bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initiation and shift of antidiabetic therapy and pancreatic cancer.
Authors: Autier Philippe , Franchi Matteo , Bota Maria , Leclercq Agnès , Guillaume Joeri , Van Damme Nancy , Corrao Giovanni , Partensky Christian , Boniol Mathieu , Boyle Peter 
Published: September 2018

4126 Background: Concerns have been raised on the risk of pancreatic cancer associated with specific anti-diabetic therapies. We have examined the risk of pancreatic cancer among patients with diabetes prescribed with an oral anti-diabetic drug (OAD) or an incretin drug (DPP4i and GLP-1 RA) or insulin. Methods: The public health insurance databases of Belgium and of Lombardy Region, Italy include nearly 100% of the population living in these countries. We created within these databases two cohorts that included adult patients who were first prescribed an incretin drug or another noninsulin antidiabetic drug (NIAD) during 01/07/2008-31/12/2013 in Belgium and during 01/01/2008-31/12/2012 in Lombardy Region. The risk of pancreatic cancer after prescription of an anti-diabetic drug was evaluated using multivariate adjusted Cox models including time-dependent variables. Adjusted hazard ratios (aHRs) from Belgium and Italy were pooled using fixed effects meta-analyses. Results: Results in both cohorts were similar. Among those patients prescribed an OAD, 45% of pancreatic cancers occurred within the 6 months following first prescription, 20% in months 7 to 12 after first prescription and proportions decreased progressively during follow-up. The aHR of pancreatic cancer among subjects prescribed an incretin compared to an OAD was 2.14 [95% CI, 1.71 to 2.67]. The aHR decreased from 3.35 [CI, 2.32 to 4.84] in the first 3 months after first incretin prescription, 2.12 [CI, 1.22 to 3.66] in months 3 to 5.9, 1.95 [CI, 1.20 to 3.16] in months 6 to 11.9, to 1.69 [CI, 1.12 to 2.55] after 12 months. The risk of pancreatic cancer among subjects who were subsequently prescribed insulin was 6.89 [CI, 6.05 to 7.85]. The time from OAD prescription to a shift to incretins or to insulin was significantly lower in patients who were subsequently diagnosed with a pancreatic cancer. Conclusions: The increased risk of pancreatic cancer associated with anti-diabetic therapies could be the consequence of an occult pancreatic cancer that provokes diabetes (reverse causation bias). The search for an occult pancreatic cancer in subjects with newly diagnosed diabetes or patients shifting to more potent anti-diabetic therapy may lead to earlier detection of this cancer.
Circulating tumor (ct)-DNA alterations in urothelial/bladder cancer (UC/BC): Updates on a dynamic genomic landscape.
Authors: Grivas Petros , Nagy Rebecca J , Pond Gregory Russell , Gupta Sumati , Wang Jue , Vaishampayan Ulka N. , Pal Sumanta K. , Bilen Mehmet Asim , Naik Gurudatta , Ghatalia Pooja , Hoimes Christopher J. , Gopalakrishnan Dharmesh , Barata Pedro , Lanman Richard B. , Talasaz AmirAli , Sonpavde Guru 
Published: September 2018

4534 Background: Cell-free ctDNA may be potentially actionable, may have prognostic/predictive role and evolve after therapy. We updated our analysis of our retrospective study to shed light on UC/BC biology. Methods: Patients (pts) with UC/BC with ctDNA analysis for potentially actionable alterations using Guardant360 were identified. A 70-gene ctDNA next generation sequencing panel from a CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) offers complete exon sequencing for 29 cancer genes, critical exons in 39 genes and amplifications (16 genes), fusions (6 genes) and indels (3 genes) harvested from 10 mL of peripheral blood. Descriptive statistics were used. Results: There were 246 pts with 276 samples. At least 1 alteration was detected in 249 (90%) samples. Median age at time of ctDNA collection was 67 years (39-85), 78% men, median number of alterations per sample was 3.5 (1-35) most pts had MIBC. In MIBC pts, the most common alterations at the 1st ctDNA sample were in TP53 (52%), PI3KCA (18%) ARID1A (17%), FGFR2 (15%), MET & NF1 (14%), EGFR (13%), BRAF (12%), FGFR3 (11%), RAF1 (10%), BRCA1 & CCNE1 (9%). In MIBC pts, the most common genes with increased copy number were RAF1 & CCNE1 (8%), ERBB2 & PI3KCA (7%), EGFR, BRAF, FGFR1, MYC (each 5%), MET (4%), KRAS (3%). Most common altered pathways included TP53 signaling (56%), RAS/RAF/MEK/ERK (51%), RTK (48%), cell cycle (38%), FGFR family (34%), DNA damage response (25%), PI3KCA/AKT/mTOR (23%) and chromatin remodeling (17%). Interestingly, FGFR3 and RAS alterations were mutually exclusive in most cases, but each may co-occur with TP53alterations. 54 serial ctDNA samples from 24 pts (18 pts with 2 samples; 6 pts with 3 samples) revealed persistent, lost and new gene alterations. Conclusions: ctDNA was detected in 90% of pts and alterations were similar to those previously seen in UC tumor tissue. Tumor heterogeneity, interim therapy, genomic instability and clonal evolution can explain differences in serial samples. Correlation assessment with prior therapies and outcomes is being pursued to inform trial designs. Prospective validation, assessment of ctDNA concordance with tumor tissue DNA, and evaluation of clinical utility is warranted.
Neoadjuvant chemotherapy followed by concomitant chemoradiation with gemcitabine in muscle invasive bladder cancer.
Authors: Mateen Abdul , Adil Allah Rakha , Hashmi Quratul Ain , Duraishi Arif Moin , Abdullah Famya 
Published: September 2018

