Commentary on "Prognostic effect of carcinoma in situ in muscle-invasive urothelial carcinoma patients receiving neoadjuvant chemotherapy."

BACKGROUND: Carcinoma in situ (CIS) is a poor prognostic finding in urothelial carcinoma. However, its significance in muscle-invasive urothelial carcinoma (MIUC) treated with neoadjuvant chemotherapy (NAC) is uncertain. We assessed the effect of CIS found in pretreatment transurethral resection of bladder tumor (TURBT) biopsies on the pathologic and clinical outcomes. MATERIALS AND METHODS: Subjects with MIUC treated with NAC before cystectomy were identified. The pathologic complete response (pCR) rates stratified by TURBT CIS status were compared. The secondary analyses included tumor response, progression-free survival (PFS), overall survival (OS), and an exploratory post hoc analysis of patients with pathologic CIS only (pTisN0) at cystectomy. RESULTS: A total of 137 patients with MIUC were identified. TURBT CIS was noted in 30.7% of the patients. The absence of TURBT CIS was associated with a significantly increased pCR rate (23.2% vs. 9.5%; odds ratio = 4.08; 95% CI: 1.19-13.98; P = 0.025). Stage pTisN0 disease was observed in 19.0% of the TURBT CIS patients. TURBT CIS status did not significantly affect the PFS or OS outcomes. Post hoc analysis of the pTisN0 patients revealed prolonged median PFS (104.5 vs. 139.9 months; P = 0.055) and OS (104.5 vs. 152.3 months; P = 0.091) outcomes similar to those for the pCR patients. CONCLUSION: The absence of CIS on pretreatment TURBT in patients with MIUC undergoing NAC was associated with increased pCR rates, with no observed differences in PFS or OS. Isolated CIS at cystectomy was frequently observed, with lengthy PFS and OS durations similar to those for pCR patients. Further studies aimed at understanding the biology and clinical effect of CIS in MIUC are warranted.

Detection and isolation of Toxoplasma gondii from fresh semen of naturally infected dogs in Southern Brazil.

The aim of this study was to isolate Toxoplasma gondii and determine the viability of the parasite in fresh semen samples of clinically healthy adult dogs naturally infected. Eleven seropositive dogs with T. gondii IgG antibodies from southern Brazil were selected to confirm the presence and viability of T. gondii in fresh semen samples using in vitro isolation in Vero cell culture, polymerase chain reaction (PCR) and sequencing analysis. The presence of viable T. gondii was confirmed by in vitro isolation and PCR in five semen samples. The ITS1 region of the isolated protozoa (TG S4) was amplified and sequenced. The nucleotide sequence obtained was 99% compatible with the T. gondii DNA sequences stored in the GenBank. It has been shown that T. gondii tachyzoites may be isolated in vitro from fresh semen samples of clinically healthy dogs seropositive for T. gondii.

Differentiation of prostate cancer from normal tissue in radical prostatectomy specimens by desorption electrospray ionization and touch spray ionization mass spectrometry.

Radical prostatectomy is a common treatment option for prostate cancer before it has spread beyond the prostate. Examination for surgical margins is performed post-operatively with positive margins reported to occur in 6.5-32% of cases. Rapid identification of cancerous tissue during surgery could improve surgical resection. Desorption electrospray ionization (DESI) is an ambient ionization method which produces mass spectra dominated by lipid signals directly from prostate tissue. With the use of multivariate statistics, these mass spectra can be used to differentiate cancerous and normal tissue. The method was applied to 100 samples from 12 human patients to create a training set of MS data. The quality of the discrimination achieved was evaluated using principal component analysis - linear discriminant analysis (PCA-LDA) and confirmed by histopathology. Cross validation (PCA-LDA) showed >95% accuracy. An even faster and more convenient method, touch spray (TS) mass spectrometry, not previously tested to differentiate diseased tissue, was also evaluated by building a similar MS data base characteristic of tumor and normal tissue. An independent set of 70 non-targeted biopsies from six patients was then used to record lipid profile data resulting in 110 data points for an evaluation dataset for TS-MS. This method gave prediction success rates measured against histopathology of 93%. These results suggest that DESI and TS could be useful in differentiating tumor and normal prostate tissue at surgical margins and that these methods should be evaluated intra-operatively.

