model., Results: Lymphovascular invasion was identified in 106 cases (21%). Univariate analysis showed a significant association between lymphovascular invasion and higher preoperative serum prostate specific antigen (PSA), advanced pathological stage, higher Gleason score, positive surgical margins, extraprostatic extension, seminal vesicle invasion, lymph node metastasis and perineural invasion (each p <0.001). No association was observed between lymphovascular invasion and patient age at surgery, prostate weight or high grade prostatic intraepithelial neoplasia. Lymphovascular invasion was an independent predictor of PSA recurrence (HR 1.6, 95% CI 1.12 to 2.38, p = 0.01) and cancer specific survival (HR 2.75, 95% CI 1.04 to 2.28, p = 0.041) after controlling for tumor stage, surgical margins and Gleason grade on multivariate analysis. Five-year cancer specific survival was 90% in men with lymphovascular invasion compared to 98% in those without lymphovascular invasion (p <0.001)., Conclusions: Lymphovascular invasion can be identified in approximately 20% of prostate cancer cases. Lymphovascular invasion is an independent risk factor for PSA recurrence and cancer death in patients with prostate cancer.

Objective: To test the hypothesis that prostate cancer patients with clinical stage cT1c and cT2 have similar outcomes and clinicopathological features, and should be grouped together., Patients and Methods: From a series of men with prostate cancer who had a radical retropubic prostatectomy (RP), we assessed those with cT1c (223) and cT2 (65) adenocarcinoma. All RP specimens were totally embedded and whole-mounted; tumour volume was measured using the grid method. Clinical and pathological characteristics were analysed., Results: Patients with cT2 tumours were more likely to have a higher Gleason score (P = 0.04) and final pathological stage (P = 0.05) than those with cT1c tumours. There was no significant difference in age (P = 0.92), preoperative PSA level (P = 0.17), prostate weight (P = 0.34), tumour volume (P = 0.16), surgical margin status (P = 0.86), multifocality (P = 0.92), the presence of perineural invasion (P = 0.09), or high-grade prostatic intraepithelial neoplasia (P = 0.99) between patients with clinical stage cT1c and those with cT2 tumours. There was no difference in PSA recurrence between patients with clinical stage T1c and those with cT2 tumours (P = 0.27)., Conclusions: Patients with clinical stage cT2 tumours have a higher Gleason score and advanced pathological stage than tumours detected because of a high serum PSA level (cT1c). These results suggest that clinical stage cT1c tumours should be separated from clinical stage cT2 disease, but the PSA recurrence rate for both tumour stages is similar, indicating a need for further evaluation and refinement of the current clinical staging system.

Purpose: The detection of low volume and early stage prostate cancer has increased with the widespread use of prostate specific antigen screening for prostatic adenocarcinoma. This increased detection has led to efforts to stratify patient risk and the potential benefits of various treatments based on preoperative clinical and biopsy data. We examined various clinical parameters and prostate biopsy features to determine which variables are most predictive of small volume (less than 0.5 ml) cancer at prostatectomy., Materials and Methods: We studied 336 patients who underwent prostatectomy for prostate cancer. Radical prostatectomy specimens were completely embedded and whole mounted. Final tumor volume in the radical prostatectomy specimens was determined by the grid method. Clinical data were gathered by a review of patient charts. Various preoperative clinical and biopsy findings were analyzed to determine factors predictive of small volume cancer at prostatectomy., Results: A total of 55 patients (16%) were found to have small volume cancer (less than 0.5 ml). On univariate logistic regression certain variables were significant predictors of small volume cancer, namely the highest Gleason score from all positive biopsy sites (p = 0.001), the Gleason score from the biopsy site with the highest percent of adenocarcinoma (p = 0.006), the highest percent of adenocarcinoma at any biopsy site (p <0.0001), the percent of adenocarcinoma at the biopsy site with the highest Gleason score (p <0.0001), the highest percent of cores positive for adenocarcinoma at any biopsy site (p = 0.001), the percent of cores with carcinoma at the site with the highest Gleason score (p = 0.002), the number of positive sites (p <0.0001) and tumor bilaterality (p <0.0001). None of the clinical parameters that we studied, including preoperative prostate specific antigen (p = 0.52), clinical stage (p = 0.62) or patient age (p = 0.94), was predictive of small volume cancer. On multivariate analysis the highest percent of adenocarcinoma at any site (adjusted OR 0.95, 95% CI 0.92 to 0.97, p <0.0001) and the number of positive biopsy sites (adjusted OR 0.97, 95% CI 0.96 to 0.99, p <0.0001) were significant predictors of small volume cancer., Conclusions: The number of positive biopsy sites and the highest percent of adenocarcinoma at any biopsy site are significant predictors of small volume cancer in radical prostatectomy specimens.

