Sara A. Farmer

T-Cell Coregulatory Molecule Expression in Urothelial Cell Carcinoma: Clinicopathologic Correlations and Association with Survival

Purpose: Aberrant expression of T-cell coregulatory molecules has been investigated as a mechanism by which certain cancers may evade host immune surveillance. We evaluated expression of the T-cell coregulators B7-H1, B7-H3, and PD-1 in urothelial cell carcinoma (UCC) of the bladder. Experimental Design: Immunohistochemistry for B7-H1, B7-H3, and PD-1 was done on paraffin-embedded sections from 318 consecutive patients with UCC who underwent radical cystectomy. Expression was correlated with clinicopathologic outcomes and postoperative survival. Results: B7-H3 was widely expressed in UCC, as 222 of 314 (70.7%) tumors showed positive staining. Expression of B7-H3 in UCC was significantly increased compared with adjacent, nontumor urothelium, as a median of 70% of tumor cells expressed B7-H3, compared with 20% of cells in nontumor specimens (P < 0.001). The increase in B7-H3 expression was independent of tumor stage (P = 0.13). Expression of B7-H1 by UCC tumors (P < 0.001) and PD-1 by tumor-infiltrating lymphocytes (P = 0.012) were significantly associated with increased pathologic stage. Patients who had received intravesical bacillus Calmette-Guerin before cystectomy tended to show increased expression of B7-H3 (P = 0.023) and PD-1 (P = 0.071) but were less likely to express B7-H1 (P = 0.027). Moreover, for the subset of patients with organ-confined disease (n = 167), B7-H1 expression independently predicted all-cause mortality after cystectomy (hazard ratio, 3.18; 95% confidence interval, 1.74-5.79; P < 0.001). Conclusions: B7-H3 is highly expressed in UCC across tumor stages, whereas B7-H1 and PD-1 expression are associated with advanced disease. B7-H1 expression predicts mortality after cystectomy for patients with organ-confined tumors. These molecules may represent novel diagnostic or prognostic markers, as well as therapeutic targets, for patients with UCC.

Long-Term Complications of Conduit Urinary Diversion

PURPOSE We evaluated long-term surgical complications and clinical outcomes in a large group of patients treated with conduit urinary diversion. MATERIALS AND METHODS We identified 1,057 patients who underwent radical cystectomy with conduit urinary diversion using ileum or colon at our institution from 1980 to 1998 with complete followup information. Patients were followed for long-term clinical outcomes and analyzed for the incidence of diversion specific complications. RESULTS A total of 844 patients died at a median of 4.1 years (range 0.1 to 28.1) following cystectomy. Median followup of the surviving 213 patients was 15.5 years (range 0.3 to 29.1). There were 643 (60.8%) patients with 1,453 complications directly attributable to the urinary diversion performed with a mean of 2.3 complications per patient. Bowel complications were the most common, occurring in 215 patients (20.3%), followed by renal complications in 213 (20.2%), infectious complications in 174 (16.5%), stomal complications in 163 (15.4%) and urolithiasis in 162 (15.3%). The least common were metabolic abnormalities, which occurred in 135 patients (12.8%), and structural complications, which occurred in 122 (11.5%). Increasing age at cystectomy (HR 1.21, p <0.001), increasing Eastern Cooperative Oncology Group performance status (HR 1.23, p = 0.02) and recent era of surgery (HR 1.68, p <0.001) were significantly associated with a higher incidence of complications. CONCLUSIONS Conduit urinary diversion is associated with a high overall complication rate but a low reoperation rate. Long-term followup of these patients is necessary to closely monitor for potential complications from the urinary diversion that can occur decades later.

