Faculty Publications

BACKGROUND: The growth kinetics of untreated solid organ malignancies are not defined. Radiographic active surveillance (AS) of renal tumors in patients unfit or unwilling to undergo intervention provides an opportunity to quantify the natural history of untreated localized tumors. The authors report the radiographic growth kinetics of renal neoplasms during a period of surveillance. METHODS: The authors identified patients with enhancing renal masses who were radiographically observed for at least 12 months. Clinical and pathological records were reviewed to determine tumor growth kinetics and clinical outcomes. Tumor growth kinetics were expressed in terms of absolute and relative linear and volumetric growth. RESULTS: The authors identified 172 renal tumors in 154 patients under AS. Median tumor diameter and volume on presentation were 2.0 cm (mean, 2.5; range, 0.4-12.0) and 4.18 cm(3) (mean, 20.0; range, 0.033-904). Median duration of follow-up was 24 months (mean, 31; range, 12-156). A significant association between presenting tumor size and proportional growth was noted, with smaller tumors growing faster than larger tumors. Thirty-nine percent (68 of 173) of tumors underwent delayed intervention, and 84% (57 of 68) were pathologically malignant. Progression to metastatic disease was noted in 1.3% (2 of 154) of patients. CONCLUSIONS: The authors demonstrated the association between a tumor's volume and subsequent growth, with smaller tumors exhibiting significantly faster volumetric growth than larger tumors, consistent with Gompertzian kinetics. Surveillance of localized renal tumors is associated with a low rate of disease progression in the intermediate term, and suggests potential overtreatment biases in select patients. Cancer 2009;115:2844-52. (C) 2009 American Cancer Society.

Objective: To assess the safety and effectiveness of AD32, a doxorubicin analogue with little systemic exposure when administered intravesically, in patients with recurrent or refractory superficial urothelial carcinoma (formerly called transitional cell carcinoma [TCC]), or carcinoma in situ (CIS), who have failed prior BCG-based immunotherapy. Methods: Eligible patients received six weekly doses (800 mg) of intravesical AD32 and Were evaluated at 12-week intervals for 24 months or until date of worsening disease. Primary analysis was the proportion of all patients recurrence-free at 12 months. Treatment-related and GU-specific toxicities were also examined. AM participating institutions submitted the protocol for Institutional Review Board (IRB) approval. Results: The study was halted due to unavailability of study drug after accrual of 48 of a planned 64 patients; 42 were included in the analysis. Of these, 28 (67%) were still alive after median follow-up of 61.1 months. Of 21 TCC patients, 18 (85.7%) experienced disease recurrence (median time to recurrence, 5.3 months). Of the 5 CIS patients with complete response (CR), 3 (60%) experienced disease recurrence; (median time to recurrence, 37.3 months). Recurrence-free rates at 12 and 24 months were 20% (90% Cl, 7.8%, 36.1%) and 15% (90 Cl, 4.9% 30.2%), respectively, for patients with TCC and 80% (90% Cl, 31.4%, 95.8%) at both intervals for CIS patients with CR. Infection was the most common treatment-related toxicity; no grade 4 or higher toxicity was observed. The most common GU-specific toxicity was increased frequency/urgency. Conclusions: AD32 is safe and active for treatment of recurrent or refractory superficial bladder carcinoma. The agent awaits more complete characterization when drug production problems can be solved. (C) 2009 Elsevier Inc. All rights reserved.