Purpose: Clinical outcome is variable in prostate cancer patients treated with radical prostatectomy. The Gleason histologic grade of prostatic adenocarcinoma is one of the strongest predictors of biologic aggressiveness of prostate cancer. We evaluated the significance of the relative proportion of high-grade cancer (Gleason patterns 4 and/or 5) in predicting cancer progression in prostate cancer patients treated with radical prostatectomy., Patients and Methods: Radical prostatectomy specimens from 364 consecutive prostate cancer patients were totally embedded and whole mounted. Various clinical and pathologic characteristics were analyzed. All pathologic data, including Gleason grading variables, were collected prospectively., Results: A multiple-factor analysis was performed that included the combined percentage of Gleason patterns 4 and 5, Gleason score, tumor stage, surgical margin status, preoperative prostate-specific antigen (PSA), extraprostatic extension, and total tumor volume. Using Cox regression analysis with bootstrap resampling for predictor selection, we identified the combined percentage of Gleason patterns 4 and 5 (P < .0001) and total tumor volume (P = .009) as significant predictors of PSA recurrence., Conclusion: The combined percentage of Gleason patterns 4 and 5 is one of the most powerful predictors of patient outcome, and appears superior to conventional Gleason score in identifying patients at increased risk of disease progression. On the basis of our results, we recommend that the combined percentage of Gleason patterns 4 and 5 be evaluated in radical prostatectomy specimens. The amount of high-grade cancer in a prostatectomy specimen should be taken into account in therapeutic decision making and assessment of patient prognosis.

Background: Coactivator-associated arginine methyltransferase 1 (CARM1) is a transcriptional coactivator of the androgen receptor (AR). It is involved in the regulation of the biologic functions of the AR. It remains to be determined whether CARM1 is involved in prostatic carcinogenesis., Methods: The expression of CARM1 in normal prostate epithelium, high-grade prostatic intraepithelial neoplasia (PIN), and prostate carcinoma tissue was examined in 66 previously untreated patients with prostate carcinomas, as well as 12 patients with hormone-independent prostate carcinoma, using immunohistochemical methods., Results: Cell staining was observed in the cytoplasm and the nucleus. In 66 patients without previous hormonal treatment, the percentage of cells that stained positively for CARM1 in benign prostate tissue specimens (mean values: cytoplasm, 23%; nucleus, 16%) was statistically significantly less than the percentage of positively stained cells in PIN (mean values: cytoplasm, 56%; nucleus, 30%; P < 0.001) and in prostatic adenocarcinoma specimens (mean values: cytoplasm, 79%; nucleus, 53%; P < 0.001). The difference between adenocarcinoma and PIN also was statistically significant (P < 0.001). The staining intensity for CARM1 was significantly lower in benign prostate tissue specimens compared with PIN and prostatic adenocarcinoma specimens (P < 0.001). In the 12 patients with androgen-independent prostatic adenocarcinoma, the expression of CARM1 was significantly increased when compared with patients without previous hormonal treatment. Expression of CARM1 was not correlated with age, Gleason score sum, pathologic stage, lymph node metastasis, extraprostatic extension, surgical margin status, vascular invasion, or perineural invasion., Conclusions: The authors found that overexpression of CARM1 was involved in the development of prostate carcinoma as well as androgen-independent prostate carcinoma. Since CARM1 is functionally different from most other transcriptional coactivators of the AR, it may serve as a new target for the treatment of hormone-independent prostate carcinoma., (Copyright 2004 American Cancer Society.)