Functional Gastrointestinal Disorders Among People With Sleep Disturbances: A Population-Based Study

OBJECTIVE To determine whether unexplained gastrointestinal (GI) symptoms are more common in people with self-reported sleep disturbance. PARTICIPANTS AND METHODS From November 1988 to June 1994, valid self-report questionnaires were mailed to age- and sex-stratified random samples of Olmsted County, Minnesota, residents aged 20 to 95 years. RESULTS Of 2269 study participants (74% response rate), 52% were women (mean age, 45.0 years). The overall age- and sex-adjusted prevalence of sleep disturbance per 100 population was 13.5% (95% confidence interval [CI], 11.7%-15.3%). Among study participants with sleep disturbance, the prevalence of irritable bowel syndrome (IBS) was 33.3% (95% CI, 26.0%-40.5%) and the prevalence of frequent dyspepsia (FD) was 21.3% (95% CI, 14.4%-28.2%). After adjusting for age, sex, and somatization score, IBS was significantly more common in those with sleep disturbance (odds ratio, 1.6; 95% CI, 1.1-2.2), but the univariate association with FD was no longer statistically significant (odds ratio, 1.3; 95% CI, 0.9-1.9). CONCLUSIONS Both IBS and FD are prevalent in those with self-reported sleep disturbance. Sleep disturbance was independently associated with IBS but not FD in the general population.

Expression and significance of androgen receptor coactivators in urothelial carcinoma of the bladder

Urothelial carcinoma (UC) of the bladder is approximately three times more common in men than women. While the etiology for this gender difference in incidence remains unknown, a role for androgen receptor (AR) signaling has been suggested. The mechanisms by which AR activity is regulated in UC cells, however, are largely elusive. Here, we explore the significance of coregulators that are critical for the formation of a functional AR transcriptional complex, in UC cells. Using two AR-positive UC cell lines, TCC-SUP and UMUC3, we demonstrate the expression of the coactivators NCOA1, NCOA2, NCOA3, CREBBP, and EP300 in UC cells. small interfering RNA-mediated knockdown of the AR or any of these coactivators markedly impacted cell viability and abrogated androgen-dependent cell proliferation. Noteworthy, contrary to AR-positive prostate cancer cells, expression of these AR-associated coactivators was not androgen regulated in UC cells. To assess the clinical relevance of coactivator expression, we performed immunohistochemistry on paraffin-embedded sections from 55 patients with UC of the bladder. We found that while 24 out of 55 (44%) of tumors expressed the AR, each of the coactivators was expressed by 85-100% of the bladder cancers. Moreover, we noted a significant downregulation of NCOA1 expression in tumors versus adjacent, non-tumor bladder urothelium, with a mean of 68% (range 0-100) of tumor cells demonstrating NCOA1 staining versus a mean of 81% (range 0-90) of non-tumor cells (P=0.03). Taken together, our data suggest an important role for AR-associated coactivators in UC and point toward differences in the regulation of AR activity between bladder and prostate cancer cells.

Functional and oncological outcomes after orthotopic neobladder reconstruction in women

To review our experience with orthotopic neobladder reconstruction (ONR) in women, highlighting functional and oncological outcomes, as ONR has been used increasingly for urinary diversion in women after radical cystectomy (RC), largely due to a better understanding of the natural history of urothelial cell carcinoma (UCC) and of the anatomy underlying the female continence mechanism, but defining the safety and long‐term efficacy of ONR remain important to expanding its use.

Significance of Distal Ureteral Margin at Radical Cystectomy for Urothelial Carcinoma

PURPOSE Urothelial carcinoma develops from a diffusely susceptible mucosa and, thus, patients who undergo cystectomy are at risk for upper tract recurrence. Management of the distal ureter at cystectomy remains controversial and the impact of a sequential sectioning strategy remains unclear. MATERIALS AND METHODS We identified 1,397 patients who underwent radical cystectomy for nonmetastatic urothelial carcinoma from 1980 to 1998. All patients underwent frozen section analysis of the distal ureteral specimen. When positive, additional specimens were obtained. We evaluated the impact of a positive ureteral margin and the effect of ultimately obtaining a negative margin after sequential resection. RESULTS At last followup 432 patients (31%) had died of urothelial carcinoma a median of 1.8 years after cystectomy. Median followup in the 315 patients alive at last evaluation was 14.0 years. A total of 178 patients (12.7%) had a positive initial ureteral margin and only 31 (2.2%) had a positive final resection margin. Associations of margin status with overall and cancer specific survival were not statistically significant. Of 1,397 patients 69 (4.9%) experienced upper tract recurrence at a median of 3.1 years. Positive initial margin status and final margin status were associated with upper tract recurrence (p <0.001). CONCLUSIONS Patients with positive ureteral margins at cystectomy are at increased risk for upper tract recurrence. With a serial sectioning strategy most positive initial margins can be converted to negative final margins. Patients who undergo conversion to a negative final margin with serial sectioning are at decreased risk for upper tract disease.