Objectives: The natural history and growth rates of untreated solid enhancing renal tumors is being defined through active surveillance series. Serial radiographic evaluation of patients who are not surgical candidates or refuse surgical treatment provides an opportunity to characterize the growth of untreated enhancing renal tumors. Here we evaluate factors that may help predict radiographic growth during observation. Materials and methods: We reviewed our renal cancer database for enhancing renal masses that were radiographically observed for a period of at least 12 months. Variables examined included patient age, gender, lesion size on presentation, radiographic tumor characteristics, duration of active surveillance linear growth rate, surgical pathology, development of new renal tumors, and stage progression. Results: One hundred nine patients with 124 sporadic enhancing renal tumors were identified undergoing a period of active surveillance of at least 12 months. Median patient age was 73 years (mean 69.8. range 35-87)-72% (78/109) of patients were males. Median duration of active surveillance was 26 months (mean 33.4, range 12-156). Multifocal disease was present in 9% (10/109) of patients on presentation, accounting for 20% (25/124) of all tumors. Tumor size on presentation was a median of 2.0 cm (mean 2.61, range 0.4-12.0). Overall median tumor growth rate was 0.21 cm/y (mean 0.28. range 1.4-2.47). Observed linear growth rates were independent of patient age, gender, tumor size on presentation. multifocality, and radiographic characteristics (solid versus cystic), P > 0.05. Of the patients initiating a period of active surveillance 36% (39/109) eventually underwent definitive therapy. Malignant pathology was present in 90% (35/39) of patients 0 undergoing treatment. In patients continuing active Surveillance [64% (70/109)], 2.9% (2/70) developed de novo renal lesions and 1.4% (1/70) developed metastatic disease. Conclusions: Currently, no clinical predictors Of tumor growth or disease progression have been identified, although. the risk of developing progressive disease over the short term appears low. Clinical and molecular markers of disease progression are needed prior to offering active surveillance to otherwise acceptable surgical candidates. (C) 2008 Elsevier Inc. All rights reserved.

OBJECTIVES: The natural history and growth rates of untreated solid enhancing renal tumors is being defined through active surveillance series. Serial radiographic evaluation of patients who are not surgical candidates or refuse surgical treatment provides an opportunity to characterize the growth of untreated enhancing renal tumors. Here we evaluate factors that may help predict radiographic growth during observation. MATERIALS AND METHODS: We reviewed our renal cancer database for enhancing renal masses that were radiographically observed for a period of at least 12 months. Variables examined included patient age, gender, lesion size on presentation, radiographic tumor characteristics, duration of active surveillance, linear growth rate, surgical pathology, development of new renal tumors, and stage progression. RESULTS: One hundred nine patients with 124 sporadic enhancing renal tumors were identified undergoing a period of active surveillance of at least 12 months. Median patient age was 73 years (mean 69.8, range 35-87); 72% (78/109) of patients were males. Median duration of active surveillance was 26 months (mean 33.4, range 12-156). Multifocal disease was present in 9% (10/109) of patients on presentation, accounting for 20% (25/124) of all tumors. Tumor size on presentation was a median of 2.0 cm (mean 2.61, range 0.4-12.0). Overall median tumor growth rate was 0.21 cm/y (mean 0.28, range 1.4-2.47). Observed linear growth rates were independent of patient age, gender, tumor size on presentation, multifocality, and radiographic characteristics (solid versus cystic), P > 0.05. Of the patients initiating a period of active surveillance 36% (39/109) eventually underwent definitive therapy. Malignant pathology was present in 90% (35/39) of patients undergoing treatment. In patients continuing active surveillance [64% (70/109)], 2.9% (2/70) developed de novo renal lesions and 1.4% (1/70) developed metastatic disease. CONCLUSIONS: Currently, no clinical predictors of tumor growth or disease progression have been identified, although, the risk of developing progressive disease over the short term appears low. Clinical and molecular markers of disease progression are needed prior to offering active surveillance to otherwise acceptable surgical candidates.

OBJECTIVES: The incidence of histologic prostate cancer (CaP) after definitive radiation therapy (RT) for localized disease is rarely quantitated. We investigated the relationship between prostate-specific antigen (PSA) and histologically residual CaP after definitive RT in patients undergoing radical cystoprostatectomy (RCP) for unrelated indications. METHODS: We reviewed our prostate cancer database to identify patients undergoing RCP who previously received definitive RT for localized CaP. Pre-radiation variables examined include PSA, Gleason score, radiation modality, and dose. Post-radiation variables reviewed include PSA, time to RCP, the presence of histologically proven prostate cancer, and Gleason score. RESULTS: We identified 21 patients who underwent RCP at a median of 60 months after RT for localized CaP. Pre-radiation Gleason scores were low (6 or less) to intermediate risk (3+4) in 82% (14 of 17), intermediate (4+3) to high (8 or greater) in 18% (3 of 17), and unavailable in 4 patients. Median pre-radiation PSA was 9 ng/mL. Median PSA before RCP in all patients was 0.8 ng/mL. A total of 52% (11 of 21) of patients demonstrated active CaP in the RCP specimen. Although 89% (16 of 18) of patients met the Phoenix definition of biochemical freedom from disease, 50% (8 of 16) of these patients had histologically residual CaP at the time of RCP. Median PSA was not significantly different between patients with and without active CaP. CONCLUSIONS: Histologic evidence of CaP was noted in 50% of patients demonstrating biochemical freedom from disease at the time of RCP. Although the biological significance of active CaP in this select population is uncertain, our findings demonstrate the limitations of PSA in monitoring CaP disease activity after definitive RT.

