The Occurrence of Gastritis in Microscopic Colitis and Inflammatory Bowel Disease.

Multiple studies have shown that Helicobacter pylori infection is associated with a lower prevalence of inflammatory bowel disease (IBD).1,2 Besides chronic active gastritis (CAG) resulting from gastric infection with H pylori, pathologists have noticed another form of CAG, which is unrelated to H pylori infection and seems to cluster in patients with IBD.3-5 The aim of the present study was to compare the prevalence of H pylori-negative and H pylori-positive CAG in patients with IBD, and microscopic colitis (MC).

Differential roles of telomere attrition in type I and II endometrial carcinogenesis.

Endometrial cancer has been generally categorized into two broad groups of tumors, type I (TI) and type II (TII), with distinct epidemiological/clinical features and genetic alterations. Because telomere attrition appears to trigger genomic instability in certain cancers, we explored the role of telomere dysfunction in endometrial cancer by analyzing telomeres and other markers of telomere status in both tumor types. We describe a new method, telomere chromogenic in situ hybridization, which permitted us to detect cells with short telomeres relative to control (stromal) cells within the same tissue section. Using this method, we found that both types of tumor cells had short telomeres. However, only TII tumors were significantly associated with critical telomere shortening in adjacent, morphologically normal epithelium, suggesting that telomere shortening contributes to the initiation of TII but not TI tumors. To explore this hypothesis, we analyzed mice with critically short telomeres and documented distinctive endometrial lesions that histologically resembled the in situ precursor of TII serous carcinomas; these lesions have not been observed previously in TI mouse models of endometrial cancer. Based on this and previous studies, we propose a model in which telomere attrition contributes to the initiation of TII and progression of TI endometrial cancers.

Contemporary laparoscopic and open radical retropubic prostatectomy: pathologic outcomes and Kattan postoperative nomograms are equivalent.

OBJECTIVES: Although contemporary cohort comparisons are lacking, open surgeons have questioned the oncologic efficacy of laparoscopic radical prostatectomy (LRP) owing to the lack of haptic feedback. As such, we compared the pathologic outcomes and predicted the progression-free survival after open radical prostatectomy (ORP) and LRP in a single referral setting within a defined period, thereby isolating the effect of the surgical technique alone. METHODS: Data were collected on 169 ORPs and 111 LRPs performed at our institution from May 2003 to May 2005. The surgical pathologic outcomes were compared, and the Kattan postoperative nomogram was used to calculate the 5 and 7-year progression-free probabilities after ORP and LRP. RESULTS: On univariate analysis, no differences were found in age, Gleason sum, stage, margin status, extracapsular extension, and seminal vesicle invasion. The positive margin rate was 29% for LRP and 35% for ORP (P = 0.29), and no difference was found even after stratifying by pathologic stage. After controlling for Gleason sum, extracapsular extension, seminal vesicle invasion, nodal involvement, margin status, and preoperative prostate-specific antigen, no difference was found in detectable prostate-specific antigen after ORP and LRP (P = 0.73). When the Kattan postoperative nomogram was used to compute the biochemical progression-free probabilities, no differences were found at 5 (P = 0.51) and 7 years (P = 0.50). CONCLUSIONS: In this contemporary series without the confounding effects of stage migration, regional practice variation, or the use of historical controls, the pathologic outcome after conventional LRP was similar to that after ORP. Biochemical progression-free survival was also similar using a validated multivariate predictive model.

uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues.

Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively.

No evidence of disease after radiofrequency ablation in delayed nephrectomy specimens.