Multifactorial, site-specific recurrence model after radical cystectomy for urothelial carcinoma

A scoring algorithm of site‐specific disease recurrence after cystectomy for urothelial carcinoma was designed.

Results of patch testing to personal care product allergens in a standard series and a supplemental cosmetic series: An analysis of 945 patients from the Mayo Clinic Contact Dermatitis Group, 2000-2007

BACKGROUND Patch testing to a standard screening series of allergens in combination with supplemental cosmetic allergens is often used to diagnose allergic contact dermatitis due to personal care products. OBJECTIVE To report results of patch testing to skin care product allergens contained in a standard series and a supplemental cosmetic series and to compare efficacy of this combined series in detecting positive reactions to personal care product allergens with the efficacy of various standard screening series. METHODS Positive reaction rates to skin care product allergens were tabulated for patients who underwent patch testing to both standard and cosmetic series allergens at Mayo Clinic between 2000 and 2007. Data were compared with skin care allergens detected on standard screening series, including the thin-layer rapid use epicutaneous (TRUE) test. RESULTS Of 945 patch-tested patients, 68.4% had at least one positive reaction and 47.3% had at least two positive reactions. Also, 49.4% of patients reacted to at least one preservative; 31.2% reacted to at least one fragrance/botanical additive. Compared with use of our standard series and cosmetic series, use of the TRUE test would have missed 22.5% of patients with preservative allergy, 11.3% with fragrance/botanical allergy, and 17.3% with vehicle allergy. LIMITATIONS Various allergens tested over time, patch test reading by residents, and lack of confirmation of allergen in personal care products. CONCLUSION Standard patch-test screening series miss a substantial number of patients with skin care product ingredient allergy.

Delayed patch test reading after 5 days: The Mayo Clinic experience

BACKGROUND Some patients may have delayed allergic patch test reactions that are not identified with a typical 5-day reading protocol. OBJECTIVE To identify allergens with delayed-positive reactions and to determine whether a late reading (day 7-9) can be substituted for the day-5 reading. METHODS We retrospectively reviewed medical records of patients who underwent patch testing for suspected allergic contact dermatitis from October 1997 through December 2006 and returned for delayed readings between days 7 and 10 or beyond. (This cohort was predominantly patients with suspected allergies to metals and corticosteroids). RESULTS A total of 36,064 individual reactions (471 allergens, 372 patients) were interpreted on day 5 and at least once during days 7 through 21. We analyzed the 170 allergens that were each tested in at least 50 patients. The 4 allergens with the highest percentage of delayed-positive reactions were gold sodium thiosulfate 0.5% (delayed-positive reactions in 22/353 patients), dodecyl gallate 0.25% (6/105), palladium chloride 2% (8/194), and neomycin sulfate 20% (10/253). We observed a low number of delayed-positive readings for p-phenylenediamine 1% (1/251) and for corticosteroids. Reactions to certain preservative and fragrance allergens dissipated after the day-5 reading. Most reactions that dissipated after day 5 were mild, whereas the reactions that became apparent after day 5 were strong. LIMITATIONS This was a retrospective study. Most patients had suspected allergies to metals and corticosteroids. CONCLUSION Late patch test readings (day 7 or beyond) were useful when interpreting reactions to metals and topical antibiotics, but it was not useful in the diagnosis of reactions to other allergens, including topical corticosteroids. Because reactions to certain fragrance and preservative allergens may dissipate after 5 days, patch test reactions therefore are optimally read at days 3 and 5, but an additional reading on day 7 or beyond is useful if patch tests to metals and topical antibiotics are performed.

Dyspepsia consulters and patterns of management: a population‐based study

Background:  Although dyspepsia is common, management patterns in the United States are unknown.