bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence and predictors of mortality following major urologic cancer surgery.
Authors: Mossanen Matthew , Krasnow Ross , Zlatev Dimitar V. , Chang Steven Lee 
Published: February 2018

435 Background: Mortality following major urologic cancer surgery is a significant outcome to patients and providers. We utilized a population based cohort to test the hypothesis that the nature and number of perioperative complications impact the probability of mortality in major urologic surgery. Methods: Using the Premier Hospital Database we identified patients that underwent major urologic cancer surgery: radical prostatectomy (RP), radical nephrectomy (RN), or radical cystectomy (RC). Ninety-day complications were captured using ICD9 codes and complications were categorized according to the Agency for Healthcare Research and Quality Clinical Classification categories. The primary outcome was predicted probability of perioperative morality. Adjusted regression models were used and analyses were survey weighted. Models were adjusted for patient, hospital, and surgery characteristics, and we examined the predicted probability of mortality in three scenarios (no complication, index complication, or readmission complication). Results: From 2005-2013 we identified 630 828 RP, 306 532 RN, and 57 533 RC patients. At 90 days, 14.2% of RP patients had a complication, compared to 39% of RN patients and 68.3% of RC patients. Readmission rates at 90 days for RP were 1.9%, 5.9% for RN, and 19.9% for RC. For RN and RC the presence of a complication resulting in readmission compared to an index complication nearly doubled the predicted probability of mortality (RN 1.7% to 3.6%, and RC 3.9% to 6.8%). The number of complications during the index stay and on readmission compounded the impact on mortality. For RN and RC, 1 complication vs. 4 complications resulted in a nearly 3-fold increase in predicted probability of mortality. The nature of complications varied by incidence however, the three most common complications that resulted in the greatest increase in predicted probability of mortality across all three operations included pulmonary, cardiac, and renal complications. Conclusions: The number and nature of complications after major urologic cancer surgery impact the predicted probability of perioperative mortality and such data may be used to counsel patients when providing urologic cancer care.
C-reactive protein as a prognostic factor in advanced urothelial carcinoma receiving chemotherapy or immunotherapy.
Authors: Zhao Yan , Pond Gregory Russell , Naik Gurudatta , Wei Xiao X. , McGregor Bradley Alexander , Sonpavde Guru 
Published: February 2018

436 Background: Clinical prognostic factors have been reported for patients receiving systemic chemotherapy. We hypothesized that markers of tissue damage and inflammation may be prognostic. We conducted a retrospective study to evaluate the prognostic impact of serum lactate dehydrogenase (LDH) and C-reactive protein (CRP) in patients with metastatic UC. Methods: We collected data for patients with metastatic UC receiving systemic therapy and measured serum LDH and CRP at baseline before initiating therapy. The variables collected were recognized clinical prognostic factors (performance status [PS], visceral metastasis, hemoglobin, albumin) and outcomes (time to failure [TTF], overall survival [OS]). TTF was defined as time from initiation of therapy to discontinuation of agent for any reason. LDH and CRP were evaluated on a log-continuous scale. The Kaplan-Meier method was used to estimate times to events. Cox proportional hazards regression and logistic regression were used to study the association of factors with TTF and OS. All tests were 2-sided and significance was defined as p≤0.05. Results: A total of 36 patients were available with a median age of 74 years. The systemic therapy was platinum-based chemotherapy in 18 patients (50%), PD1/PD-L1 inhibitor in 8 patients (22.2%) and the remaining received other agents (taxane or investigational). Twenty-nine (80.5%) had PS 0-1, 13 (36.1%) had visceral metastasis and 16 (44.4%) had received prior platinum-based chemotherapy. A total of 31 patients were evaluable for this analysis with 5 inevaluable due to missing data or inadequate follow-up. On multivariable analyses, only CRP was associated with TTF (HR 1.55 [95% CI: 1.10, 2.20], p = 0.013) and OS (HR 1.77 [95% CI1.10, 2.85], p = 0.018). The limitations of a small dataset and retrospective analysis apply. Conclusions: In patient with advanced UC receiving systemic chemotherapy or PD1/PD-L1 inhibitors as first-line or salvage therapy, CRP was significantly prognostic for both TTF and OS, while other factors were not. Given the potentially powerful prognostic impact of CRP, investigation in larger datasets is warranted to enable better prognostic stratification.
Correlation of MTOR protein expression in the tumor and its microenvironment with more aggressive pathology at cystectomy.
Authors: Winters Brian , Vakar-Lopez, MD Funda , Brown, BS Lisha , Montgomery Robert B. , Seiler Roland , Hsieh Andrew Caleb , Wright Jonathan L. , Lam Hung-Ming 
Published: February 2018

