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Biomedical subjects

Paul F Schellhammer

Publications and source records attributed to Paul F Schellhammer.

33 records · Page 2Linked to original sources
PubMed2003

Prostate cancer grade assignment: the effect of chronological, interpretive and translation bias.

PURPOSE: Surveillance, Epidemiology and End Results (SEER) data reveal an increasing incidence in the detection of moderately differentiated prostate cancer and a stable or decreasing incidence in well and poorly differentiated cancer. Plausible reasons for this phenomenon include the decrease in transurethral resections performed and an increase in the number of prostate specific antigen triggered ultrasound guided needle biopsies. We examined additional explanations for the grade shift with time and addresses the impact of this grade shift on clinical end points. MATERIALS AND METHODS: Archived slides from 100 patients (82 needle biopsy specimens and 18 transurethral resection specimens) treated for prostate cancer between 1975 and 1985 were reexamined. Current grades were assigned using the WHO and the Gleason grading systems, and they were compared with the original grade assignments. Current Gleason score was translated to WHO grade by operational SEER criteria (2 to 4-well, 5 to 7-moderately and 8 to 10-poorly differentiated). Analysis of the 100 specimens by life table methodology calculated cancer specific survival according to the era of grade assignment. RESULTS: There was significant upward grade migration from the historic to the current WHO grade and from the translation by SEER methodology of the current Gleason score to WHO grade (p <0.0001). Interpretive and chronological bias caused expansion of the moderately differentiated category at the expense of well differentiated cancer and significant deviation in cancer specific survival curves (p <0.013). SEER translation bias resulted in expansion of the moderately differentiated grade category at the expense of poorly differentiated cancer and eliminated the significant difference in cancer specific survival between Gleason 5/6 and 7 (p <0.006). CONCLUSIONS: Contemporary understanding of Gleason grading has lowered the threshold for assignment to higher grade. While a change in tumor biology may be partially responsible for the trend toward higher grade assignment, grade migration as described is also a significant contributing factor in reported histological trends for newly diagnosed prostate cancer and it significantly compromises efforts at historical comparisons.

Bias↗
PubMed2003

Data reduction using a discrete wavelet transform in discriminant analysis of very high dimensionality data.

We present a method of data reduction using a wavelet transform in discriminant analysis when the number of variables is much greater than the number of observations. The method is illustrated with a prostate cancer study, where the sample size is 248, and the number of variables is 48,538 (generated using the ProteinChip technology). Using a discrete wavelet transform, the 48,538 data points are represented by 1271 wavelet coefficients. Information criteria identified 11 of the 1271 wavelet coefficients with the highest discriminatory power. The linear classifier with the 11 wavelet coefficients detected prostate cancer in a separate test set with a sensitivity of 97% and specificity of 100%.

Data Compression↗
PubMed2002

Serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men.

The prostate-specific antigen test has been a major factor in increasing awareness and better patient management of prostate cancer (PCA), but its lack of specificity limits its use in diagnosis and makes for poor early detection of PCA. The objective of our studies is to identify better biomarkers for early detection of PCA using protein profiling technologies that can simultaneously resolve and analyze multiple proteins. Evaluating multiple proteins will be essential to establishing signature proteomic patterns that distinguish cancer from noncancer as well as identify all genetic subtypes of the cancer and their biological activity. In this study, we used a protein biochip surface enhanced laser desorption/ionization mass spectrometry approach coupled with an artificial intelligence learning algorithm to differentiate PCA from noncancer cohorts. Surface enhanced laser desorption/ionization mass spectrometry protein profiles of serum from 167 PCA patients, 77 patients with benign prostate hyperplasia, and 82 age-matched unaffected healthy men were used to train and develop a decision tree classification algorithm that used a nine-protein mass pattern that correctly classified 96% of the samples. A blinded test set, separated from the training set by a stratified random sampling before the analysis, was used to determine the sensitivity and specificity of the classification system. A sensitivity of 83%, a specificity of 97%, and a positive predictive value of 96% for the study population and 91% for the general population were obtained when comparing the PCA versus noncancer (benign prostate hyperplasia/healthy men) groups. This high-throughput proteomic classification system will provide a highly accurate and innovative approach for the early detection/diagnosis of PCA.

