Robert F. Tarrell

A Multivariable Model Using Advanced Cytologic Methods for the Evaluation of Indeterminate Pancreatobiliary Strictures

BACKGROUND & AIMS Ancillary cytologic tests including digital image analysis (DIA) and fluorescence in situ hybridization (FISH) have been developed to improve the sensitivity of routine cytology (RC) for the diagnosis of malignancy in pancreatobiliary strictures. The goal of this study was to retrospectively compare the performance of RC, DIA, and FISH on clinical brushing specimens. METHODS Endoscopic retrograde cholangiopancreatography brushings were obtained from 498 consecutive patients with pancreatobiliary strictures and analyzed by RC, DIA, and FISH as per standard practice. RC diagnostic categories included negative, atypical, suspicious, or positive. Aneuploid/tetraploid histograms were considered positive for DIA. FISH was performed using UroVysion (Abbott Molecular, Inc, Des Plaines, IL) and classified as negative, trisomy, tetrasomy, or polysomy. RESULTS The sensitivity of polysomy FISH (42.9%) was significantly higher than RC (20.1%) when equivocal RC results were considered negative (P < .001) with identical specificity (99.6%). There was a significant difference in time for diagnosis of carcinoma between FISH diagnostic categories (P < .001) and between RC diagnostic categories (P < .001). Logistic regression analysis revealed that polysomy FISH, trisomy FISH, suspicious cytology, primary sclerosing cholangitis status, and age were associated with carcinoma (P < .05). CONCLUSIONS Polysomy FISH had high sensitivity without compromise to specificity. DIA was not a significant independent predictor of malignancy. Multivariable modeling using RC, FISH, age, and primary sclerosing cholangitis status can be used to estimate the probability of carcinoma for an individual patient. We recommend including FISH as a routine test where available, along with RC, in the evaluation of indeterminate pancreatobiliary strictures.

Sarcopenia in patients with bladder cancer undergoing radical cystectomy: Impact on cancer‐specific and all‐cause mortality

The authors evaluated sarcopenia as a predictor of cancer‐specific survival (CSS) and overall survival (OS) among patients with urothelial cancer of the bladder undergoing radical cystectomy (RC).

The Impact of Perioperative Blood Transfusion on Cancer Recurrence and Survival Following Radical Cystectomy

BACKGROUND While the receipt of a perioperative blood transfusion (PBT) has been associated with an increased risk of mortality for a number of malignancies, the relationship between PBT and survival following radical cystectomy (RC) for bladder cancer (BCa) has not been well established. OBJECTIVE To evaluate the association of PBT with disease recurrence and mortality following RC. DESIGN, SETTING, AND PARTICIPANTS We identified 2060 patients who underwent RC at the Mayo Clinic between 1980 and 2005. PBT was defined as transfusion of allogenic red blood cells during RC or postoperative hospitalization. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Survival was estimated using the Kaplan-Meier method and was compared with the log-rank test. Cox proportional hazard regression models were used to evaluate the association of PBT with outcome, controlling for clinicopathologic variables. RESULTS AND LIMITATIONS A total of 1279 patients (62%) received PBT. The median number of units transfused was 2 (interquartile range [IQR]: 2-4). Patients receiving PBT were significantly older (median: 69 yr vs 66 yr; p<0.0001), had a worse Eastern Cooperative Oncology Group performance status (p<0.0001), and were more likely to have muscle-invasive tumors (56% vs 49%; p = 0.004). Median postoperative follow-up was 10.9 yr (IQR: 7.9-15.7). Receipt of PBT was associated with significantly worse 5-yr recurrence-free survival (58% vs 64%; p = 0.01), cancer-specific survival (59% vs 72%; p<0.001), and overall survival (45% vs 63%; p<0.001). On multivariate analyses, PBT remained associated with significantly increased risks of postoperative tumor recurrence (hazard ratio [HR]: 1.20; p = 0.04), death from BCa (HR: 1.31; p = 0.003), and all-cause mortality (HR: 1.27; p = 0.0002). Among patients who received PBT, an increasing number of units transfused was independently associated with increased cancer-specific mortality (HR: 1.07; p<0.0001) and all-cause mortality (HR: 1.05; p<0.0001). Limitations include selection bias and lack of standardized transfusion criteria. CONCLUSIONS We found that PBT is associated with significantly increased risks of cancer recurrence and mortality following RC. While external validation is required, continued efforts to reduce the use of blood products in these patients are warranted.