438 Background: The mechanistic target of rapamycin (mTOR) has been implicated in driving tumor biology in multiple malignancies, including urothelial carcinoma (UC). We investigate how mTOR and phosphorylated mTOR (pmTOR) protein expression in both the tumor, and the tumor microenvironment, correlate with final pathologic stage at cystectomy after neoadjuvant chemotherapy (NAC). Methods: A single-institution retrospective analysis was performed on 62 patients with cT2-4Nany UC undergoing NAC followed by radical cystectomy. Diagnostic (transurethral resection specimens, TURBT) and post-NAC radical cystectomy specimens were evaluated for mTOR and pmTOR protein expression using immunohistochemistry of the tumor, peritumoral stroma, and normal surrounding tissue. Protein expression levels were compared between TURBT and cystectomy samples. Whole transcriptome analysis was performed to evaluate mRNA expression relative to mTOR pathway activation. Results: Baseline levels of mTOR and pmTOR within TURBT specimens were not associated with clinical stage or response to NAC overall. Non-responder patients, defined as pT2-T4/pTanyN+, had significantly elevated mTOR tumor staining (p = 0.006) and sustained mTOR and pmTOR staining in the peritumoral and surrounding normal stroma of cystectomy specimens compared with baseline TURBT samples (NS). In contrast, complete responders (pT0), had significant decreases in tumoral mTOR and pmTOR protein expression at cystectomy (p = 0.01-0.03). Several genes relevant to mTOR activity were found to be overexpressed in post-NAC cystectomy samples (compared with TURBT) of non-responder patients (THBS1, FN1, FOS, CNN1, COL1A2). Conclusions: Our results suggest that mTOR pathway activity is increased in the tumor and sustained the tumor microenvironment of patients with adverse pathologic findings at cystectomy after NAC. These findings suggest the relevance of targeting the mTOR pathway in bladder cancer.
The impact of tertiary Gleason pattern 5 in the grade group system on recurrence following radical prostatectomy in patients with prostate cancer.
Authors: Kato Masashi , Tsuzuki Toyonori , Ishida Ryo , Kimura Tohru , Kamihira Osamu , Sassa Naoto , Gotoh Momokazu 
Published: February 2018

44 Background: The current ISUP/WHO grade group system classified the Gleason grade into five groups. Although presence of tertiary Gleason pattern 5 (tG5) reported to be related with unfavorable tumor characteristic, only a few data is available about influences on the grade group system of tG5 so far. In this study, we evaluated the effect of tG5 on recurrence following radical prostatectomy in patients with prostate cancer. Methods: We retrospectively evaluated 1,020 patients with prostate cancer who underwent radical prostatectomy without neoadjuvant therapy at the hospitals that the authors were affiliated with between 2005 and 2013. After excluding the patients with missing data or slides, 1000 patients were enrolled in this study. All prostatectomy specimen slides were reviewed by a single genitourinary pathologist according to ISUP 2014. Recurrence following radical prostatectomy was defined according to European Association of Urology guidelines. The endpoint was defined as an increase in PSA level. Results: Patient median age was 67 years (range 49–77 years). The median serum PSA was 6.9 ng/mL (range 0.4–82 ng/mL). The median follow-up period was 69 months (range 0.7–134 months). All the patients showed Group1:163 cases (16.3%), Group2: 436 (43.6%), Group 2 with tG5: 54 (5.4%), Group 3:121 (12.1%), Group 3 with tG5: 89 (8.9%), Group 4: 39 (3.9%), and Group 5: 98 (9.8%). PSA progression-free survival was significantly different among the five groups (Group1-5) (p = 0.0001). As concerning tG5, it showed significant difference between Group 2 and Group 2 with tG5 by using log rank test (p < 0.0001). Similarly, there was significant difference between Group 3 and Group 3 with tG5 (p = 0.001). On the other hand, there was no difference between Group 2 with tG5 and Group 3 (p = 0.916), and in the same way, no difference between Group 3 with tG5 and Group 4 (p = 0.854). Conclusions: The Presence of tG5 on the grade group system increase PSA progression following radical prostatectomy in patients with prostate cancer. Especially, Group 2 and 3 showed upgrade by presence of tG5. Integrating tG5 into the grade group system will improve the accuracy of patient outcome predictions.
Heat targeted drug delivery (COMBAT) in superficial TCC : First midterm results in a cohort of high-risk patients scheduled for cystectomy.
Authors: Voegeli Thomas Alexander , Frank Eric , Bach Christian , Nzeh Catejan 
Published: February 2018

