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Background & Aims: The aim of this study was to identify genes that play a role in colorectal cancer (CRC) carcinogenesis by analysis of differential gene expression of normal and transformed CRC cell lines. Methods: Gene expression array analysis ([RG-U34] GeneChip) was performed in normal and transformed rat intestinal epithelial cells before and after exposures to celecoxib. In particular, we were looking for (1) altered gene expression in the transformed cells that reverts to normal following exposure to a selective cyclooxygenase-2 inhibitor, (2) novel genes, and (3) genes encoding membrane receptors or ligands. As a validation of the results and for human patients, immunohistochemistry was performed on 398 biological samples from the gastrointestinal tract (normal, polyps, and adenocarcinomas). Human cancer cell lines were tested for their response to anti-CD24 monoclonal antibodies. Results: A total of 1081 genes were differently expressed following malignant transformation; 71 genes showed altered expression that reverted to normal following treatment with celecoxib, including the CD24 gene. Immunohistochemistry confirmed that increased expression of CD24 is an early event in CRC carcinogenesis. It was expressed in 90.7% of adenomas and 86.3% of CRCs. Very low expression was seen in normal epithelium (16.6%). Human cancer cell lines showed growth inhibition in response to the antibodies, according to their expression levels of CD24 and in dose- and time-dependent manners. These results were repetitive for 3 different antibodies. Conclusions: CD24 is overexpressed in the colonic mucosa, already at an early stage of carcinogenesis. It may be a useful target for early detection and in CRC therapy. [Copyright &y& Elsevier]

Objectives: To retrospectively compare the biochemical disease-free survival (BDFS) of patients treated with standard dose external beam radiotherapy (SD-EBRT), SD-EBRT plus androgen deprivation (AD), and brachytherapy-based treatment (brachytherapy with or without EBRT with or without AD). Methods: All 297 patients with intermediate-risk prostate cancer treated with these radiation-based treatments at our institution from August 1989 to June 2001 were included. Biochemical relapse was defined according to the American Society for Therapeutic Radiology and Oncology (ASTRO) definition, a prostate-specific antigen level of 1.5 ng/mL or greater and rising on two consecutive occasions (the “Bolla” definition), and the current prostate-specific antigen nadir plus 2 ng/mL with failure dated “at call” (the “Houston/Phoenix” definition). The number of patients treated with SD-EBRT, SD-EBRT plus AD, and brachytherapy-based treatment was 141, 84, and 72, respectively. The year of treatment was analyzed as a prognostic factor. The median follow-up was 32.3, 34.7, and 41.5 months for the ASTRO, Bolla, and Houston/Phoenix definitions, respectively. Results: The brachytherapy-based treatment resulted in improved BDFS compared with SD-EBRT (ASTRO definition, 5-year BDFS rate 88% ± 5% versus 49% ± 5%, P <0.01; Bolla definition, 88% ± 8% versus 49% ± 5%, P <0.01; Houston/Phoenix definition, 81% ± 10% versus 64% ± 5%, P = 0.01). SD-EBRT plus AD was superior to SD-EBRT alone using the Bolla definition (5-year BDFS 76% ± 7% versus 49% ± 5%, P <0.01) and the Houston/Phoenix definition (85% ± 6% versus 64% ± 5%, P = 0.01), but not using the ASTRO definition (P = 0.17). Multivariate analysis, including prostate-specific antigen, clinical stage, Gleason score, and year of treatment, demonstrated improved biochemical outcomes for brachytherapy-based treatment versus SD-EBRT (ASTRO, P <0.01; Bolla, P <0.01; and a trend toward significance with Houston/Phoenix, P = 0.07) and for the addition of AD to SD-EBRT (Bolla, P <0.01 and Houston/Phoenix, P = 0.03). The year of treatment trended toward significance (P = 0.077) on multivariate analysis using the ASTRO definition. Conclusions: For patients with intermediate-risk prostate cancer, brachytherapy-based treatment and the addition of AD to SD-EBRT resulted in improved biochemical outcomes compared with the outcomes with SD-EBRT alone; however, these findings were dependent on the definition of biochemical failure used. The year of treatment may be an important prognostic factor in intermediate-risk prostate cancer. [Copyright &y& Elsevier]