Aged↗
PubMed2002

Superficial bladder carcinoma treated with bacillus Calmette-Guerin: progression-free and disease specific survival with minimum 10-year followup.

PURPOSE: Intravesical bacillus Calmette-Guerin (BCG) treatment of high risk superficial bladder cancer has reduced recurrence and progression, and lengthened disease specific survival. However, documentation of treatment durability is limited. MATERIALS AND METHODS: Between 1981 and 1989, 98 patients with high risk or recurrent transitional cell carcinoma were treated with complete transurethral resection followed by 1 or more 6-week induction courses of BCG, and were followed through 2000. No maintenance regimen was used. A total of 44 cases were carcinoma in situ plus or minus papillary and 35 were stage T1, which was assigned only if muscularis propria free of tumor was present on the biopsy specimen. RESULTS: Of 98 patients with minimum followup greater than 10 years disease progressed to stage T2 or greater in 27 at a median of 30.7 months (range 1.2 to 143.7), of whom cystectomy was performed in 16, cystectomy for recurrent high risk Ta/T1 disease was required in 10, death from transitional cell carcinoma occurred in 13 at a median of 69.7 months (range 11 to 135), upper tract tumor developed in 13 at a median of 49 months (range 9 to 146) and there was evidence of prostatic urethral involvement in 21. The 10-year progression-free survival was 67%, and progression-free survival with a retained bladder 59%. The total cystectomy rate was 26%, permitting a number of patients to be rendered disease-free. The 10-year disease specific survival was 85%. CONCLUSIONS: After complete tumor resection and careful pathological staging intravesical BCG for high risk and/or recurrent superficial bladder carcinoma resulted in overall progression-free and disease specific survival rates that support this bladder sparing strategy. Patients must be followed closely and cystectomy recommended for those with an initial incomplete response after initial therapy or recurrent high risk disease.

Aged↗
PubMed2002

An evaluation of bicalutamide in the treatment of prostate cancer.

Prostate cancer is a major health problem in men, causing significant morbidity and mortality. Although traditionally considered a disease of old age, improved diagnostic techniques have resulted in earlier diagnosis and many men are now treated while still physically and sexually active. Current therapies for prostate cancer, which include medical or surgical castration, have a significant impact on many aspects of quality of life. The non-steroidal antiandrogen bicalutamide (Casodex, AstraZeneca) has a favourable tolerability profile with demonstrated efficacy in several stages of prostate cancer and represents an alternative therapeutic strategy to castration. Mature survival data from men with previously untreated, locally-advanced disease reveal that bicalutamide monotherapy provides survival benefits that do not differ significantly from castration, while offering important advantages with respect to the maintenance of physical capacity and sexual interest. Recent data from a prospective randomised trial, the largest prostate cancer treatment study ever conducted, demonstrate that immediate therapy with bicalutamide (alone or as an adjuvant to therapy of curative intent) significantly reduces the risk of objective disease progression in patients with localised or locally-advanced prostate cancer. Antiandrogens are also used in combination with castration (combined androgen blockade) for advanced disease. Another large, randomised trial demonstrated that combined androgen blockade with bicalutamide is associated with a similar survival outcome to combined androgen blockade with flutamide and is better tolerated. The evidence reviewed demonstrates that bicalutamide currently has a favourable risk:benefit ratio in several stages of prostate cancer. The role of bicalutamide will be further defined by ongoing studies.

Anilides↗
PubMed2002

The pursuit of prostate cancer in patients with a rising prostate-specific antigen and multiple negative transrectal ultrasound-guided prostate biopsies.