Pretreatment Neutrophil-to-Lymphocyte Ratio Is Associated with Advanced Pathologic Tumor Stage and Increased Cancer-specific Mortality Among Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy

BACKGROUND Pretreatment neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been associated with adverse survival in a variety of malignancies. However, the relationship between NLR and oncologic outcomes following radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) has not been well studied. OBJECTIVE To evaluate the association of preoperative NLR with clinicopathologic outcomes following RC. DESIGN, SETTING, AND PARTICIPANTS We identified 899 patients who underwent RC without neoadjuvant therapy at our institution between 1994 and 2005 and who had a pretreatment NLR. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Preoperative NLR (within 90 d prior to RC) was recorded. Recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox proportional hazard and logistic regression models were used to analyze the association of NLR with clinicopathologic outcomes. RESULTS AND LIMITATIONS Median postoperative follow-up was 10.9 yr (interquartile range: 8.3-13.9 yr). Higher preoperative NLR was associated with significantly increased risks of pathologic, extravesical tumor extension (odds ratio [OR]: 1.07; p=0.03) and lymph node involvement (OR: 1.09; p=0.02). Univariately, 10-yr cancer-specific survival was significantly worse among patients with a preoperative NLR (≥2.7 [51%] vs. <2.7 [64%]; p<0.001). Moreover, on multivariate analysis, increased preoperative NLR was independently associated with greater risks of disease recurrence (hazard ratio [HR]: 1.04; p=0.02), death from bladder cancer (HR: 1.04; p=0.01), and all-cause mortality (HR: 1.03; p=0.01). CONCLUSIONS Elevated preoperative NLR among patients undergoing RC is associated with significantly increased risk for locally advanced disease as well as subsequent disease recurrence, and cancer-specific and all-cause mortality. These data suggest that serum NLR may be a useful prognostic marker for preoperative patient risk stratification, including consideration for neoadjuvant therapy and clinical trial enrollment.

Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.

Does Partial Cystectomy Compromise Oncologic Outcomes for Patients with Bladder Cancer Compared to Radical Cystectomy? A Matched Case-Control Analysis

PURPOSE To our knowledge long-term oncologic outcomes following partial cystectomy for urothelial carcinoma remain to be defined. We evaluated patterns of recurrence and survival among matched patients treated with partial vs radical cystectomy for bladder cancer. MATERIALS AND METHODS We identified 86 patients who underwent partial cystectomy for pT1-4N0-1Mx urothelial carcinoma between 1980 and 2006 at our institution. They were matched 1:2 to patients undergoing radical cystectomy based on age, gender, pathological T stage and receipt of neoadjuvant chemotherapy. Survival was estimated using Kaplan-Meier analysis and compared with the log rank test. RESULTS Median postoperative followup was 6.2 years (range 0 to 27). No difference was noted for 10-year distant recurrence-free survival (61% vs 66%, p = 0.63) or cancer specific survival (58% vs 63%, p = 0.67) between patients treated with partial and radical cystectomy, respectively. Interestingly, 4 of 86 patients (5%) who underwent partial cystectomy showed extravesical pelvic tumor recurrence postoperatively vs 29 of 167 (17%) who underwent radical cystectomy (p = 0.004). In addition, 33 of 86 patients (38%) were diagnosed with intravesical recurrence of tumor after partial cystectomy and 16 of 86 (19%) initially treated with partial cystectomy ultimately underwent radical cystectomy. CONCLUSIONS Our matched analysis demonstrated no difference in metastasis-free or cancer specific survival between select patients undergoing partial cystectomy and those undergoing radical cystectomy. Nevertheless, patients treated with partial cystectomy remain at risk for intravesical recurrence and, thus, they should be counseled and surveilled accordingly.

Outcomes following radical cystectomy for nested variant of urothelial carcinoma: a matched cohort analysis.

PURPOSE We evaluated oncological outcomes after radical cystectomy in patients with the nested variant of urothelial carcinoma and compared survival to that in patients with pure urothelial carcinoma of the bladder. MATERIALS AND METHODS We identified 52 patients with the nested variant who were treated with radical cystectomy between 1980 and 2004. Pathological specimens were re-reviewed by a single genitourinary pathologist. Patients were matched 1:2 by age, gender, ECOG (Eastern Cooperative Oncology Group) performance status, pathological tumor stage and nodal status to patients with pure urothelial carcinoma. Survival was estimated using the Kaplan-Meier method and compared with the log rank test. RESULTS Patients with the nested variant had a median age of 69.5 years (IQR 62, 74) and a median postoperative followup of 10.8 years (IQR 9.3, 11.2). Nested variant cancer was associated with a high rate of adverse pathological features since 36 patients (69%) had pT3-T4 disease and 10 (19%) had nodal invasion. Eight patients (15%) with nested variant cancer received perioperative chemotherapy. When patients with the nested variant were matched to a cohort with pure urothelial carcinoma, no significant differences were noted in 10-year local recurrence-free survival (83% vs 80%, p = 0.46) or 10-year cancer specific survival (41% vs 46%, p = 0.75). CONCLUSIONS The nested variant of urothelial carcinoma is associated with a high rate of locally advanced disease at radical cystectomy. However, when stage matched to patients with pure urothelial carcinoma, patients with the nested variant did not have an increased rate of recurrence or adverse survival. Further studies are required to validate these findings and guide the optimal multimodal treatment approach to these patients.

Perioperative Blood Transfusion and Radical Cystectomy: Does Timing of Transfusion Affect Bladder Cancer Mortality?