Abstract: Objectives: To present extended follow-up on a cohort of patients with renal cortical tumors treated with partial or radical nephrectomy and preoperatively assess for carbonic anhydrase 9 tumor marker expression in the peripheral blood. Methods: All patients were originally enrolled in an institutional review board-approved study assessing the role of a reverse-transcriptase polymerase chain reaction peripheral blood assay designed to detect the tumor-specific gene carbonic anhydrase-9 (CA9). A total of 41 patients with renal cortical tumors confined to the kidney were enrolled at a single institution and assessed preoperatively with peripheral blood test for CA9 expression before undergoing partial or radical nephrectomy. A Kaplan-Meier estimated survival analysis and log-rank test were performed to determine whether detection of peripheral blood cells expressing the CA9 gene influences disease-free and disease-specific survival. Results: The median follow-up was 4.3 years. The median age was 71 years. Of the 41 patients, 26 were men and 15 were women. The estimated 5-year disease-free survival for patients with detectible expression of the CA9 gene in the peripheral blood was 39.5% compared with 88.1% for patients without detection of the CA9 gene (P = 0.048). On bivariate analysis, disease-free survival correlated with histologic type, tumor diameter, and tumor grade. Conclusions: The expression of the tumor-specific marker CA9 in the peripheral blood is associated with decreased disease-free survival in patients with renal cortical tumors. This is the first study reporting on the prognostic value of this peripheral blood-based tumor marker for kidney tumors. [Copyright &y& Elsevier]

: ObjectivesTo determine the natural history of patients younger than 40 years (young patient [YP] group) who are diagnosed with a sporadic renal cortical tumor (RCT) and to compare the natural history of these patients with the more typical older patient (OP) with RCT.: MethodsWe reviewed our database and identified 34 patients (younger than 40 years old, median age 35) who underwent surgery for a sporadic RCT. The YP group outcomes were compared with 100 patients between 41 and 85 years (median 65). We fit a Cox proportional hazards model to examine the relationship between age at presentation and recurrence risk.: ResultsThe median tumor size in the YP group was 3.8 cm (range 0.6 to 19) and in the OP group was 5.0 cm (range 0.9 to 22; P = 0.225). Tumors were discovered incidentally in 51% and 56% of the YP and OP groups, respectively (P = 0.65). The frequency of partial nephrectomy did not differ between the two groups (35% YP and 30% OP, P = 0.55). The frequency of malignant histologic subtypes did not differ between the groups (P = 0.439). In the YP group, only larger tumor size (hazard ratio 1.23, 95% confidence interval 1.02 to 1.50, P = 0.034) was associated with a statistically significant increased risk of recurrence. Those in the YP group were not more or less likely to develop recurrence than those in the OP group (hazard ratio 0.79, 95% confidence interval 0.22 to 2.85, P = 0.72). The 5-year disease-free survival rate was 73% and 80% in the YP and OP groups, respectively (P = 0.23). The 5-year disease-specific survival rate was 85% and 84% in the YP and OP groups, respectively (P = 0.88).: ConclusionsThe findings of our study indicate that the natural history of RCTs is similar in both younger and older patients. Young patients were neither more nor less likely to develop recurrence compared with their older counterparts. [Copyright &y& Elsevier]