To determine if patients with persistently elevated prostate-specific antigen (PSA) levels who have had transrectal ultrasound (TRUS)-guided prostate biopsies negative for carcinoma will benefit from additional saturation (> or =14 cores) TRUS biopsies with or without transurethral (TUR) biopsies. A retrospective review of 35 men between ages 51-74 with PSA values between 4.5-46 ng/mL, normal digital rectal examinations, and > or =2 previously negative sextant TRUS biopsies. Seventeen patients had TUR biopsies in addition to saturation TRUS biopsies. Eighteen patients had saturation TRUS biopsies only (median 20 cores). Seven patients who had no cancer detected with the combined TRUS/TUR biopsies had an additional saturation biopsy performed (median 20 cores). Seven (20%) of the 35 patients who had a saturation biopsy had cancer detected, and one (5.9%) cancer was detected in the 17 men that had a TUR biopsy. Five (71.4%) of the seven patients who had an additional TRUS biopsy had cancer detected (total core range 45-60). The overall yield of prostate cancer was therefore 37.1%, with 1-9 cores positive (median 5 cores). For patients with a rising PSA and > or =2 negative sextant TRUS biopsies, the cancer yield of the initial saturation TRUS biopsies was 20%. Furthermore, a significant proportion of patients with negative initial saturation biopsies had cancer detected on repeat TRUS biopsy. The cancer yield of adding TUR biopsies in this same group of patients is < 6.

Aged↗
PubMed2002

Normal, benign, preneoplastic, and malignant prostate cells have distinct protein expression profiles resolved by surface enhanced laser desorption/ionization mass spectrometry.

PURPOSE: The objective of this study was to discover protein biomarkers that differentiate malignant from nonmalignant cell populations, especially early protein alterations that signal the initiation of a developing cancer. We hypothesized that Surface Enhanced Laser Desorption/Ionization-time of flight-mass spectrometry-assisted protein profiling could detect these protein alterations. EXPERIMENTAL DESIGN: Epithelial cell populations [benign prostatic hyperplasia (BPH), prostate intraepithelial neoplasia (PIN), and prostate cancer (PCA)] were procured from nine prostatectomy specimens using laser capture microdissection. Surface Enhanced Laser Desorption/Ionization-time of flight-mass spectrometry analysis was performed on cell lysates, and the relative intensity levels of each protein or peptide in the mass spectra was calculated and compared for each cell type. RESULTS: Several small molecular mass peptides or proteins (3000-5000 Da) were found in greater abundance in PIN and PCA cell lysates. Another peak, with an average mass of 5666 Da, was observed to be up-regulated in 86% of the BPH cell lysates. Higher levels of this same peak were found in only 22% of the PIN lysates and none of the PCA lysates. Expression differences were also found for intracellular levels of prostate-specific antigen, which were reduced in PIN and PCA cells when compared with matched normals. Although no single protein alteration was observed in all PIN/PCA samples, combining two or more of the markers was effective in distinguishing the benign cell types (normal/BPH) from diseased cell types (PIN/PCA). Logistic regression analysis using seven differentially expressed proteins resulted in a predictive equation that correctly distinguished the diseased lysates with a sensitivity and specificity of 93.3 and 93.8%, respectively. CONCLUSIONS: We have shown that the protein profiles from prostate cells with different disease states have discriminating differences. These differentially regulated proteins are potential markers for early detection and/or risk factors for development of prostate cancer. Studies are under way to identify these protein/peptides, with the goal of developing a diagnostic test for the early detection of prostate cancer.

Adult↗
PubMed2002

Boosted decision tree analysis of surface-enhanced laser desorption/ionization mass spectral serum profiles discriminates prostate cancer from noncancer patients.