OBJECTIVES: Computed tomography and magnetic resonance imaging are routinely used during follow-up of radiofrequency ablation (RFA) of renal masses. Widespread acceptance of needle ablation is limited by the need to rely on radiographic criteria to confirm effective ablation. In this report, we correlated the long-term radiographic appearance of RFA with the histologic findings in three delayed nephrectomy specimens. This should enhance our understanding of the histopathologic features of successful RFA and highlight potential shortcomings of modern imaging after ablation. METHODS: Radiographic and histologic data were analyzed in 3 patients who underwent delayed partial or total nephrectomy after RFA, performed for complications or misinterpretation of postablation surveillance imaging findings. RESULTS: Two delayed nephrectomies were performed for new enhancement at the periphery of the ablation zone margin and one for RFA-related ureteropelvic junction obstruction. At the initial ablation, all 3 patients had biopsy-proven renal cell carcinoma, and the mean time to delayed nephrectomy was 18 months. Histologically, all three demonstrated absence of residual cancer within the ablation zone. In the patients with enhancement at the periphery of the ablation zone, a granulomatous foreign body giant cell reaction was found. CONCLUSIONS: RFA is an effective technology for eradicating small renal cell carcinomas. However, proper image interpretation after ablation is a crucial component of patient care. New enhancement at the peripheral margin of the tumor ablation zone does not invariably suggest malignant recurrence, but a benign granulomatous reaction. Additional experience with interpretation of cross-sectional imaging is required to better understand the radiographic evolution of radiofrequency-ablated renal tumors.

Alpha(2) macroglobulin, a PSA binding protein, is expressed in human prostate stroma.

BACKGROUND: Benign prostatic hyperplasia (BPH) is characterized as a stromal process. The stroma smooth muscle (SM) may alter its phenotype during the progression of BPH. We have identified gene transcripts that may be differentially expressed in BPH using a differential display method. Among the fragments isolated, alpha(2) macroglobulin (alpha(2)-M) is one of the most interesting. alpha(2)-M is a binding protein of a variety of proteinases, including prostatic specific antigen (PSA). It also plays roles in molecular trapping and targeting. In this study, we characterized alpha(2)-M expression in the human prostate. METHODS: Differential display was used to identify and isolate the differentially expressed transcripts between normal prostate and BPH tissues. RT-PCR, Western blot, in situ hybridization, and immunohistochemistry were utilized to confirm and characterize alpha(2)-M expression in the prostate. RESULTS: Real-time RT-PCR results revealed that a 3.2-fold increase in alpha(2)-M mRNA expression is observed in BPH compared with normal prostate tissue. A 1.9-fold increase at protein level was also observed. In situ hybridization and immunohistochemistry showed that alpha(2)-M expression is primarily localized to the stromal compartment. Cultured primary stroma cells maintained alpha(2)-M expression, while prostate epithelial cells had a significantly lower level of alpha(2)-M expression. Furthermore, stromal cells in culture produce and secrete alpha(2)-M in the medium. CONCLUSIONS: We identified alpha(2)-M expression in the human prostate. An increased alpha(2)-M expression appears to be associated with BPH. Considering the unique features of its protein binding and targeting properties, alpha(2)-M expressed in the prostate may play an important role in regulating benign and malignant prostatic growth.

MIB1 labeling index as an indicator of chemoresponse in carcinoma of the breast.

In this study, we determined the extent of variation in proliferative markers and hormone receptor status in breast carcinoma between core biopsies and subsequent resections, and determined the impact of clinical and histologic parameters on such variation. We performed a paired comparison of biomarkers in 87 core biopsies and subsequent resections of breast carcinomas in patients with and without preoperative chemotherapy. The markers included estrogen receptor, progesterone receptor, Her2/neu, DNA ploidy (diploidy versus nondiploidy), DNA index (difference of > or = 0.5), and MIB1 labeling index (<15% vs. >15%). The tumor biomarkers were evaluated with standard IHC and scored by automated cellular imaging systems. The number of patients showing prominent changes were as follows: ploidy, 12; DI, 15; ER, 6; PR, 15; MIB1, 17; and Her2/neu, 15. Seventeen of 87 patients sustained a significant change in MIB1 index (above or below 15%). The patients who received chemotherapy had a larger proportion with a change in MIB1 status (P < 0.05). DI showed a similar trend, although it was not statistically significant. Of the patients with MIB1 values higher in biopsy specimens, a majority showed values to decrease below 15%. MIB1 index reduction by greater than 25% was seen in 8 of 16 (50%) cases with chemotherapy, compared with only 3 of 32 (9%) without chemotherapy. MIB1 and DNA index values postchemotherapy can be a useful measure of chemoresponse. Our study underscores the need to perform prognostic markers on both biopsy and subsequent resections, especially in the setting of preoperative chemotherapy.