OBJECTIVES The incidence of histologic prostate cancer (CaP) after definitive radiation therapy (RT) for localized disease is rarely quantitated. We investigated the relationship between prostate-specific antigen (PSA) and histologically residual CaP after definitive RT in patients undergoing radical cystoprostatectomy (RCP) for unrelated indications. METHODS We reviewed our prostate cancer database to identify patients undergoing RCP who previously received definitive RT for localized CaP. Pre-radiation variables examined include PSA, Gleason score, radiation modality, and dose. Post-radiation variables reviewed include PSA, time to RCP, the presence of histologically proven prostate cancer, and Gleason score. RESULTS We identified 21 patients who underwent RCP at a median of 60 months after RT for localized CaP. Pre-radiation Gleason scores were low (6 or less) to intermediate risk (3+4) in 82% (14 of 17), intermediate (4+3) to high (8 or greater) in 18% (3 of 17), and unavailable in 4 patients. Median pre-radiation PSA was 9 ng/mL. Median PSA before RCP in all patients was 0.8 ng/mL. A total of 52% (11 of 21) of patients demonstrated active CaP in the RCP specimen. Although 89% (16 of 18) of patients met the Phoenix definition of biochemical freedom from disease, 50% (8 of 16) of these patients had histologically residual CaP at the time of RCP. Median PSA was not significantly different between patients with and without active CaP. CONCLUSIONS Histologic evidence of CaP was noted in 50% of patients demonstrating biochemical freedom from disease at the time of RCP. Although the biological significance of active CaP in this select population is uncertain, our findings demonstrate the limitations of PSA in monitoring CaP disease activity after definitive RT.

BACKGROUND: NF-kappaB and AP-1 transcriptional factors contribute to the development and progression of prostate malignancy by regulating the expression of genes involved in proliferation, apoptosis, angiogenesis, and metastasis. METHODS: NF-kappaB and AP-1 activities were examined by TransAm assay. Cytokines levels were assessed by ELISA. ICAM-1 and gp130 expression was examined by flow cytometry. Cell adhesion was examined by the ability of cells to adhere to fibronectin-coated plates. Cell viability was determined by propidium iodide staining. RESULTS: Treatment with alpha-tocopherol succinate (VES) inhibits NF-kappaB but augments AP-1 activity, reduces expression of IL-6, IL-8, and VEGF, suppresses cell adhesion, ICAM-1 and gp130 expression in androgen-independent PC-3, DU-145, and CA-HPV-10 cells. VES supplementation also decreases the expression of anti-apoptotic XIAP and Bcl-X(L) proteins and sensitizes androgen-dependent LNCaP cells to androgen deprivation. CONCLUSIONS: Our findings propose a potential mechanism of VES-mediated anti-tumor activity and support the role of vitamin E analogs as potential chemopreventative agents against prostate cancer. (c) 2007 Wiley-Liss, Inc.

Purpose: The natural history of small renal masses is generally to slowly increase in size. However, a subset of lesions does not show radiographic growth. We compared clinical, radiographic and pathological characteristics of enhancing renal masses under active surveillance with zero net radiographic growth vs those with positive growth. Materials and Methods: We identified 106 enhancing renal masses that were observed for 12 months or greater. Lesions were grouped according to growth characteristics. Group 1 consisted of lesions demonstrating zero or negative growth. Group 2 tumors showed positive growth during surveillance. Clinical, radiographic and pathological parameters were then compared. A MEDLINE (R) search was performed regarding zero growth lesions during observation for suspected renal cell carcinoma in the world literature. Results: Group 1 consisted of 35 lesions (33%) with a median growth rate of 0.0 cm yearly. Group 2 included 70 lesions (67%) showing growth at 0.31 cm yearly (p < 0.0001). No differences were detected with regard to patient age (p = 0.96), lesion size (p = 0.41), solid/cystic appearance (p = 1.00) or the incidental detection rate (p 0.38). While 17% of group 1 lesions (6 of 35) underwent intervention, 51% (36 of 71) in group 2 were ultimately treated (p = 0.001). Pathological assessment showed a similar incidence of malignancy in groups 1 and 2 (83% and 89%, respectively, p = 0.56). A literature review revealed that 78 of 295 observed lesions (26%) failed to demonstrate radiographic growth. Conclusions: We were unable to identify definable clinical characteristics to predict the future growth of enhancing renal masses under active surveillance. Our analysis demonstrated that 26% to 33% of these tumors do not demonstrate growth at 29 months median follow up. These lesions have similar rates of malignancy compared to growing lesions and rates of progression to metastatic disease are similarly low. A brief period of active surveillance may be feasible with treatment limited to lesions that increase in size.