BACKGROUND: The low specificity of the prostate-specific antigen (PSA) test makes it a poor biomarker for early detection of prostate cancer (PCA). Because single biomarkers most likely will not be found that are expressed by all genetic forms of PCA, we evaluated and developed a proteomic approach for the simultaneous detection and analysis of multiple proteins for the differentiation of PCA from noncancer patients. METHODS: Serum samples from 386 men [197 with PCA, 92 with benign prostatic hyperplasia (BPH), and 96 healthy individuals], randomly divided into training (n = 326) and test (n = 60) sets, were analyzed by surface-enhanced laser desorption/ionization (SELDI) mass spectrometry. The 124 peaks detected by computer analyses were analyzed in the training set by a boosting tree algorithm to develop a classifier for separating PCA from the noncancer groups. The classifier was then challenged with the test set (30 PCA samples, 15 BPH samples, 15 samples from healthy men) to determine the validity and accuracy of the classification system. RESULTS: Two classifiers were developed. The AdaBoost classifier completely separated the PCA from the noncancer samples, achieving 100% sensitivity and specificity. The second classifier, the Boosted Decision Stump Feature Selection classifier, was easier to interpret and used only 21 (compared with 74) peaks and a combination of 21 (vs 500) base classifiers to achieve a sensitivity and specificity of 97% for the test set. CONCLUSIONS: The high sensitivity and specificity achieved in this study provides support of the potential for SELDI, coupled with a bioinformatics learning algorithm, to improve the early detection/diagnosis of PCA.

Algorithms↗
PubMedDate not supplied

A phase II clinical trial of oral bropirimine in combination with intravesical bacillus Calmette-Guérin for carcinoma in situ of the bladder: a Southwest Oncology Group Study.

OBJECTIVES: To estimate the probability of response when intravesical bacille Calmette-Guérin (BCG) is given in combination with oral bropirimine for bladder carcinoma in situ, and to evaluate toxicity when the 2 agents are combined. METHODS: A total of 51 patients with histologic evidence of carcinoma in situ and no prior treatment with BCG or bropirimine were enrolled in a cooperative group multicenter phase II trial. Initial treatment included Tice BCG 50 mg weekly for 6 weeks and oral bropirimine 3.0 g/day for 3 consecutive days each week for 12 weeks. Response was assessed after 12 weeks by cystoscopy, biopsy, and barbotage cytology. Most patients received a second course followed by an identical assessment. Toxicity was recorded according to the Southwest Oncology Group toxicity criteria. RESULTS: A total of 51 patients were enrolled and treated. There were 42 patients who were eligible and valuable for response and toxicity. There were 28 complete responders (67%, 50% to 80% 95% confidence interval). The 5-year progression-free survival estimate is 53%, and the 5-year survival estimate is 80%. There were no deaths, 2 patients had grade 4 toxicity, 14 grade 3 toxicity, 17 grade 2 toxicity, 6 grade 1 toxicity, and only 3 had no toxicity reported as their worst toxicity grade. CONCLUSIONS: The combination failed to show an estimated response higher than 80%. It is not recommended that further evaluation of this combination be conducted.

Aged↗
PubMedDate not supplied

Overexpression of alpha-defensin is associated with bladder cancer invasiveness.

Alpha-defensin (alpha-defensin) has been identified as a potential marker for bladder cancer in urine by surface enhanced laser desorption ionization studies, and confirmed using both immunoabsorption and immunodepletion studies. The objective of this study was to investigate the role of alpha-defensin in bladder cancer. Immunohistochemical analysis of tissue sections showed that alpha-defensin peptides are frequently expressed in bladder cancer cells. It is noteworthy that expression of alpha-defensins increased with tumor invasiveness. Surface enhanced laser desorption ionization analysis showed the presence of alpha-defensin in the T24 and A498 cancer cell lines. These cell lines show higher classically aggressive in vitro characteristics compared with the J82 cells that did not express alpha-defensin. Exogenously added alpha-defensin increased the proliferation and motility/invasiveness of these cell lines using respective assays. It is interesting that alpha-defensin peptides increased intracellular calcium ions (Ca2+). These data are consistent with a role for alpha-defensin in bladder cancer via modulation of cell motility and invasiveness using common intracellular signals, such as Ca2+. We propose that autocrine tumor expression of alpha-defensins may play an important role in facilitating the invasive phenotype of bladder cancer in patients.