Association of antibodies against Neospora caninum in mares with reproductive problems and presence of seropositive dogs as a risk factor.

Sera from 112 mares from 5 horse-breeding farms was examined for the presence of antibodies to Neospora caninum and Toxoplasma gondii by an indirect fluorescent antibody test (IFAT), as well as from dogs and cattle present on these properties for the presence of antibodies to N. caninum. Among the 112 mares, 35 had a history of reproductive problems in the last breeding season and 77 had no reproductive problems. The rates of seroprevalence of N. caninum in mares with and without a history of reproductive problems were 25.71% and 6.49% and from T. gondii 2.85% and 1.29%, respectively. In dogs and cattle, the rates of seroprevalence of N. caninum were 10.52% and 15.55%, respectively. A positive correlation was found between the presence of antibodies against N. caninum (p=0.010) in mares and the occurrence of reproductive problems using the Fisher's exact test. Significantly higher seroprevalence for N. caninum in mares was observed on the farm that had seropositive dogs (p=0.018). Cattle on this farm were also seropositive. No significant differences in seropositivity were found on farms where dogs were seronegative, or absent. This result suggests, for the first time, the presence of seropositive dogs as a risk factor for N. caninum in mares and the necessity for further investigation of the epidemiology of this parasite in horse-breeding farms with reproductive problems and the presence of cattle and dogs. This is the first report on the occurrence of antibodies against N. caninum in horses from the state of Santa Catarina, Brazil.

The influence of extent of surgical margin positivity on prostate specific antigen recurrence.

BACKGROUND: Positive surgical margins are an adverse prognostic factor in patients undergoing prostatectomy for prostate cancer. The extent of margin positivity varies and its influence on clinical outcome is uncertain. AIMS: To evaluate the linear extent of margin positivity and the number and location of positive sites as prognostic indicators in a series of prostatectomy specimens evaluated with the whole mount technique. METHODS: Eighty six consecutive margin positive prostatectomy specimens were evaluated, and all pathology data were collected prospectively. The linear extent of margin positivity was measured with an ocular micrometer and the total extent of all positive sites was summed. The total number of sites with positive margins and anatomical sites of the positive margins were analysed. RESULTS: The linear extent of margin positivity ranged from 0.01 to 68 mm (mean, 6.8; median, 3.0) and was associated with prostate specific antigen (PSA) recurrence in univariate logistic regression (p = 0.031). In addition, the extent of margin positivity weakly correlated with preoperative PSA (p = 0.017) and tumour volume (p = 0.013), but not with age, prostate weight, Gleason score, pathological stage, or perineural invasion. The total number of positive sites was significantly higher in patients with PSA recurrence (p = 0.037). The location of the positive margin site was not associated with PSA recurrence. The extent of margin positivity correlated with PSA recurrence in univariate analysis, although it had only marginal predictive value when adjusted for Gleason score (p = 0.076). CONCLUSIONS: The extent of margin positivity correlates with PSA recurrence in univariate analysis, although it has no predictive value independent of Gleason score.

The presence of benign prostatic glandular tissue at surgical margins does not predict PSA recurrence.

BACKGROUND: Serum prostate specific antigen (PSA) increases after radical prostatectomy are thought to indicate recurrent disease, although some suggest they result from benign prostatic epithelial tissue left at surgical margins. AIMS: To investigate whether presence, location, and extent of benign prostatic tissue at radical prostatectomy surgical margins influence patient outcome. METHODS: One hundred and ninety nine patients with prostate cancer and negative surgical margins were studied. The prostectomy specimens were totally embedded using the whole mount technique. The apex and bladder neck, dissected as a cone from the specimen, were serially sectioned. The total length of benign prostatic tissue at the margins, measured for each location using an ocular micrometer, was obtained by summing the length of all positive sites. The presence, anatomical location, and extent of benign prostatic tissue at the margin were correlated with clinicopathological characteristics and postoperative PSA increases. RESULTS: Fifty five cases had benign prostatic glandular tissue at the surgical margin. The mean length was 2.19 mm (0.1-14.7). The most frequent location of benign prostatic tissue was the apex (40 patients). Presence, anatomical location, and length of benign prostatic tissue at the margin were not significantly associated with age, preoperative PSA, prostate weight, pathological stage, tumour volume, largest tumour dimension, Gleason score, extraprostatic extension, seminal vesical invasion, tumour multifocality, perineural invasion, or PSA recurrence. CONCLUSIONS: Benign prostatic tissue was frequently found in margins of apex and bladder base, but uncommon in the anterior or posterior prostate. The presence of benign prostatic tissue at surgical margins had no prognostic relevance.