Purpose: The alpha/beta ratio for prostate cancer is postulated to be between 1 and 3, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. The dosimetry and acute toxicity are described in the first 100 men enrolled in a randomized trial. Patients and Methods: The trial compares 76 Gy in 38 fractions (Arm 1) to 70.2 Gy in 26 fractions (Arm II) using intensity modulated radiotherapy. The planning target volume (PTV) margins in Arms I and 11 were 5 mm and 3 mm posteriorly and 8 mm and 7 mm in all other dimensions. The PTV D95% was at least the prescription dose. Results: The mean PTV doses for Arms I and II were 81.1 and 73.8 Gy. There were no differences in overall maximum acute gastrointestinal (GI) or genitourinary (GU) toxicity acutely. However, there was a slight but significant increase in Arm II GI toxicity during Weeks 2, 3, and 4. In multivariate analyses, only the combined rectal DVH parameter of V65 Gy/V50 Gy was significant for GI toxicity and the bladder volume for GU toxicity. Conclusion: Hypofractionation at 2.7 Gy per fraction to 70.2 Gy was well tolerated acutely using the planning conditions described. (C) 2006 Elsevier Inc.

This study examined the efficacy of a couple-focused group intervention on psychological adaptation of women with early stage breast cancer and evaluated whether perceived partner unsupportive behavior or patient functional impairment moderated intervention effects. Two hundred thirty-eight women were randomly assigned to receive either 6 sessions of a couple-focused group intervention or usual care. Intent-to-treat growth curve analyses indicated that participants assigned to the couples' group reported lower depressive symptoms. Women rating their partners as more unsupportive benefited more from the intervention than did women with less unsupportive partners, and women with more physical impairment benefited more from the intervention group than did women with less impairment. Subgroup analyses comparing women attending the couple-focused group intervention with women not attending groups and with usual care participants indicated that women attending sessions reported significantly less distress than did women receiving usual care and women who dropped out of the intervention. ((c) 2005 APA, all rights reserved). PURPOSE: To compare several characteristics of alternative definitions of biochemical failure (BF) in men with extended follow-up after radiotherapy (RT) with or with androgen deprivation therapy (ADT) for prostate cancer. METHODS AND MATERIALS: From December 1, 1991, to April 30, 1998, 688 men with Stage T1c-T3NX-N0M0 prostate cancer received RT alone (n = 586) or RT plus ADT (n = 102) with a minimal follow-up of 4 years and five or more "ADT-free" posttreatment prostate-specific antigen levels. BF was defined by three methods: (1) the ASTRO definition (three consecutive rises in prostate-specific antigen level); (2) a modified American Society for Therapeutic Radiology Oncology (ASTRO) definition requiring two additional consecutive rises when a decline immediately subsequent to three consecutive rises occurred; and (3) the "Houston" or nadir plus 2-ng/mL definition (a rise of at least 2 ng/mL greater than the nadir). The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were determined for each using clinical progression as the endpoint. Furthermore, the misclassification rates for a steadily rising prostate-specific antigen level, ability to satisfy the proportional hazards (RT with or without ADT), effects of short follow-up, and intervals to the diagnosis of BF were compared. RESULTS: The misclassification rate for BF using the nadir plus 2-ng/mL definition was 2% for RT alone and 0% for RT plus ADT compared with 0% and 0% for the modified ASTRO definition, and 5% and 23% for the ASTRO definition, respectively. The hazard rates for RT alone and RT plus ADT were proportional only for the nadir plus 2 ng/mL definition and seemingly unaffected by the length of follow-up. For RT with or without ADT, the nadir plus 2 ng/mL definition was the most specific (RT, 80% vs. RT plus ADT, 75%) with the greatest positive predictive value (RT, 36% vs. RT plus ADT, 25%) and overall accuracy (RT, 81% vs. RT plus ADT, 77%). A greater proportion of BF was diagnosed in the first 2 years of follow-up with the nadir plus 2 ng/mL definition compared with the ASTRO definition (13% vs. 5%, p = 0.0138, chi-square test). CONCLUSION: The nadir plus 2 ng/mL definition was the best predictor of sustained, true, biochemical, and clinical failure, and was not affected by the use of ADT or follow-up length. Clinical experience has resulted in the identification of a relatively small number of absolute contraindications to breast-conserving therapy (BCT). These contraindications are readily identified by a clinical evaluation and