Mutant allele specific imbalance (MASI) was initially coined to describe copy number alterations associated with the mutant allele of an oncogene. The copy number gain (CNG) specific to the mutant allele can be readily observed in electropherograms. With the development of genome-wide analyses at base-pair resolution with copy number counts, we can now further differentiate MASI into those with CNG, with copy neutral alteration (also termed acquired uniparental disomy; UPD), or with loss of heterozygosity (LOH) due to the loss of the wild-type (WT) allele. Here we summarize the occurrence of MASI with CNG, aUPD, or MASI with LOH in some major oncogenes (such as EGFR, KRAS, PIK3CA, and BRAF). We also discuss how these various classifications of MASI have been demonstrated to impact tumorigenesis, progression, metastasis, prognosis, and potentially therapeutic responses in cancer, notably in lung, colorectal, and pancreatic cancers. [ABSTRACT FROM AUTHOR]

Objectives: There is little data available on the effects of energy-based surgical devices (ESD) on tissues other than arteries and veins. As such, we quantified the lateral thermal damage associated with contemporary ESD: the Harmonic ACE, a prototype bipolar device known as the Gyrus Trisector, the Harmonic LCS-C5, and the LigaSure V. Methods: We divided 24 domestic pigs into 4 groups, 1 group for each ESD tested. Segments of bladder, stomach, small bowel, colon, ureter, peritoneum, arteries, and veins were exposed to each ESD. The tissues were stained with hematoxylin and eosin and evaluated by an experienced pathologist to quantitate the lateral energy spread associated with each device. We measured blade temperatures of each device using the IR-Flex thermal camera. Results: The Trisector developed the lowest mean blade temperature (97.84°F), whereas the LigaSure’s was the second lowest (103.14°F). The ACE and LCS-C5 created the highest blade temperatures, measuring 220.5°F and 205.6°F, respectively. The Trisector’s mean full thickness and superficial lateral energy damage were 6.3 mm and 7.0 mm, respectively, whereas the Ligasure’s was 4.5 mm and 5.9 mm, respectively. For the ACE, however, mean full thickness and superficial energy spread were 2.4 mm and 2.8 mm, respectively, whereas the LCS-C5’s were 3.1 mm and 4.3 mm, respectively. Conclusions: The Harmonic ACE and LCS-C5 produced the least thermal damage in the tissues tested. ESD-associated tissue energy damage is not directly related to blade temperature, but is likely the result of several factors including blade temperature, transection time, tissue properties, and the vascularity of each transected tissue. [Copyright &y& Elsevier]

Objectives: To describe the changes in the Gleason grading system over time and evaluate how a shift in Gleason grading has affected the overall predictive accuracy of the system in predicting biochemical disease-free survival after radical prostatectomy. Methods: The Columbia University Urologic Oncology Database was reviewed, and 1515 patients who met the inclusion criteria were identified who had undergone radical prostatectomy from 1988 to 2004. The patients were divided into two time cohorts (1988 to 1997 and 1998 to 2004). To determine whether a shift in the Gleason sum distribution has occurred, a chi-square test was performed. Survival curves and log-rank tests were used to compare the biochemical disease-free survival between cohorts stratified by the Gleason sum. To estimate the predictive ability of the Gleason system over time, concordance indexes were calculated. Results: A shift toward greater Gleason sums over time was confirmed using the chi-square test (P <0.001). A significant difference was observed in biochemical disease-free survival between the two time cohorts for those with Gleason sum 6 cancer (P <0.01). The concordance indexes corresponding to Gleason sum alone for each time cohort were 0.71 and 0.87, demonstrating that the Gleason sum’s predictive ability improved significantly over time. After adjusting for other variables, the Gleason sum continued to demonstrate a significantly improved predictive ability in the more recent time cohort. Conclusions: We found a trend toward the assignment of increasing Gleason sums over time in our data set. This shift in Gleason sum distribution between the two time cohorts has resulted in a significant improvement in the predictive ability of the Gleason system. [Copyright &y& Elsevier]