442 Background: Due to the suboptimal outcomes in recurrent superficial TCC over the last 30 years the search for new treatments continues. We report the first mid term results of a high risk cohort of heavily pretreated patients by a circulating device for intravesical thermochemotherapy.It is known that the effect of mitomycin increases at a temperature over 40 C. Methods: 58 patients with different failed methods of former intravesical therapy and recurrent TCC (21 intermediate risk and 37 high risk patients) were treated with the COMBAT device which facilitates irrigation of the bladder with mitomycin 40 mg at exactly 43 degree Celsius for 1 hour/6 courses weekly.Side effects were monitored prospectively and success of the treatment was controlled by ReTUR whenever possible and afterwards by 3 monthly cystoscopy and cytology. Results: 22 patients had dysuria during treatment and 9/58 suffered from hematuria but without intervention. In 6 cases urinary tract infection occured and 3 patients had allergic reaction. In one patient thermochemotherapy must be terminated due to pain and discomfort, no long term morbidity was recorded over the whole period. The FU was 14 month (3-29) for the entire cohort, 17 patients had a FU of over 2 years. One Patient had recurrent pTaGIII Tumor managed successfully by TUR. 2 patients underwent cystectomy because of invasive recurrence early after intravesical therapy, one patient developed bone metastasis 2 years after therapy without intravesical tumor. Conclusions: Thermochemotherapy with heated mitomycin is a well tolerated new option for patients with superficial TCC who are at high risk of recurrence or progression.The toxicity is acceptable and no long term morbidity was obeserved. The rate of cystectomies in this heavily pretreated group of patients including 18 BCG failures was very low with N= 2 respective 1,9%. Intravesical thermochemotherapy seems to be a new therapeutic bladder preserving option in high risk patients with superficial TCC. It is of note that thermochemotherapy has now been included in the European Guidelines.
Evaluation of the timing of adjuvant mitomycin C following nephroureterectomy for urothelial carcinoma of the upper urinary tract.
Authors: Noennig Blake , Bozorgmehri Shahab , Terry Russell , Otto Brandon , Blute Mike , Su Li-Ming , Crispen Paul 
Published: February 2018

444 Background: Results of randomized trials support a single dose of intravesical chemotherapy (IVC) following radical nephroureterectomy (RNU) for urothelial carcinoma. Our goal was to evaluate the impact of the timing of intravesical mitomycin C (MMC) administration on the rate of bladder tumor recurrence (BTR) following RNU. Methods: After obtaining IRB approval, we performed a retrospective review of patients who underwent RNU for upper tract urothelial carcinoma (UTUC) and received intravesical MMC between 2008 and 2016 at our institution. Patients were categorized into two separate groups based on the timing of MMC administration: (1) patients who received MMC on the day of surgery (POD0) and (2) patients who received MMC on post-operative day 1 or later (POD1). Our primary endpoint was BTR rate within the first year after surgery. Our secondary endpoint was overall BTR rate. Results: Fifty-one patients met our inclusion criteria: (POD0: n = 30; POD1: n = 21). Mean length of follow-up for each group was 22.1 and 12.5 months, respectively (p = 0.02). There were no statistically significant differences in baseline characteristics of age, gender, race, surgical approach, tumor grade, tumor stage, surgical margins, nodal status, concomitant CIS, or history of bladder cancer. BTR rates at 1 year for the POD0 and POD1 groups were 16% and 33%, respectively (p = 0.17). Overall BTR rates were 23% and 33%, respectively (p = 0.43). Multivariate analysis noted that the POD0 patients had a significantly lower rate of BTR in the first year postoperatively (HR = 0.082, 95% CI = 0.01-0.56, p = 0.01). Other factors that were associated with a higher rate of BTR within the first year were open surgery (HR = 7.9, 95% CI = 1.18-53.88, p = 0.03), positive surgical margins (HR = 37.9, 95% CI = 1.74-825.35, p = 0.02), and concomitant CIS (HR = 10.8, 95% CI = 1.08-108.72). Conclusions: Our results suggest that the timing of intravesical MMC administration may impact the rate of BTR following RNU for urothelial carcinoma. This is the first study of its kind to attempt to identify the importance of timing of MMC administration relative to BTR following RNU. Further prospective studies are warranted to validate our current findings.
Response to platinum-based therapy (PBT) and immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC) patients (pts) with genomic alterations (GA) in homologous recombination repair (HRR) genes.
Authors: Mendiratta Prateek , Loehr Andrea , Simmons Andrew , Barata Pedro C. , Klek Stefan , Pritchard Amy , Emamekhoo Hamid , Funchain Pauline , Sohal Davendra , Ali Siraj Mahamed , Gilligan Timothy D. , Ornstein Moshe Chaim , Garcia Jorge A. , Rini Brian I. , Grivas Petros 
Published: February 2018