diagnostic mammography. Local failure rates of less than 10% at 10 years support the idea that patients can be reliably selected for BCT with standard clinical modalities. The availability of magnetic resonance (MR) imaging has raised questions about its role in patient selection for BCT. MR imaging identifies additional cancer in 10-54% of patients with apparently localized disease, resulting in mastectomies that would not otherwise have been done. Clinical experience suggests that the majority of this disease is controlled by radiotherapy. Studies demonstrating clinical benefit in terms of decreased rates of local recurrence or fewer surgeries are needed before MR is used for routine selection of patients for BCT. It is well known that the biological and carcinogenic effects of 17beta-estradiol (E(2)) are mediated via nuclear estrogen receptors (ERs) by regulating nuclear gene expression. Several rapid, non-nuclear genomic effects of E(2) are mediated via plasma membrane-bound ERs. In addition, there is accumulating evidence suggesting that mitochondria are also important targets for the action of estrogens and ERs. This review summarized the studies on the effects of estrogens via ERs on mitochondrial structure and function. The potential physiological and pathophysiological implications of deficiency and/or overabundance of these E(2)/ER-mediated mitochondrial effects in stimulation of cell proliferation, inhibition of apoptosis, E(2)-mediated cardiovascular and neuroprotective effects in target cells are also discussed. Proprotein convertases (PCs) are a group of Ca(2+)-dependent serine proteases that have homology to the endoproteases subtilisin (bacteria) and kexin (yeast). This group is comprised of less than a dozen members, known as furin/PACE, PC1/PC3, PC2, PC4, PACE4, PC5/PC6, PC7/PC8/LPC, SKI/S1P, and NARC-1/PCSK9. Four PCs (Furin, PACE4, PC5, and PC7) have been localized to several different tissues and epithelial or nervous system tumors. PCs activate their cognate substrates by limited proteolysis at the consensus sequence RXR/KR downward arrow. Many PC substrates are well known cancer-associated proteins such as growth factors, growth factor receptors, integrins, and matrix metalloproteases (MMPs). For example, IGF-1 and its receptor, TGF-beta, VEGF-C, and MT-MMPs have direct roles in tumor progression and metastasis. Furin, a well-studied member of the PC family, has been associated with enhanced invasion and proliferation in head and neck, breast, and lung cancer. Conversely, inhibition of PC activity by PDX or several PC pro-segments, resulted in reduced processing of these key cancer-related substrates in human squamous cell carcinomas (SCC), colon adenocarcinoma, and astrocytoma cell lines. In parallel to these changes in cell proliferation and invasiveness as well as metastatic ability were markedly impaired. By controlling the maturation/activation of key cancer-associated proteins, PCs act as "master switches" at different levels during tumor development and progression. The manifold effects of PCs, influencing tumor cell proliferation, motility, adhesiveness, and invasiveness, should be exploited by further developing competitive/inhibitory therapeutic strategies that would be able to neutralize simultaneously the most salient cancer cell properties. (c) 2005 Wiley-Liss, Inc. Squamous cell cancer of the head and neck is a debilitating disease. Combined modality treatments with surgery, chemotherapy, and radiation have been evaluated in multiple settings over the past 30 years. While surgery and radiation remain the potentially curative modalities, the addition of chemotherapy can in some cases decrease the rate of distant metastasis. When concurrent chemoradiation is employed, overall survival is improved, although toxicity can be higher. Studies have also shown a role for concurrent treatment in an effort to avoid total laryngectomy and preserve organ function. Multidisciplinary evaluation should be a routine part of care in this patient population. Future areas of research include the epidermal growth factor inhibitors, which have shown promise in early studies. Malignant mesothelioma has been linked to asbestos exposure and generally has a poor prognosis because it is often diagnosed in advanced stages and is refractory to conventional therapy. Human malignant mesotheliomas accumulate multiple somatic genetic alterations, including inactivation of the NF2 and CDKN2A/ARF tumor suppressor genes. To better understand the significance of NF2 inactivation in malignant mesothelioma and identify tumor suppressor gene alterations that cooperate with NF2 loss of function in malignant mesothelioma pathogenesis, we treated Nf2 (+/-) knockout mice with asbestos to induce malignant mesotheliomas. Asbestos-exposed Nf2 (+/-) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates. Loss of the WT Nf2 allele, leading to biallelic inactivation, was observed in all nine asbestos-induced malignant mesotheliomas from Nf2 (+/-) mice and in 50% of malignant mesotheliomas from asbestos-exposed WT mice. For a detailed comparison with the murine model, DNA analyses were also done on a series of human malignant mesothelioma samples. Remarkably, similar to human malignant mesotheliomas, tumors from Nf2 (+/-) mice showed frequent homologous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus. As in the human disease counterpart, malignant mesotheliomas from the Nf2 (+/-) mice also showed frequent activation of Akt kinase, which plays a central role in tumorigenesis and therapeutic resistance. Thus, this murine model of environmental carcinogenesis faithfully recapitulates many of the molecular features of human malignant mesothelioma and has significant implications for the further characterization of malignant mesothelioma pathogenesis and preclinical testing of novel therapeutic modalities. Brain metastases are an important sequelae of many types of cancer, most commonly lung cancer. Current treatment options include whole-brain radiation therapy (WBRT), surgical resection, stereotactic radiosurgery, and chemotherapy. Corticosteroids and antiepileptic medications are commonly used for palliation of mass effect and seizures, respectively. The overall median survival is only 4 months after WBRT. Combined-modality strategies of WBRT with either chemotherapy or novel anticancer agents are under clinical investigation. Promising results have been obtained with several experimental agents and confirmatory phase III trials are underway. Although improvement in overall survival has not been seen universally, reduction in death due to progression of brain metastases and prolongation of the time to neurologic and neurocognitive progression have been reported in selected series. On the basis of these findings, it might be possible to identify new agents that may enhance the efficacy of WBRT. PURPOSE: Laparoscopic renal and adrenal surgery is an accepted standard of care. This can be accomplished by a transperitoneal or retroperitoneal approach. In patients with extensive prior intra-abdominal surgery with or without radiation the retroperitoneal laparoscopic approach may avoid bowel adhesions and potential operative complications. We compared clinical outcomes of the laparoscopic retroperitoneal approach in patients with prior open abdominal surgery with or without radiation to outcomes in those with no surgical history. MATERIALS AND METHODS: We evaluated clinical and functional parameters in 78 consecutive patients undergoing retroperitoneoscopic renal or adrenal surgery performed by a single surgeon in a 36-month period, including radical nephrectomy with or without ureterectomy in 50, nerve sparing surgery in 8, ablation in 16 and adrenalectomy in 4. All transperitoneal procedures during the same period were excluded from analysis. Patients were divided into 48 who underwent prior abdominal surgery with or without radiation (group 1) and 30 who did not (group 2). Prior abdominal surgeries in group 1 patients were open and they were major in 42 and/or minor in 39. An additional 6 patients in group 1 received prior abdominal radiation overlapping the planned surgical field. RESULTS: No statistically significant differences were noted between the groups in any parameter assessed, including operative time, blood loss, time to first oral intake, hospital stay or the complication rate (p >0.05). There were no enterotomies in either group. There were no open conversions in group 1, while there were 2 in group 2 (renal vein injury and splenorrhaphy secondary to lymphoma, respectively). Pathological findings showed malignancy in 57 cases (renal cell carcinoma, transitional cell carcinoma, carcinoid disease and metastases) and benign disease in 21 (oncocytoma, adenoma, pyelonephritis and complex cysts). All margins were negative except in 1 group patient with carcinoma in situ at the bladder cuff margin. CONCLUSIONS: The retroperitoneoscopic approach to the kidney and adrenal glands can be used in patients with extensive prior open abdominal surgery and/or radiation without significant increases in morbidity or convalescence. SUMMARY: Molecular Integrated Development Environment (MolIDE) is an integrated application designed to provide homology modeling tools and protocols under a uniform, user-friendly graphical interface. Its main purpose is to combine the most frequent modeling steps in a semi-automatic, interactive way, guiding the user from the target protein sequence to the final three-dimensional protein structure. The typical basic homology modeling process is composed of building sequence profiles of the target