A useful algorithm for determining fluence and pulse width for vascular targets using 1,064 nm Nd:YAG laser in an animal model.

BACKGROUND AND OBJECTIVES: Many current parameters to ablate vascular beds using 1,064 nm lasers are based on high-energy settings and often fail to consider vessel diameter and/or pulse width. This study attempts to define the minimal effective dosage (MED) of energy and pulse width for specific vessel diameters in an animal model. STUDY DESIGN/MATERIALS AND METHODS: 1,064 nm Nd: YAG was used in 15 Sprague-Dawley rats. Bilateral extended dorsolateral skin flaps were elevated and vessel diameters from 0.1 to 1 mm were identified. Pulse widths (PW) in a range of 15-60 milliseconds and fluences between 70-110 J/cm2 with contact cooling at 5 degrees C (Celsius) were utilized. Results were determined clinically and histologically. RESULTS: Ideal pulse width and MED for each vessel diameter were determined using a 6 mm spot size. Histology showed early hemostasis and subsequent thrombosis, which are consistent with clinical findings. CONCLUSIONS: This model allows in vivo monitoring of vessel ablation. Optimal pulse width and MED levels versus vessel diameter determined in this animal model provide a useful algorithm that may allow for more effective treatment of vascular targets utilizing the 1,064 nm Nd:YAG laser.

Predictive value of primary Gleason pattern 4 in patients with Gleason score 7 tumours treated with radical prostatectomy.

OBJECTIVE: To examine whether Gleason score (GS) 3 + 4 and 4 + 3 cancers at radical prostatectomy behave differently and whether this behaviour is independently associated with prostate cancer outcome. PATIENTS AND METHODS: From July 1994 to December 2002 309 consecutive men who had a radical retropubic prostatectomy for clinically localized disease had final GS 7 tumours in their prostatectomy specimen. Statistical analyses, including multivariate logistic regression, were used to evaluate the association between variables, i.e. standard preoperative features, stage, PSA progression, standard pathological variables, metastasis and death. RESULTS: In all, 215 patients (70%) had a final GS of 3 + 4 and 94 (30%) of 4 + 3. A final GS of 4 + 3 was associated with clinical stage T2 disease (P = 0.024), a higher biopsy GS (P < 0.001), seminal vesicle involvement (P < 0.001), positive surgical margins (P = 0.036), lymphovascular invasion (P = 0.018), metastases to regional lymph nodes (P = 0.008), higher preoperative serum prostate-specific antigen (PSA) (P = 0.042), and percentage positive biopsy cores (P = 0.006). In univariate analysis, patients with GS 4 + 3 had a significantly higher risk of biochemical progression than those with GS 3 + 4 (P = 0.002). The 5-year actuarial risk of biochemical progression was 17% and 35% for GS 3 + 4 and 4 + 3, respectively (P = 0.0016). In a standard postoperative multivariate analysis, only preoperative PSA and metastases to regional lymph nodes were associated with PSA progression (P < 0.001 and 0.002, respectively). However, patients with final GS 4 + 3 had a shorter PSA doubling time after progression than those with GS 3 + 4 (P = 0.009). CONCLUSIONS: Tumours with a final GS of 4 + 3 are more aggressive than GS 3 + 4 tumours. Recognising the distinction in GS 7 between predominant 4 vs 3 scores after radical prostatectomy should improve the ability of clinicians to counsel patients. The GS 4 pattern deserves further molecular study.

The percent of biopsy cores positive for cancer is a predictor of advanced pathological stage and poor clinical outcomes in patients treated with radical prostatectomy.