447 Background: Deleterious GA in genes of the HRR pathway and tumor mutational load (TML; mutations/Mb) were shown to predict response to PBT and ICI; further validation can be informative. We assessed the predictive role of such GA in mUC. Methods: Tissue from mUC pts treated with PBT or ICI in the 1st line setting underwent genomic profiling (GP) via FoundationOne. Pts were analyzed in 2 groups based on the presence of potentially function-impairing GA (using classification criteria) in any of 15 pre-selected HRR genes. Exploratory assessment of overall response rate (ORR; RECIST v1.1), progression-free and overall survival (PFS, OS) based on presence of relevant GA was performed using Cox proportional hazards model, Kaplan Meier estimates, and Fisher’s exact test. Results: GA were noted in 22% of 88 identified mUC pts with available GP from 2012 to 2017. The most common deleterious GA were BRCA1/2 (n=6), ATM (n=6), CDK12 (n=2), BRIP1 (n=2), BARD1 (n=1), RAD51 (n=1), and CHEK2 (n=1). Of 88 pts, 62 were treated in the 1st line setting (median age 69; 27% women; 42% never smokers). Of these 62 pts, 42 received PBT and 20 ICI. Deleterious GAs were noted in ≥1 HR gene in 24% and 10% of pts in each group, respectively. The ORR was 40% and 43% in PBT pts with and without GA in any HRR gene, respectively. Analysis showed a median OS (10.6 vs 14.3 months, p=0.11), median PFS (6.1 vs 7.9 months, p=0.05), and no difference in the rate of responders vs non-responders (p=0.53) to PBT in pts with vs without GA in HRR genes. Analysis of ICI treated pts was not feasible (only 2 had GA in HRR genes). Median TML was 8 and 10 in pts with available data treated with PBT and ICI, respectively. There was no correlation between TML and response to either 1st line therapy (analysis underpowered). Of pts with GA in HR genes, the one with the longest OS had 2 GA (CDK12; FANCA). Conclusions: Deleterious GAs in genes of HRR pathway are frequent in mUC supporting TCGA and other datasets but did not confer sensitivity to 1st line PBT in our relatively small cohort. Further biomarker validation combined with LOH assessment can inform decision making and clinical trial designs.
Nivolumab demonstrates benefit over nomogram-predicted 12-month survival as salvage therapy for metastatic urothelial carcinoma.
Authors: Pond Gregory Russell , Sonpavde Guru , Galsky Matt D. , Sharma Padmanee , Rosenberg Jonathan E. , Choueiri Toni K. , Bellmunt Joaquim , Lee Jae-Lyun , Lee Soon Il , Azrilevich Alex , Yang Shuo , Gooden Kyna McCullough , Bajorin Dean F. 
Published: February 2018