sequence family, secondary structure prediction, sequence alignment with PDB structures, assisted alignment editing, side-chain prediction and loop building. All of these steps are available through a graphical user interface. MolIDE's user-friendly and streamlined interactive modeling protocol allows the user to focus on the important modeling questions, hiding from the user the raw data generation and conversion steps. MolIDE was designed from the ground up as an open-source, cross-platform, extensible framework. This allows developers to integrate additional third-party programs to MolIDE. AVAILABILITY: http://dunbrack.fccc.edu/molide/molide.php CONTACT: rl_dunbrack@fccc.edu. Two-hybrid screening is a standard method used to identify and characterize protein-protein interactions and has become an integral component of many proteomic investigations. The two-hybrid system was initially developed using yeast as a host organism. However, bacterial two-hybrid systems have also become common laboratory tools and are preferred in some circumstances, although yeast and bacterial two-hybrid systems have never been directly compared. We describe here the development of a unified yeast and bacterial two-hybrid system in which a single bait expression plasmid is used in both organismal milieus. We use a series of leucine zipper fusion proteins of known affinities to compare interaction detection using both systems. Although both two-hybrid systems detected interactions within a comparable range of interaction affinities, each demonstrated unique advantages. The yeast system produced quantitative readout over a greater dynamic range than that observed with bacteria. However, the phenomenon of "autoactivation" by baits was less of a problem in the bacterial system than in the yeast. Both systems identified physiological interactors for a library screen with a cI-Ras test bait; however, non-identical interactors were obtained in yeast and bacterial screens. The ability to rapidly shift between yeast and bacterial systems provided by these new reagents should provide a marked advantage for two-hybrid investigations. In addition, the modified expression vectors we describe in this report should be useful for any application requiring facile expression of a protein of interest in both yeast and bacteria. Defining Biochemical Failure after Radiotherapy with and without Androgen Deprivation for Prostate Cancer Limiting breast surgery to the proper minimum Regulation of mitochondrial respiratory chain structure and function by estrogens/estrogen receptors and potential physiological/pathophysiological implications Proprotein convertases: "Master switches" in the regulation of tumor growth and progression Combined modality treatment of squamous cell cancer of the head and neck A mouse model recapitulating molecular features of human mesothelioma Regulation of cell death in oncogenesis Current management of brain metastases, with a focus on systemic options Prior abdominal surgery and radiation do not complicate the retroperitoneoscopic approach to the kidney or adrenal gland MollDE: a homology modeling framework you can click with A combined yeast/bacteria two-hybrid system: development and evaluation

BACKGROUND. Cranial nerve lesions due to metastases from prostate carcinoma to the skull base are an uncommon yet clinically significant finding. METHODS. The authors report the clinical features, treatment, and outcomes for 15 patients who presented with cranial nerve palsies complicating metastatic prostate carcinoma. Patient charts identified from a Fox Chase Cancer Center treatment data base were reviewed. RESULTS. All patients had hormone-refractory disease at the time of symptom onset. Twelve of 15 patients had received prior chemotherapy, and 13 of 15 patients had received prior radiation therapy to areas of bony pain. Symptoms varied from recognized clinical syndromes involving multiple cranial nerves to isolated cranial nerve lesions. All patients had lesions at the skull base that were visualized on computed tomography scans or magnetic resonance images. All patients were treated with palliative radiation therapy to either the whole brain or the skull base. Fourteen of 15 patients had a clinical (either partial or complete) response to radiation therapy. All responding patients subsequently died of prostate carcinoma without worsening of residual or development of new cranial nerve symptoms. Ten of 15 patients (67%) died within 3 months of developing symptoms, and the remaining 5 patients lived between 9 months and 31 months from onset of symptoms. CONCLUSIONS. The authors concluded that palliative radiation therapy should be considered in this heterogeneous group of patients given the potential for significant symptom improvement. (C) 2004 American Cancer Society.