PURPOSE: We examined if the percent of positive biopsies is associated with features of biologically aggressive prostate cancer, biochemical progression and development of distant metastases in patients undergoing radical prostatectomy (RP). MATERIALS AND METHODS: Multivariate analyses of preoperative features in 605 consecutive patients who underwent RP for clinically localized disease were evaluated to determine the association between the percent positive biopsy cores (PosBx), pathological stage and grade, and biochemical progression following RP. The percent of PosBx cores was defined using the formula, (number of positive biopsy cores/total number of biopsy cores) x 100. RESULTS: The mean number of biopsy cores and percent PosBx cores +/- SE was 8.8 +/- 6.0 and 31.4 +/-21.1, respectively. Higher percent PosBx was significantly associated with higher preoperative prostate specific antigen (PSA), extracapsular extension, seminal vesicle invasion, positive surgical margins, higher final Gleason sum, lymphovascular invasion, perineural invasion and metastases to regional lymph nodes. On multivariate analyses adjusted for the effects of standard preoperative features percent PosBx was associated with nonorgan confined disease, seminal vesicle invasion and biochemical progression after surgery (p = 0.049, 0.050 and 0.006, respectively). Percent PosBx retained its independent association with PSA progression after adjustment for the effects of postoperative pathological features (p = 0.015). Higher percent PosBx was associated with shorter PSA doubling time after PSA progression, and an increased risk of distant metastases and overall mortality (p = 0.039, 0.001 and 0.018, respectively). CONCLUSIONS: Percent PosBx is associated with established pathological features, biochemical progression, distant metastases and overall death in patients who undergo RP for clinically localized disease. Percent PosBx should be included in preoperative predictive models for prognosticating outcomes after primary treatment and it may assist in selecting patients for inclusion in neoadjuvant and/or adjuvant therapy trials.

Survivin expression is associated with features of biologically aggressive prostate carcinoma.

BACKGROUND: Survivin counteracts cell death and controls mitotic progression. The objectives of the current study were to compare the expression patterns of survivin in normal prostate, primary prostate carcinoma, and lymph node tissues involved with prostate carcinoma and to determine whether the expression of survivin is associated with prostate carcinoma characteristics and progression. METHODS: Immunohistochemical staining for survivin and for transforming growth factor beta1 (TGF-beta1) and its receptors (types I and II; TGF-betaR1 and TGF-betaR2, respectively) was carried out on archival specimens from 114 consecutive patients who underwent radical prostatectomy (median follow-up, 64.8 months). Punch biopsies of the index carcinoma and normal tissue from each specimen were sectioned onto a single slide and stained. The authors also evaluated the expression of survivin in normal and malignant lymph node tissue from eight patients. RESULTS: Survivin was expressed in 41 of 114 normal prostate specimens (36%) from prostates that contained carcinoma, in 81 of 114 primary prostate carcinoma specimens (71%), in 3 of 8 normal lymphoid specimens (38%), and in 7 of 8 prostate carcinoma lymphoid specimens (88%). Survivin expression was associated with higher final Gleason sum (P = 0.001), loss of TGF-betaR1 and TGF-betaR2 expression (P = 0.041 and P = 0.008, respectively), and an increased risk of biochemical progression on univariate analysis (P = 0.0441). Among patients who had disease progression, survivin was expressed more commonly in those who had tumors with features of aggressive behavior. CONCLUSIONS: The expression of survivin gradually increased from normal prostate tissue, to low-grade primary carcinoma, to high-grade primary carcinoma and was highest in lymph node metastases. Survivin expression was associated further with alteration of the TGF-beta pathway and with overall and aggressive biochemical progression after radical prostatectomy.

Lymphovascular invasion is a pathological feature of biologically aggressive disease in patients treated with radical prostatectomy.