Biochemical disease-free survival in patients with a high prostate-specific antigen level (20-100 ng/mL) and clinically localized prostate cancer after radical prostatectomy.

OBJECTIVE: To examine our experience with radical prostatectomy (RP) in patients with a serum prostate-specific antigen (PSA) level of > 20 ng/mL (who are sometimes considered poor candidates for RP) to determine the outcome and possible predictors of a favourable outcome. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 79 patients who underwent RP with an initial PSA of 20-100 ng/mL. Biochemical disease-free survival (BDFS) was assessed using the Kaplan-Meier method and predictors of treatment outcome examined by uni- and multivariate analysis. Patients excluded from the analysis were 11 (14%) whose surgery was aborted after finding cancerous pelvic nodes and who did not undergo RP; four others with normal nodes during RP who had metastatic tumour on permanent sections; and 14 who had follow-up data for < 2 years. RESULTS: The mean (sd) age of the 50 patients in the final study population was 63 (7) years and the mean PSA 37.9 (16.0) ng/mL. The median (range) follow-up was 54 (24-120) months. The BDFS was 60% at 3 years and 48% at 5 years of follow-up. Two patients developed a local recurrence and eight developed metastatic disease. On logistic regression analysis of factors influencing BDFS, only extracapsular extension of disease was predictive of PSA recurrence; no preoperative factor was significant. When time to PSA recurrence was assessed by Cox regression analysis, again only extracapsular extension was predictive, with no preoperative variable a statistically significant predictor. CONCLUSIONS: Patients with a high serum PSA level (20-100 ng/mL) may be appropriate candidates for RP. While the cancer-free survival is not as good as in patients with a lower PSA, a significant percentage of patients achieve BDFS. No preoperative variables were predictive of disease-free survival or time to PSA recurrence.

Molecular genetic evidence for different clonal origin of components of human renal angiomyolipomas.

Renal angiomyolipoma is a benign neoplasm composed of variable proportions of blood vessels, smooth muscle, and adipose tissue. Smooth muscle, adipose tissue, blood vessels, and adjacent normal kidney tissue were separately microdissected from sections prepared from formalin-fixed, paraffin-processed tissues from angiomyolipomas from 18 women. X chromosome inactivation analysis using the methylation pattern at exon 1 of the human androgen receptor gene on chromosome Xq11-12 was used to study the clonal origin of each component. Nonrandom inactivation of X chromosomes was found in six of the 15 informative tumors. The smooth muscle and adipose tissue showed differing patterns of nonrandom inactivation of X chromosomes in five angiomyolipomas and the same pattern of nonrandom inactivation of X chromosomes in one. Samples from the blood vessels showed random inactivation of X chromosomes in all informative cases. Our data showed that the adipose tissue and smooth muscle cells of renal angiomyolipoma are both monoclonal but may arise independently. The coexistence of tumor subclones with morphologic heterogeneity can lead to the formation of a clinically detectable tumor.

Accuracy of predicting long-term prostate specific antigen outcome based on early prostate specific antigen recurrence results after radical prostatectomy.