Carcinoma, Transitional Cell↗
PubMedDate not supplied

Sural nerve graft during laparoscopic radical prostatectomy. Initial experience.

OBJECTIVE: To determine the technical feasibility of sural nerve grafting for restoration of cavernous nerve continuity after radical retropubic prostatectomy by the laparoscopic approach. MATERIALS AND METHODS: 15 potent men (mean age: 56+/-4 years) underwent laparoscopic radical prostatectomy with deliberate wide uni- or bilateral neurovascular bundle resection. After prostatectomy, but before the vesicourethral anastomosis, an autologous sural nerve graft was interposed between the divided end of the cavernous nerves using a laparoscopic approach. RESULTS: All 15 procedures could be completed laparoscopically. Visual cooptation between the nerve graft and the cut ends of the neurovascular bundles was possible in all 15 cases. Surgical time for the entire procedure ranged between 210 to 275 min with 30 to 60 min of this time required for the nerve harvest and graft. CONCLUSION: This experience demonstrates that sural nerve graft replacement is technically feasible by the laparoscopic approach. The magnified optics, bloodless surgical field, and improved instrumentation create an optimal environment for sural nerve grafting to the cut ends of the neurovascular bundles. Quality of life survey data at 12 to 18 month follow-up will be needed to assess functional return.

Feasibility Studies↗
PubMedDate not supplied

Prostate tumor microenvironment alters immune cells and prevents long-term survival in an orthotopic mouse model following flt3-ligand/CD40-ligand immunotherapy.

A novel orthotopic metastatic model of mouse prostate cancer was developed using MHC-negative TRAMP-C1P3 (transgenic adenocarcinoma of mouse prostate) cells derived by serial passage of the parental TRAMP-C1 line in mouse prostate glands. TRAMP-C1P3 cells grew efficiently in mouse prostate glands and reproducibly metastasized to draining lymph nodes. Using this model, we show that Fms-like tyrosine kinase-3 ligand (flt3-L) dramatically inhibited growth of preexisting orthotopic TRAMP-C1P3 tumors and the development of metastatic disease. Mice remained in remission for several months following termination of flt3-L treatment but eventually relapsed and died of progressive disease. flt3-ligand treatment induced a pronounced mixed inflammatory cell infiltrate that consisted of CD8alpha-CD4- dendritic cells (CD11c+), macrophages, granulocytes (Gr-1+) and to a lesser extent T cells (CD4+ and CD8+). Dendritic cells isolated from TRAMP-C1P3 tumors were phenotypically immature (CD11c+ B7.2-I-A-CD40-), and this phenotype was also predominant in peripheral organs of mice treated with flt3-L alone or in combination with the DC maturation factor, CD40-L. Diminished expression of TCR-beta, CD3-epsilon, and CD3-zeta was also observed on intratumoral T cells, although these signaling proteins were reexpressed following in vitro culture with IL-2. The TCR/CD3 complex remained intact on peripheral T cells except in mice treated with flt3-L where CD3-zeta loss was observed. In contrast to alphabeta-T cells, tumor-infiltrating gammadelta-T cells maintained expression of their antigen receptors but not CD3epsilon. Thus, TRAMP-C1P3 tumors quickly establish a microenvironment that profoundly diminishes expression of molecules critical for normal dendritic cell and T cell function, thus limiting the efficacy of flt3-L and CD40-L immunotherapy. Overall, these data suggest that long-term cures of established MHC-negative tumors may not be achieved until therapeutic interventions are engineered to overcome this immunosuppressive microenvironment.

Animals↗