UNLABELLED: We examined whether invasion of lymphatic and/or vascular vessels (LVI), or perineural spaces (PNI) is associated with prostate cancer features and outcome. MATERIALS AND METHODS: A total of 630 consecutive men underwent radical retropubic prostatectomy for clinically localized disease. LVI and PNI examination was part of the routine specimen evaluation. RESULTS: Foci of LVI were identified in 32 patients (5%) and 381 (60.5%) had PNI. LVI and PNI were associated with clinical stage T2 disease, higher biopsy and final Gleason sum, extraprostatic extension, seminal vesicle involvement, positive surgical margins and a higher percent of positive biopsy cores (p <0.001). LVI was associated with metastases to regional lymph nodes and higher preoperative serum prostate specific antigen (p <0.001 and 0.004, respectively). PNI and LVI were associated with an increased risk of rapid biochemical progression after radical prostatectomy on univariate (p <0.001 and 0.001, respectively) but not on multivariate analysis. LVI was associated with shorter prostate specific antigen doubling time after biochemical progression (p = 0.012) and higher probabilities of failed local salvage radiation therapy (p = 0.0169), distant metastases (p <0.001) and death (p <0.001). CONCLUSIONS: Only LVI is associated with metastases to regional and distant sites, and most importantly with overall survival. LVI and PNI are associated with established markers of biologically aggressive disease and rapid biochemical progression in patients who underwent radical prostatectomy. Our findings support the routine evaluation of LVI status in radical prostatectomy specimens and its inclusion in predictive models for clinical outcomes, since it appears to be a pathological marker of the lethal phenotype of prostate cancer.

Interpretive disparity among pathologists in breast sentinel lymph node evaluation.

BACKGROUND: Immunohistochemical staining on breast sentinel lymph nodes (SLN) is controversial. METHODS: Twenty-five SLN cases were reviewed by 10 pathologists (three academic, seven private) including 5 negative by both hematoxylin and eosin (H&E) and immunohistochemistry, 11 micrometastases (<2 mm) negative by H&E but positive by immunohistochemistry, and 8 micrometastases and 1 macrometastasis (>2 mm) positive for both H&E and immunohistochemistry. Answers included "positive," "negative," and "indeterminate" for each slide. RESULTS: The mean number of incorrect responses was 6.6 for immunohistochemistry and 5 for H&E. Twelve percent of cases were correct by all 10 pathologists; 80% of positive IHC cases had at least one pathologist score it incorrectly. As tumor cells decrease in number, incorrect responses increase. When tumor cells numbered less than 10, more than 30% of pathologists answered incorrectly. CONCLUSIONS: As tumor cells decrease in number pathologists' ability to recognize them decreases. We propose adding "indeterminate" to "positive" and "negative" when tumor cells number less than 10.

Sutureless laparoscopic heminephrectomy using laser tissue soldering.

BACKGROUND AND PURPOSE: Widespread application of laparoscopic partial nephrectomy has been limited by the lack of a reliable means of attaining hemostasis. We describe laser tissue welding using human albumin as a solder to control bleeding and seal the collecting system during laparoscopic heminephrectomy in a porcine model. MATERIALS AND METHODS: Laparoscopic left lower-pole heminephrectomy was performed in five female domestic pigs after occluding the hilar vessels. Using an 810-nm pulsed diode laser (20 W), a 50% liquid albumin-indocyanine green solder was welded to the cut edge of the renal parenchyma to seal the collecting system and achieve hemostasis. Two weeks later, an identical procedure was performed on the right kidney, after which, the animals were sacrificed and both kidneys were harvested for ex vivo retrograde pyelograms and histopathologic analysis. RESULTS: All 10 heminephrectomies were performed without complication. The mean operative time was 82 minutes, with an average blood loss of 43.5 mL per procedure. The mean warm ischemia time was 11.7 minutes. For each heminephrectomy, a mean of 4.2 mL of solder was welded to the cut parenchymal surface. In three of the five acute kidneys and all five 2-week kidneys, ex vivo retrograde pyelograms demonstrated no extravasation. In addition, no animal had clinical evidence of urinoma or delayed hemorrhage. Histopathologic analysis showed preservation of the renal parenchyma immediately beneath the solder. DISCUSSION: Laser tissue welding provided reliable hemostasis and closure of the collecting system while protecting the underlying parenchyma from the deleterious effect of the laser during porcine laparoscopic heminephrectomy.