PURPOSE: Bladder cancer is potentially curable in the majority of cases; however, the prognosis for patients with advanced disease at presentation remains poor. Current noninvasive tests such as cytol. lack sufficient sensitivity to detect low-grade, low-stage tumors. Silencing of tumor suppressor genes, such as p16INK4a, VHL, and the mismatch repair gene hMLH1, has established promoter hypermethylation as a common mechanism for tumor suppressor inactivation in human cancers. It is also a promising new target for mol. detection in bodily fluids including urine, a readily accessible fluid known to contain bladder cancer cells. Methylation-specific PCR (MSP) can det. the presence or absence of methylation of a gene locus at a sensitivity level of up to 1 methylated allele in 1000 unmethylated alleles, appropriate for identifying cancer cell DNA in a bodily fluid. Exptl. Design: We first detd. the frequency of hypermethylation of the Rb tumor suppressor gene by bisulfite sequencing and of the p16INK4a, p14ARF, APC, and RASSF1A tumor suppressor genes by MSP in 45 bladder cancers. We then designed a panel optimal for diagnostic coverage composed of the APC, RASSF1A, and p14ARF tumor suppressor genes. This panel was tested for detection of hypermethylation in matched sediment DNA from urine specimens obtained before surgery from the same 45 bladder cancer patients (2 Tis, 16 Ta, 10 T1, and 17 T2-4) as well as normal and benign control DNAs. RESULTS: Hypermethylation of at least one of three suppressor genes (APC, RASSF1A, and p14ARF) was found in all 45 tumor DNAs (100% diagnostic coverage). We detected gene hypermethylation in the matched urine DNA from 39 of 45 patients (87% sensitivity), including 16 cases that had neg. cytol. No hypermethylation of APC, RASSF1A, or p14ARF was obsd. in normal transitional cell DNAs or in urine DNAs from normal healthy individuals and patients with inflammatory urinary disease (cystitis). Furthermore, an unmethylated gene in the tumor DNA was always found to be unmethylated in the matched urine DNA (100% specificity). CONCLUSIONS: Promoter hypermethylation of tumor suppressor genes is common in bladder cancer and was found in all grades and stages of tumors examd. Hypermethylation was detected in the urine DNA from 39 of 45 (87%) patients, including cases of early-stage disease amenable to cure. MSP may enhance early detection of bladder cancer using a noninvasive urine test. [on SciFinder (R)]

Objectives. To review the world literature for reports of cutaneous metastases from primary genitourinary malignancies and compare them with our experience during a 10-year period. Cutaneous metastases from primary visceral malignancies are uncommon manifestations of advanced disease. Among patients with urologic malignancies, the incidence and appearance of cutaneous metastases are not well established and recognition is poor among practicing urologists. Methods. A Medline search and manual bibliographic review was performed to identify peer-reviewed reports pertaining to cutaneous metastases from all visceral malignancies. A comparative review of all pertinent cases arising from primary urologic malignancies was performed. A comprehensive search of our institution's tumor registry was performed to identify all analytic cases of urologic malignancy diagnosed, treated, and followed up between 1990 and 2000. Clinical and pathologic data were collated. Results. We identified 2,369 reported cases of cutaneous metastases arising from 81,618 primary solid visceral malignancies, for an overall incidence of 2.9%. Dermatologic spread from primary urologic malignancies of the kidney, bladder, prostate, or testes was noted in 116 (1.3%) of 10,417. The incidence of cutaneous metastases from the kidney, bladder, prostate, and testes was 3.4%, 0.84%, 0.36%, and 0.4%, respectively. Overall, 436 cases of cutaneous metastases from urologic organs were identified in the English-language literature. We identified nine additional cases of pathologically confirmed cutaneous metastatic urologic tumors at our institution in the past 10 years. The most common presentation was an infiltrated plaque or nodules. Most cases displayed clinical features that mimicked common skin disorders. The median disease-specific survival was less than 6 months from the presentation of cutaneous metastasis. Conclusions. Cutaneous metastases from urologic tumors are uncommon and occur in 1% of patients with advanced disease. Urologic skin metastases are most common from renal tumors, followed by those of the bladder and then prostate. Their clinical appearance may mimic other common dermatologic disorders affecting patients with advanced malignancies. Definitive diagnosis requires an index of suspicion and skin biopsy. Cutaneous metastases from urologic malignancies are associated with a poor prognosis. (C) 2004 Elsevier Inc.