PURPOSE: We determined how prostate specific antigen (PSA) doubling time changed with time and whether an early measure of doubling time would accurately predict long-term PSA values and clinical outcome in a cohort of patients followed expectantly after radical prostatectomy. MATERIALS AND METHODS: We analyzed data on 121 patients with PSA recurrence after radical retropubic prostatectomy. Group and individual analyses were performed on 60 patients who met study inclusion criteria. PSA doubling time was calculated and a curve was plotted using logarithmic transformation with linear regression and least squares analysis. In analysis 1 patients were placed into 3 subgroups according to doubling time. Doubling time was calculated per subgroup and the slopes of the aggregate curves were compared to determine how doubling time changed with time. In analysis 2 we calculated early doubling time per patient using only the initial 2 detectable PSA values and compared it with eventual doubling time in each using all PSA values. In addition, we analyzed how doubling time correlated with the clinical course. RESULTS: Using the group methodology there was no statistically significant acceleration or deceleration with time in doubling time slope in any of the 3 subgroups. On individual analysis we noted a weak correlation of early with eventual doubling time (correlation coefficient 0.69, p = 0.01). In 88% of patients eventual doubling time was not within 10% of early doubling time. Metastasis developed in 60% of patients with an eventual DT of 0 to 6 months, while 80% with an eventual doubling time of 6 to 12 months had no evidence of local or metastatic disease. No patients with an eventual doubling time of greater than 12 months have had metastatic disease and only 4 (16%) had local recurrence, which was treated with radiation therapy. In 8 of the 14 patients (23%) with local recurrence or metastatic disease early doubling time predicted eventual doubling time. Early doubling time was more rapid and slower than eventual doubling time in 5 and 1, respectively, of the remaining cases, which would have placed them in a different subgroup. CONCLUSIONS: On group analysis PSA doubling time appeared to be constant with time and there was no evidence that it accelerated with time in our dataset of PSA recurrence after radical prostatectomy. On individual analysis early doubling time showed a weak but statistically significant correlation with eventual doubling time. However, there was significant inaccuracy when predicting PSA doubling time based on early PSA values in individuals. Generally early projections of doubling time tend to over predict tumor biological aggressiveness, that is local recurrence or metastasis. A need remains for more accurate predictors of the rate of disease progression at initial PSA recurrence to determine accurately early in the clinical course the patients who may benefit from additional therapy. Currently no patient in our study has died of prostate cancer.

Spiral ileal neobladder substitution with orthotopic ureteral reimplantation: early results.

PURPOSE: The aim of this report is to present our experience with the spiral ileal neobladder. MATERIALS AND METHODS: From September 1996 to August 1999, 39 patients (35 men and 4 women) underwent radical cystectomy and spiral ileal orthotopic substitution for muscle invasive bladder cancer. Seventy ureters in 37 patients were reimplanted orthotopically using the nonrefluxing Ghoneim technique. Evaluation of these patients included video urodynamics, intravenous pyelogram, renal ultrasound, and patient history relating to urinary incontinence. RESULTS: There were no perioperative deaths. There were 8 (20.5%) early complications. One patient developed a small bowel anastomotic leak, and another patient presented with a vesicovaginal fistula repaired transabdominally. Of the 70 ureters reimplanted in Ghoneim fashion, 5 (7.1%) developed an anastomotic stricture. Three of these patients had stable hydronephrosis and were managed by observation alone; one stricture was treated successfully transurethrally with balloon dilation; and the last patient was managed with a percutaneous nephrostomy tube and surgical reimplantation. Urodynamics in eight patients revealed a Valsalva leak point pressure >50 in two patients and >100 in the six patients. All women experienced mild daytime and nighttime urinary incontinence. Ninety percent of the men were either dry or complained of mild daytime incontinence. No patient experienced bowel dysfunction from the ileal resection. CONCLUSIONS: The spiral ileal neobladder offers the potential advantages of construction from a relatively short bowel segment, excellent length for ureteral anastomosis, acceptable continence rates, and orthotopically reimplanted ureters, which allow transurethral upper tract access. The nonrefluxing ureteral anastomosis has a high stricture rate, and we currently are reimplanting the ureters orthopically in a nontunneled fashion.

Cytokeratin 7 and cytokeratin 20 in primary urinary bladder carcinoma and matched lymph node metastasis.