Clinical relevance of reverse transcriptase-polymerase chain reaction for the detection of axillary lymph node metastases in breast cancer.

BACKGROUND: The mammary sentinel lymph node procedure can increase the detection of axillary metastases by 45% compared with standard axillary dissection. Some investigators have reported that reverse transcriptase-polymerase chain reaction (RT-PCR) increases metastasis detection even more, but it is uncertain whether a positive RT-PCR test in the face of a negative histological evaluation is clinically meaningful. METHODS: RT-PCR for epithelial glycoprotein 2 and cytokeratin 19 was performed on sentinel and pooled nonsentinel axillary lymph nodes from 108 women with clinical stage I or II breast cancer who were followed up for a median of 40 months. RESULTS: Axillary metastases were detected on standard tissue sections in 26% and by RT-PCR in 30%. Results for the two tests were concordant for 80% of the cases. RT-PCR upstaged 16%. Tumors from women whose lymph nodes were positive only by RT-PCR were phenotypically similar to those from women with no metastases detected by any method. Moreover, 4-year actuarial distant disease-free survival was 100% for women with metastases detected by RT-PCR only, as compared with 74% for those with metastases detected by routine histology (P =.03) and 93% for those with no metastases detected by either method (P =.04). CONCLUSIONS: Analysis of sentinel lymph nodes by RT-PCR for epithelial glycoprotein 2 and cytokeratin 19 is unlikely to provide clinically useful information.

Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant.

PURPOSE: Numerous studies of circulating epithelial cells (CECs)have been described in cancer patients, and genetic abnormalities have been well documented. However, with one exception in colorectal cancer, there has been no report of matching the genetic abnormalities in the CECs with the primary tumor. The purpose of this investigation was to determine (a) whether CECs in patients including those with early tumors are aneusomic and (b) whether their aneusomic patterns match those from the primary tumor, indicating common clonality. EXPERIMENTAL DESIGN: Thirty-one cancer patients had CECs identified by immunofluorescence staining using a monoclonal anti-cytokeratin antibody. Their CECs were analyzed by enumerator DNA probes for chromosomes 1, 3, 4, 7, 8, 11, or 17 by dual or tricolor fluorescence in situ hybridization. Touch preparations of the primary tumor tissue were available from 17 of 31 patients and hybridized with the same set of probes used to genotype the CECs. RESULTS: The number of CECs from each patient ranged from 1-92 cells/cytospin. CECs showed abnormal copy numbers for at least one of the probes in 25 of 31 patients. Touch preparations from the primary tumors of 13 patients with aneusomic CECs were available. The pattern of aneusomy matched a clone in the primary tumor in 10 patients. CONCLUSIONS: We conclude that the vast majority of CECs in breast, kidney, prostate, and colon cancer patients are aneusomic and derived from the primary tumor.

Validating the performance of the mammary sentinel lymph node team.

BACKGROUND AND OBJECTIVES: The mammary sentinel lymph node (SLN) procedure has the potential to improve the accuracy and lower the morbidity of axillary staging in breast cancer patients, but results are closely linked to experience and can vary widely between institutions. Standardized performance measures need to be established in order to optimize the transition to SLN biopsy only. METHODS: Performance data were prospectively collected for the first 156 mammary SLN procedures performed by three surgeons in our institution. RESULTS: Seventy-five cases were required to achieve an SLN visualization rate of > 80% on preoperative lymphoscintigraphy. The SLN visualization rate was 90% for the last 52 cases. Two surgeons required 25 cases before consistently achieving a > or = 90% SLN identification rate in the operating room and one required 15 cases. The metastasis detection rate increased from 22% for the first 52 cases to 31% for the last 52 cases. The false negative rate for the procedure was 5%. CONCLUSIONS: The following performance criteria and benchmarks are suggested for validating the performance of the SLN team: (1) SLN visualization rate on preoperative lymphoscintigraphy > or = 80%, (2) SLN identification rate in the operating room > or = 90%, (3) False negative rate for the procedure 5%. Thirty procedures per surgeon were sufficient to achieve these benchmarks in our group.