Summary: Pten-/- cells display a partially defective checkpoint in response to ionizing radiation (IR). The checkpoint defect was traced to the ability of AKT to phosphorylate CHK1 at serine 280, since a nonphosphorylated mutant of CHK1 (S280A) complemented the checkpoint defect and restored CDC25A degradation. CHK1 phosphorylation at serine 280 led to covalent binding of 1 to 2 molecules of ubiquitin and cytoplasmic CHK1 localization. Primary breast carcinomas lacking PTEN expression and having elevated AKT phosphorylation had increased cytoplasmic CHK1 and displayed aneuploidy (p < 0.005). We conclude that loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells. [Copyright &y& Elsevier]

Background: Metastatic renal cell carcinoma (RCC) is an aggressive entity that frequently invades the venous system. We evaluated the morbidity and survival of patients with tumor thrombus who undergo cytoreductive nephrectomy. Materials and methods: We identified 56 patients from our institution’s database who had a primary renal tumor in place and documented metastases at the time of surgery. We reviewed demographic and pathologic characteristics from these patients as well as complications and overall survival. Results: Median age was 58 (37–77). There were 33 patients (59%) who had tumor thrombus with 21 (64%) involving the renal vein, 10 (30%) involving the infradiaphragmatic inferior vena cava (IVC), and 2 (6%) involving the supradiaphragmatic IVC. Median tumor size for thrombus patients was 12 cm (5–29). There were 8 (14.2%) who had complications, including 1 death. Thrombus patients were significantly more likely to have a complication (P = 0.008). Median survival for all patients was 10.7 months (0.3–61). There was no significant difference in overall survival between patients with and without thrombus (P = 0.76). Conclusions: Patients who undergo cytoreductive nephrectomy with a tumor thrombus have a higher rate of complications as compared to patients undergoing cytoreductive nephrectomy without tumor thrombus. The long-term survival, however, was not statistically different and thus aggressive surgery for select metastatic RCC patients is warranted. [Copyright &y& Elsevier]

Two groups of renal oncocytomas have been cytogenetically defined by the loss of one or both of chromosomes Y and 1 or by structural rearrangement involving 11q12~q13. We report five renal oncocytomas with structural chromosomal rearrangements involving 11q13 with previously unreported partner chromosomes (namely, 1, 6, and 7). For two of the five cases, a t(6;11)(p21;q13) translocation was revealed; the others had t(1;11)(p13;q13), t(7;11)(q11.2;q13), and t(5;11)(q35; q13). Fluorescence in situ hybridization confirmed translocation of CCND1 at 11q13 to partner chromosomes 5, 6, and 7. Overexpression of cyclin D1, the protein product of CCND1, was detected in three of the five cases (60%) by means of immunohistochemical staining of formalin-fixed, paraffin-embedded tumor sections. In three cases for which fresh tissue was available, Southern blot analysis using the MDL-5 probe for the BCL1 breakpoint did not reveal rearrangement of BCL1. In addition, six consecutive renal oncocytomas diagnosed at our institution between 1999 and 2002 whose karyotypes did not show 11q13 translocations were all negative for cyclin D1 overexpression under immunohistochemical analysis. The findings of CCND1 rearrangement with FISH and correlation with cyclin D1 overexpression under immunohistochemical analysis suggest that cyclin D1 alterations play a role in the subset of renal oncocytomas with 11q translocations, although other genes may also be involved. [Copyright &y& Elsevier]

Progressive multiple myeloma may manifest features of ‘de-differentiation’, including a plasmablastic appearance, failure to secrete paraprotein, extramedullary involvement, and resistance to treatment. A 44-year-old woman with κ-light chain myeloma underwent allogeneic stem cell transplantation (SCT). Twenty months later she developed paraspinal plasmablastic myeloma in the absence of paraprotein in urine or myeloma in the marrow. The paraspinal masses responded to chemotherapy. At 30 months she developed myelomatous meningitis, which proved resistant to intrathecal chemotherapy, irradiation, and donor lymphocyte infusion (DLI). The leptomeningeal disease led to death at 38 months. This is the first report of leptomeningeal relapse of myeloma after allografting. [Copyright &y& Elsevier]