BACKGROUND: -Cytokeratin 7 (CK7) and cytokeratin 20 (CK20) are 2 types of intermediate filament protein. Expression of CK7 is seen in the majority of primary urinary bladder carcinomas. CK20 is restricted to superficial and occasional intermediate cells of the normal urothelium of the bladder. Aberrant CK20 expression has been documented in urothelial carcinoma and has proved useful as an ancillary diagnostic aid for urinary bladder tumor. Our hypothesis is that the pattern of CK7 and CK20 expression in metastatic urothelial carcinoma duplicates the expression of the same markers in the primary tumors. Therefore, immunohistochemical staining of metastatic tumors for these 2 markers may be helpful for differential diagnosis in ambiguous metastatic tumor deposits. OBJECTIVE: -To determine the concordance of CK7 and CK20 expression in primary bladder urothelial carcinoma and the matched lymph node metastasis. DESIGN: -We studied 26 patients with lymph node metastases who underwent radical cystectomy and bilateral lymphadenectomy for bladder carcinoma. Immunohistochemical staining for CK7 and CK20 was performed on formalin-fixed paraffin-embedded tissues containing primary cancers and lymph node metastases. RESULTS: -In all cases, there was a concordant expression of CK20 in the primary cancer and its matched lymph node metastasis. Twelve cases (46%) showed positive CK20 immunoreactivity in the primary tumor and its matched lymph node metastases, whereas 14 cases (54%) were negative for CK20 in both the primary tumor and lymph node metastasis. All cases showed positive CK7 immunoreactivity in the primary cancers and matched lymph node metastases. CONCLUSIONS: -CK20 immunoreactivity is reliably observed in metastases from bladder cancer when the primary tumor expresses CK20.

Aortic replacement during post-chemotherapy retroperitoneal lymph node dissection.

PURPOSE: We reviewed the records of 15 patients with metastatic germ cell cancer who underwent aortic resection and replacement during post-chemotherapy retroperitoneal lymph node dissection to determine the morbidity and the therapeutic benefit. MATERIALS AND METHODS: Between 1970 and 1998, 1,250 patients underwent post-chemotherapy retroperitoneal lymph node dissection. Our retrospective review revealed that 15 patients underwent aortic replacement at that operation. RESULTS: In addition to aortic replacement 11 patients underwent 15 additional procedures, including nephrectomy in 7, vena caval resection in 3, pulmonary resection in 1, small bowel resection in 2, 1 hepatic resection in 1 and L4 vertebrectomy in 1. No patient had necrosis as the only pathological condition. Three patients (20%) had teratoma and 12 (80%) had viable tumor in the retroperitoneal specimen. All 4 patients who underwent post-chemotherapy retroperitoneal lymph node dissection and aortic replacement after induction chemotherapy alone have no evidence of disease. Only 1 of the 11 patients who received salvage chemotherapy with or without previous post-chemotherapy retroperitoneal lymph node dissection have no evidence of disease. Overall 33% of the patients have no evidence of disease. There were no graft related complications. CONCLUSIONS: Aortic resection at post-chemotherapy retroperitoneal lymph node dissection is justified based on therapeutic benefit and morbidity.

Characterization and predictors of prostate specific antigen progression rates after radical retropubic prostatectomy.

PURPOSE: Detectable serum prostate specific antigen (PSA) after radical prostatectomy indicates recurrent disease and treatment failure. We characterized PSA recurrence after prostatectomy and identified predictors of rapid PSA progression. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 165 patients with detectable PSA after radical prostatectomy to characterize the rate of PSA increase and correlate this rate with the possible predictors of rapid PSA progression known at prostatectomy. RESULTS: For a median of 48 months postoperatively we followed 142 patients with PSA recurrence after radical prostatectomy who received no immediate adjuvant therapy. PSA doubling time was less than 6, greater than 6, 12, 18 and 24 months in 46%, 54%, 18%, 11% and 9% of cases, while time to PSA 50 ng./ml. was greater than 5, 10, 15 and 20 years in 69%, 34%, 22% and 9%, respectively. Univariate and multivariate analyses revealed that rapid PSA doubling time was associated with Gleason secondary grade, Gleason score and time to initial detectable PSA (p = 0.019, 0.031 and 0.0001, and p = 0.043, 0.045 and 0.0001, respectively). CONCLUSIONS: PSA recurrence progresses at a greatly variable rate and many recurrences progress slowly with a long doubling time. Gleason secondary grade and score appear to be predictive of rapid PSA progression. No other pathological features were predictive of rapid PSA progression.

Enhanced expression of cyclooxygenase-2 in high grade human transitional cell bladder carcinomas.