Background: The Gleason grading system uniquely combines data from different areas of carcinoma in the same prostate specimen. Prostatic adenocarcinoma often is multifocal, and different Gleason grades may be present in different foci. The current study was undertaken to compare the Gleason grades of individual adenocarcinoma foci in a given specimen with the overall Gleason grades (primary and secondary) of that specimen., Methods: Data were obtained from 115 consecutive radical prostatectomy specimens via whole-mount processing and complete sectioning. Diagrams were constructed by tracing the outline of each whole-mount section, and tumor maps subsequently were generated. The largest focus was considered the index tumor. Each prostatectomy specimen was assigned primary and secondary Gleason grades, and each tumor focus was assigned its own primary and secondary Gleason grades. Tumor volume was measured using the grid method., Results: Two or more adenocarcinoma foci were present in 87% of all specimens (2 foci, n = 20; 3 foci, n = 33; 4 foci, n = 17; 5 foci, n = 13; > 5 foci, n = 17). Specimens (n = 15) containing a single tumor were excluded from further analysis. Among the remaining specimens (n = 100), all tumor foci had Gleason grades that were the same as the corresponding overall Gleason grades in only 9 cases (9%). The Gleason score (i.e., the sum of the primary and secondary grades) of the index tumor was correlated with the overall Gleason score in 68% of specimens. The primary grade of the index tumor was the same as the overall primary grade in 97 specimens, whereas the secondary grade of the index tumor was the same as the overall secondary grade in only 68 specimens. The primary and secondary grades of the index tumor, compared with the overall Gleason primary and secondary grades, were reversed in 17 specimens., Conclusions: The findings of the current study demonstrated the histologic heterogeneity of multifocal prostate malignancies. Although the Gleason grading system was used to determine an overall score for prostate carcinoma within a specimen, the scores of individual tumors, including index tumors, often did not agree with this overall score. These findings may have implications with respect to future biomarker and tissue array studies., (Copyright 2004 American Cancer Society.)

Purpose: PCDGF (PC cell-derived growth factor), also called progranulin, is a M(r) 88000 glycoprotein precursor of granulin. It is a novel growth factor that stimulates cell proliferation, confers epithelial tumorigenesis, and promotes tumor invasion. Here we investigate the potential of PCDGF as a therapeutic target for prostate cancer., Experimental Design: We studied the expression of PCDGF in invasive prostate cancer, adjacent high-grade prostatic intraepithelial neoplasia (PIN), and benign prostate tissue from 99 human prostate specimens. The level of PCDGF expression was correlated with various clinicopathological characteristics., Results: Normal prostate tissue did not express (53/99), or expressed low levels (46/99) of PCDGF. In the 46 normal prostate specimens that expressed PCDGF, most of them had less than 10% of cells expressing PCDGF. PCDGF expression could be detected in more than 50% of cells in all specimens of PIN and invasive prostate cancer. The expression of PCDGF in normal prostate tissue was much less intense and in a smaller fraction of cells than in PIN and invasive adenocarcinoma (P < 0.0001). There was no correlation of PCDGF expression with age, Gleason score, pathological stage, status of lymph node metastasis, extraprostatic extension, perineural invasion, surgical margins, and vascular invasion., Conclusions: Our data suggest that the induction of PCDGF expression occurs during the development of PIN. PCDGF may be a new molecular target for the treatment and prevention of prostate cancer.

Objectives: To evaluate the ability of abarelix, a gonadotropin-releasing hormone antagonist, to provide an alternative treatment to bilateral orchiectomy in men with advanced prostate cancer symptoms and to evaluate its safety, clinical and biochemical efficacy, and effects on prostate-specific antigen and serum hormone levels., Methods: For 168 days, 81 patients from 17 centers received monthly intramuscular injections of open-label abarelix 100 mg (at least one dose). Patients were evaluated for the avoidance of bilateral orchiectomy, efficacy, disease response, percentage of change in prostate-specific antigen level, change in the intensity of pain, neurologic compromise, and other efficacy variables. Safety was evaluated through reports of adverse events and abnormal laboratory values., Results: No patients required bilateral orchiectomy, but 2 patients were withdrawn from the study because of treatment-related events and were considered as failures to avoid orchiectomy. Treatment produced an 88% (38 of 43) objective response rate on day 85. Sixty-five (90%) of 72 patients experienced improvement in the pain score and/or analgesic use, urinary obstruction, urinary catheter removal, hydronephrosis, and/or azotemia. No patient with impending neurologic compromise at study entry developed spinal cord compression. The median reduction from the baseline prostate-specific antigen value was 75% on day 15 and greater than 95% from day 57 onward. Abarelix was well tolerated, and adverse events were the sequelae of advanced prostate cancer, comorbid medical disorders, or medical castration., Conclusions: These results suggest that abarelix provides a safe and effective medical alternative to surgical castration in symptomatic patients with advanced prostate cancer without the risk of the clinical flare associated with luteinizing hormone-releasing hormone agonists.