451 Background: Intermediate endpoints of benefit in metastatic urothelial carcinoma (mUC) nonrandomized trials are necessary to identify promising drugs, particularly for checkpoint inhibitors, where response and progression-free survival remain suboptimal. We previously reported a nomogram (Pond GR et al, 2017 GU Cancers Symposium) using 5 prognostic factors (hemoglobin < 10 g/dL, Eastern Cooperative Oncology Group performance status ≥1, presence of liver metastasis, time from last treatment ≤3 months, and albumin < lower limit of normal) from phase 2 trials of historical agents (eg, taxanes) to estimate 12-month overall survival (OS), against which observed survival could be compared. Nivolumab was granted approval as salvage therapy for patients with mUC, based on the CheckMate (CM) 275 trial; it is thus of interest to compare the nivolumab observed survival versus nomogram-predicted survival results. Methods: Data were obtained from CM 275, including survival and all 5 prognostic factors. Nomogram points were calculated and the expected 12-month OS was estimated. Bootstrap analyses based on 2000 replications were used to estimate 95% confidence intervals (CIs) for the median expected, observed, and difference between the expected and observed 12-month OS values. All tests were 2-sided, with statistical significance defined as P≤0.05. Results: Data were available from 270 patients from CM 275. Fifteen patients did not have albumin recorded and were excluded. Among the 255 evaluable patients, 46 (18.0%) patients had 0 adverse prognostic factors, 85 (33.3%) had 1, and 124 (48.6%) had 2 or more. The observed nivolumab 12-month OS from CM 275 (43.3% [95% CI, 37.0%-50.5%]) was 19.8% higher (95% CI, 13.6%-26.4%) when compared with the nomogram-predicted 12-month OS (23.5%; [95% CI, 22.5%-25.5%]) if patients received historical chemotherapy. Across all 2000 bootstrap samples, the observed nivolumab 12-month OS exceeded the nomogram-predicted 12-month OS. Conclusions: Nivolumab was associated with a significantly improved 12-month OS compared with historical chemotherapy based on the value predicted by the validated nomogram incorporating baseline prognostic factors. Clinical trial information: NCT02387996.
Prognostic value of CD56, ASCL1, and other biomarkers in small cell bladder cancer (SCBC).
Authors: Koshkin Vadim S. , Reynolds Jordan , Elson Paul , McKenney Jesse , Isse Kumiko , Saunders Laura R. , Hu Ming , Stephenson Andrew J. , Fergany Amr Farouk , Lee Byron , Rini Brian I. , Garcia Jorge A. , Mian Omar Y. , Grivas Petros 
Published: February 2018

452 Background: Increased DLL3 expression (exp) and small cell % (SC%) were found in prior analyses to predict worse outcomes in SCBC. Assessment of gene and protein exp of other Notch pathway and neuroendocrine (NE) markers, such as ASCL1 and CD56, can help with prognostication and treatment target identification in SCBC. Methods: Among 63 patients (pts) with biopsy-confirmed SCBC seen at Cleveland Clinic (1993-2015), 52 had tissue available for IHC analysis of tumor biomarkers: DLL3, PD-L1, ASCL1 and CD56. All pts had clinical and outcomes data, and had SC% quantified by central path review. A subset of 39 pts had gene exp analysis using HTG EdgeSeq OBP assay. Correlations among biomarkers, between biomarkers and pt characteristics as well as gene exp were assessed. Multivariate analyses (MVA) were used to identify predictors of overall (OS) and progression-free survival (PFS). Results: In the 52 pt cohort, median age was 71, 83% were men, 39% had LN+ disease, and 79% had SC% > 50%. Protein exp ( > 1% of tumor cells) of DLL3, PD-L1, ASCL1 and CD56 was noted in 68%, 30%, 52% and 81% of pts, respectively. ASCL1 protein exp correlated with protein exp of DLL3 (r = 0.73, p < .0001), CD56 (r = 0.35, p = .01), and SC% (r = 0.34, p = .01) and correlated with gene exp of several Notch genes and NE markers: DLL3, DLL4, Notch1, CHGA (p < .05 for all). CD56/NCAM1 protein exp correlated with DLL3 protein exp (r = 0.32, p = .02) and with SC% (r = 0.26, p = .06) and with gene exp of DLL4, Notch1, SYP and NCAM1 (p < .05 for all). In MVA, increased CD56 protein exp ( > 30%) was associated with shorter OS (HR: 2.23; 95%CI 1.06-4.70, p = .03) and PFS (HR: 2.07; 95%CI 1.02-4.20, p = .04). Pts with low protein exp of both CD56 (≤30%) and DLL3 (≤10%) had longer median OS (103.4 vs 18.4 months, p = .01) and PFS (92.2 vs 11.4 months, p = .02) relative to pts with high protein exp of either biomarker. Conclusions: Most SCBC tumors expressed CD56, and increased exp predicted shorter OS and PFS, findings similar to those reported for DLL3. Low concurrent exp of both CD56 and DLL3 proteins was associated with better outcomes. Strong correlation of CD56/NCAM1 gene and protein exp suggests that its regulation may be at the transcriptional level. Gene exp signature prognostic of outcomes is currently being pursued in SCBC.