BACKGROUND While perioperative blood transfusion (BT) has been associated with adverse outcomes in multiple malignancies, the importance of BT timing has not been established. OBJECTIVE The objective of this study was to evaluate whether intraoperative BT is associated with worse cancer outcomes in bladder cancer patients treated with radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS Outcomes from two independent cohorts of consecutive patients with bladder cancer treated with RC were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Recurrence-free survival, cancer-specific survival (CSS), and overall survival were estimated and multivariate analyses were performed to evaluate the association of BT timing with cancer outcomes. RESULTS AND LIMITATIONS In the primary cohort of 360 patients, 241 (67%) received perioperative BT, including 162 intraoperatively and 79 postoperatively. Five-year CSS was 44% among patients who received an intraoperative BT versus 64% for patients who received postoperative BT (p=0.0005). After multivariate analysis, intraoperative BT was associated with an increased risk of cancer mortality (hazard ratio [HR]: 1.93; p=0.02), while receipt of postoperative BT was not (p=0.60). In the validation cohort of 1770 patients, 1100 (62%) received perioperative BT with a median postoperative follow-up of 11 yr (interquartile range: 8.0-15.7). Five-year RFS (p<0.001) and CSS (p<0.001) were significantly worse among patients who received an intraoperative BT. Intraoperative BT was independently associated with recurrence (HR: 1.45; p=0.001), cancer-specific mortality (HR: 1.55; p=0.0001), and all-cause mortality (HR: 1.40; p<0.0001). Postoperative BT was not associated with risk of disease recurrence or cancer death. CONCLUSIONS Intraoperative BT is associated with increased risk of bladder cancer recurrence and mortality. PATIENT SUMMARY In this study, the effects of blood transfusion on bladder cancer surgery outcomes were evaluated. Intraoperative blood transfusion, but not postoperative transfusion, was associated with higher rates of recurrence and cancer-specific mortality.

Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome

Micropapillary urothelial carcinoma exhibits amplification of the human epidermal growth factor receptor, ERBB2(HER2), and overexpression of the ERBB2 protein product. The clinical significance of this has yet to be established. The objective of this study was to examine ERBB2 amplification and protein expression in micropapillary urothelial carcinoma and stage-matched typical urothelial carcinoma treated by radical cystectomy to assess the frequency of amplification and protein expression, and to determine the association with cancer-specific survival. Pathologic material and data from patients undergoing cystectomy at Mayo Clinic between 1980 and 2008 were reviewed. ERBB2 amplification by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry were assessed. Univariate and multivariate Cox proportional hazards regression models were used to evaluate for associations of ERBB2 amplification and protein expression with survival. ERBB2 amplification was identified in 9 (15%) of 61 micropapillary carcinomas compared with 9 (9%) of 100 urothelial carcinomas. In patients with micropapillary carcinoma, ERBB2 amplification was associated with a nearly threefold increased risk of cancer death. ERBB2 amplification (hazard ratio 4.3; P=0.0008) remained associated with an increased risk of death from bladder cancer among patients with micropapillary urothelial carcinoma on multivariate analysis. The association of cancer-specific survival and ERBB2 amplification was not seen in patients with urothelial carcinoma. ERBB2 immunohistochemistry correlated with ERBB2 amplification but there was no association of ERBB2 protein expression and survival. ERBB2 amplification is more frequent in micropapillary urothelial carcinoma than typical urothelial carcinoma, and patients with micropapillary carcinoma who have ERBB2 amplification have worse cancer-specific survival than those who do not. Identification of ERBB2 amplification in micropapillary carcinoma could provide important prognostic information and possibly provide a role for ERBB2 targeted therapy.

Cystectomy for Refractory Hemorrhagic Cystitis: Contemporary Etiology, Presentation and Outcomes

PURPOSE We evaluate the clinical presentation, management and outcomes of patients undergoing cystectomy for refractory hemorrhagic cystitis. MATERIALS AND METHODS We identified 21 patients with refractory hematuria treated with cystectomy at our institution between 2000 and 2012. Clot evacuation, bladder fulguration and bladder irrigation had failed in all patients before cystectomy. In addition, 45% of patients had received prior intravesical therapy (aminocaproic acid, alum or formalin), hyperbaric oxygen therapy (25%), nephrostomy tube placement for attempted urinary diversion (15%) and/or selective bladder angioembolization (5%). RESULTS Median patient age at surgery was 77 years (IQR 72, 80) and 81% (17 of 21) of patients were male. The most common etiology for hemorrhagic cystitis was prior radiation therapy for prostate cancer (17, 81%). Median time from receipt of radiation to cystectomy in these patients was 91 months (IQR 73, 125). Median ASA® (American Society of Anesthesiologists) score at cystectomy was 3 and median preoperative hemoglobin was 10.2 gm/dl. Median length of stay after cystectomy was 10 days (IQR 7, 19). Severe (Clavien grade III to V) complications were noted in 42% of patients (8 of 19) and the 90-day mortality rate in this cohort was 16% (3 of 19). With a median postoperative followup of 13 months (IQR 4, 21), the 1 and 3-year overall survival was 84% and 52%, respectively. CONCLUSIONS Cystectomy for hemorrhagic cystitis is associated with a high risk of perioperative complications and mortality, consistent with the baseline clinical status of this patient cohort and, as such, should remain a last resort to control bleeding after failure of conservative measures.