Background: Some evidence suggests a role for HER-2/neu overexpression in prostate carcinoma progression. Reported rates of HER-2/neu overexpression in patients with prostate carcinoma vary greatly., Methods: The authors studied radical prostatectomy specimens from 38 patients who had biochemical failure after undergoing radical prostatectomy for prostate carcinoma. Immunohistochemistry for HER-2/neu overexpression using the HercepTest kit (Dako Corporation, Carpenteria, CA) was employed. Two different antigen-retrieval techniques were used: 1) the standard U.S. Food and Drug Administration (FDA)-approved HercepTest assay and 2) a modified HercepTest, which employed an alkaline citrate buffer, pH 9.0, for antigen retrieval and a 1-hour primary antibody incubation time. The level of HER-2/neu expression was evaluated on a scale from 0 (no staining) to 3+ according to the published guidelines. Fluorescent in situ hybridization for gene amplification was performed on all specimens., Results: With the standard technique, only one specimen had 2+ staining, and no specimens had 3+ staining. With the modified technique, 10 specimens (26%) had 2+ staining, and 9 specimens (24%) had 3+ staining. There was a significant association between the level of HER-2/neu expression shown with the modified technique and tumor stage (P = 0.03) as well as Gleason grade (P = 0.01). None of the specimens had HER-2/neu gene amplification., Conclusions: The authors report a simple modification of the HercepTest that resulted in an increased rate of HER-2/neu expression, which was correlated with poor-risk pathologic findings. The findings suggest that adenocarcinoma of the prostate should be evaluated for HER-2/neu expression with a prostate specific immunohistochemical procedure that differs from the FDA-approved standard procedure., (Copyright 2002 American Cancer Society.)

Background: Fas is a Type I membrane receptor of the tumor necrosis factor/nerve growth factor family. On binding to Fas ligand, a Type II transmembrane protein, the Fas/Fas ligand complex, induces apoptosis in target cells. Dysregulation of Fas and Fas ligand expression has been found in some malignant neoplasms., Methods: Using immunohistochemical analysis, the authors studied the expression of Fas and Fas ligand in prostatic adenocarcinoma, high-grade prostatic intraepithelial neoplasia (PIN), and adjacent benign prostate tissue from 95 radical prostatectomy specimens., Results: The percentage of cells that stained positively with Fas in benign prostate tissue (mean, 2%) was statistically significantly lower compared with that in prostatic intraepithelial neoplasia (mean, 13%; P = 0.0014) and prostatic adenocarcinoma (mean, 31%; P = 0.0001). The staining intensity of Fas was significantly less in benign prostate tissue compared with the staining intensity in PIN and prostatic adenocarcinoma. The percentage of cells that stained positively with Fas ligand in benign prostate tissue (mean, 13%) was statistically significantly lower compared with that in PIN (mean, 47%; P = 0.0001) and in prostatic adenocarcinoma (mean, 53%; P = 0.0001). The staining intensity of Fas ligand was significantly less in benign prostate tissue compared with that in PIN and prostatic adenocarcinoma., Conclusions: Data from the current study indicate that Fas/Fas ligand is elevated in prostatic malignancy, suggesting that Fas-mediated apoptosis may be a potential target for therapeutic intervention., (Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10674)