Studies in human and animal models have shown that cyclooxygenase (COX)-2 is up-regulated in several epithelial carcinomas including colon, breast, and lung. To elucidate the possible involvement of COX-2 in human bladder cancer we examined the expression of COX isoforms in benign tissue and in bladder carcinoma specimens. Paraffin embedded tissues from 75 patients with urothelial carcinomas were immunostained with specific antibodies raised against COX-1 and COX-2. COX-1 expression was detected in smooth muscle cells in both benign and malignant bladders. COX-2 immunoreactivity was absent in benign tissue and in specimens with low-grade urothelial carcinoma (0/23). In contrast, expression of COX-2 was detected in malignant epithelial cells in 38% (17/47) of specimens with high-grade urothelial carcinomas. Expression of COX-2 in high-grade bladder cancer was confirmed by radioactive in situ hybridization using a COX-2-selective riboprobe. Both immunohistochemistry and in situ hybridization showed COX-2 expression in a small subset of malignant cells. COX-2 mRNA was also expressed in three out of seven malignant urothelial cell lines. These data demonstrate elevated expression of COX-2 in a high percentage of high-grade bladder carcinomas, suggesting a possible role of COX-2 in the progression of bladder urothelial carcinoma and supporting its potential as a therapeutic target in human bladder carcinoma.

Continent urinary reconstruction versus ileal conduit: a contemporary single-institution comparison of perioperative morbidity and mortality.

OBJECTIVES: To compare postoperative morbidity and mortality in a concurrent and contemporary series of patients who underwent radical cystectomy with ileal conduit versus orthotopic neobladder. METHODS: The data of 198 patients were reviewed, 117 with orthotopic reconstruction and 81 with ileal conduit during a 5-year time frame. Thirty-day morbidity, mortality, reoperative rates, and parameters associated with the surgical procedures were obtained from chart review. RESULTS: No perioperative or postoperative deaths occurred in either group. The median operative time for the ileal conduit was 201 minutes (range 140 to 373), and for the orthotopic neobladder, it was 270 minutes (range 230 to 425). The median blood loss was 389 and 474 mL, respectively. The median length of hospitalization was 8 days for the ileal conduit group and 7 days for the orthotopic neobladder group. Diversion-related complications recognized within 30 days that ultimately required a return to the operating room occurred in 3.4% of those with a neobladder and 1.2% of those with an ileal conduit. CONCLUSIONS: The orthotopic neobladder is a longer and technically more complex procedure than the ileal conduit procedure. However, no demonstrable difference in morbidity or perioperative complications were found between the two procedures in our review.

Management of the dorsal vein complex during radical retropubic prostatectomy.

An understanding of the prostatic dorsal venous anatomy allows dissection of the prostatic apex in a manner that results in minimal bleeding while preserving the rhabdosphincter, urethra, and neurovascular bundles during radical retropubic prostatectomy. This article reviews the pertinent venous anatomy of the prostatic apex. A surgical technique is described that allows secure venous control and that has resulted in consistently low blood loss and an allogeneic transfusion rate of less than 1% of patients.

Early post-prostatectomy pelvic floor biofeedback.

PURPOSE: We determined whether biofeedback enhanced pelvic floor exercises begun 6 weeks after radical prostatectomy improve the early recovery of continence. MATERIALS AND METHODS: We randomized 30 patients who underwent radical retropubic prostatectomy into a group that received 5 biofeedback sessions and a control group. RESULTS: Overall 87% of patients were pad-free at 6 months with similar results in the treatment and control groups (86% versus 88%). There was no statistically significant difference in pad test results or voiding diary records in the 2 groups. CONCLUSIONS: A treatment program of biofeedback enhanced pelvic floor exercises begun 6 weeks after radical retropubic prostatectomy did not significantly affect continence in this study.

Cost-effective strategies for the follow-up of patients with germ cell tumors.

Cost-effective strategies for the follow-up of patients with germ cell tumors must be based on the known natural history of the disease, the accuracy and cost of diagnostic modalities, and the efficacy and effectiveness of therapy when recurrences are detected. The natural history of stage I and stage II germ cell tumors are reviewed, including the unique circumstances of late recurrences. The accuracy and cost of imaging modalities are also reviewed and general recommendations to cost-effective follow-up are proposed.