Introduction: Her-2/neu overexpression has been recently shown to be a poor prognostic factor in breast carcinoma. Overexpression has also been demonstrated in adenocarcinoma of the pancreas but the significance is unclear. We attempted to study the role of Her-2/neu overexpression, detected by immunohistochemistry, in pancreatic carcinoma and also examined for variability of overexpression across different tissue sections on individual tumor specimen., Materials and Methods: Records of all patients with adenocarcinoma of the pancreas, diagnosed and followed between 1986 and 2001 at a tertiary care oncology center were reviewed. Archival pathological samples were analyzed for Her-2/neu expression using the Hercep immunohistochemical assay (DAKO). A score of 2+ or greater on the assay was considered positive for Her-2/neu expression. When tumors were found to be Her-2/neu-positive, they were assessed for variability of expression of Her-2/neu by staining different sections of individual tumor blocks. Log-rank tests and Cox proportional hazards methods were used to analyze survival data., Results: Three hundred and eight patients were included in our study. The mean age was 70 years. Forty-eight out of 308 specimens (16%) were positive for Her-2/neu expression. The mean survival in the Her-2/neu-positive group was 11 months and in the Her-2/neu-negative group was 7 months (p=.03). Of the 48 patients with Her-2/neu-positive tumors, 16 showed variable overexpression (33%). Multivariate analysis did not reveal statistical difference in survival between the uniformly expressing and variably expressing tumors., Conclusion: Her-2/neu overexpression detected by immunohistochemistry does not appear to be a poor prognostic factor in patients with adenocarcinoma of the pancreas. Also, there is significant variability in the level of Her-2/neu expression across tumor sections in individual patients, which can potentially lead to considerable misclassification. Hence, we believe that, pending further studies, Her-2/neu may not be an appropriate target for therapy in pancreatic adenocarcinoma.

Phospholipase A2 (PLA2) enzymes release arachidonic acid from cellular phospholipids in a variety of mammalian tissues, including prostate. Group IIa secretory PLA2 (sPLA2) can generate arachidonate from cellular phospholipids. We examined the group IIa sPLA2 expression in benign prostatic tissues, prostatic intraepithelial neoplasia (PIN), and adenocarcinoma to determine whether sPLA2 expression is altered in the carcinogenesis of human prostatic cancer. Thirty-three of 74 total cases (45%) of benign prostatic tissue showed positive immunohistochemical staining for group IIA sPLA2, whereas 63 of 69 total cases (91%) of high-grade PINs and 70 of 78 total cases (90%) of adenocarcinomas gave positive results. Four of 10 cases of low-grade PIN showed positive immunoreactivity for sPLA2. The number of cells staining for sPLA2 was significantly less in benign epithelium (4%) and low-grade PIN (4%) compared to high-grade PIN (40%) or adenocarcinoma (38%) (P < 0.001). There was no significant difference between high-grade PIN and adenocarcinoma in the number of cells staining positively for sPLA2. The intensity of sPLA2 immunoreactivity was also different among benign prostatic tissue, low-grade PIN, high-grade PIN, and prostatic adenocarcinoma specimens. The malignant cells demonstrated more intense immunohistochemical staining (moderate to strong staining in 81% and 69% cases for high-grade PIN and adenocarcinoma, respectively) than benign glands (moderate staining in 11% of cases). No strong staining was observed in benign glands or low-grade PIN. Our data are consistent with the contention that group IIA sPLA2 expression is elevated in neoplastic prostatic tissue and support the hypothesis that dysregulation of sPLA2 may play a role in prostatic carcinogenesis.

Pancreatic cancer is the fourth leading cause of cancer death in both men and women with a mortality incidence ratio of 0.99. In an effort to describe the role of clinical features at initial presentation, we conducted a retrospective observational study in patients with a biopsy-proven diagnosis of adenocarcinoma of the pancreas. Between 1986 and 2001, 308 patients (160 males, 148 females) were diagnosed with pancreatic adenocarcinoma. The mean age at diagnosis was 70.1 yr (range: 34-96 yr). The mean survival was 7.6 mo (range: 0-97 mo). Statistical analysis was performed using log-rank tests and analysis of variance. As expected, age at diagnosis was a significant factor affecting survival, with older patients doing relatively poorly (p < 0.05). Patients with a good performance status performed significantly better than those with a poor performance status (p < 0.01). In addition, the presence of the tumor in the head of the pancreas was a predictor for improved survival (p < 0.01). Although smoking increased the chances of detection at an earlier age, neither diabetes mellitus nor a positive smoking history had a statistically significant effect on the survival. Pancreatic adenocarcinoma is a disease of the elderly associated with a poorer outcome. Knowledge of possible clinical predictors of survival may lead to better patient counseling regarding prognosis.