4541 Background: Urinary bladder cancer is one of the most prevelent genitourinay cancer in Pakistan. It is especially common in population that consumes smokeless tobacco. Advanced stage at diagnosis is usual presentaion due to illiteracy, poverty and lack of primary health facilities. The study was aimed to optimize treatment of muscle invasive bladder cancer in poor resource country. Methods: A total of 65 patients were enrolled for the study. All patients had muscle invasive disease on transurethral resection. Patients were to in stage range from T2-3, N0 and M0 to be selected. The patients were planned for gemcitabine and cisplatinum (GC) every three weeks in a dose of 1000 mg/m² and 40 mg/m² on D1 and D8 of each cycle respectively. Ultrasonography was performed to assess for any bladder mass at this point. The patients with no visible tumor were planned for whole bladder external radiotherapy (ERT) along with weekly gemcitabine 100 mg/m². A total of 63 Gray (Gy) was planned with 1.8 Gy per fraction and five fractions a week. Gemcitabine was given on 1st day of every week during whole course of ERT.Treatment interruptions were allowed depending upon chemotherapy and ERT related toxicity. Primary end point was to assess disease free survival (DFS) while overall survival was also assessed as a secondary end point. Results: 54 patients (83%) were available for assessment to treatment and to assess DFS and OS. Rest of the patients 11/65 (17%) were excluded from the analysis due to inability to complete the treatment. Five patients (8%) showed disease recurrence during treatment and were switched to other treatment. 11 patients (20%) showed bowel, 15 patients (28%) showed bladder and 8 patients (15%) showed hematological related grade 1-2 toxicity. Four year DFS and OS were 43% and 52% respectively. Mean and median DFS (year) were 3.16±0.36 (95% confidence interval [CI] 2.91 to 3.42) and 2.68±0.54 (95% CI 2.41 to 2.93) respectively. Mean and median OS (year) were 3.95±0.43 (95% CI 3.67 to 4.21) and 3.55±0.31 (95% CI 3.37 to 3.76) respectively. Conclusions: Neoadjuvant chemotherapy with GC followed by concomitant CRT using gemcitabine is an excellent choice for bladder preservation in poor resource countries.
Cabazitaxel in patients with locally advanced or metastatic transitional cell carcinoma who developed disease progression within 12 months of platinum based chemotherapy: Results of a phase II trial—CAB-B1.
Authors: Zarkar Anjali , Marshall Andrea , Dunn Janet , Davies Amanda , Ford Daniel , James Nicholas D. 
Published: September 2018

4542 Background: There is a paucity of chemotherapy options for the treatment of patients who have relapsed following platinum based chemotherapy (CT). Cabazitaxel is a new taxane that showed in-vivo antiproliferative activity on resistant cell lines. Methods: CAB-B1 was a single centre phase II randomised controlled trial of Cabazitaxel (CAB; 25mg/m2 q3 week for 6 cycles) versus best supportive care (BSC) in patients (pts) with histologically proven transitional cell carcinoma (TCC), locally advanced or metastatic, who had received platinum based treatment and recurred within 12 months of the last cycle of CT. Primary outcome was overall response rate (ORR) using RESIST. Secondary outcomes were Progression Free Survival (PFS), Overall Survival (OS), Quality of Life assessment, safety and tolerability. A total of 96 pts required to detect differences in ORR from 5% to 30%; 80% power; 5% alpha level; 10% dropouts. Stopping rules, using Simon’s two stage optimal design to assess the individual effectiveness of CAB, required at least 1 ORR from 10 pts on CAB during 1st stage (i.e. total of 20 pts randomised) and 4 from 29 CAB pts in 2nd stage (assuming lower ORR limit of 0.05, target ORR of 0.20, 80% power, 5% alpha level). The trial was supported by grant from Sanofi. Results: Between January 2013 and October 2016, 20 pts were randomised (10 on each arm). 75% males; median age 68 years; 65% had recurred within 6 months of previous CT. BSC included paclitaxel CT for 9 pts and radiotherapy for 1 pt. 8 pts completed 6 cycles of CT (3 on CAB; 5 on BSC). 6 pts on each arm were evaluated for response after having 2/3 cycles; 2 pts had an ORR on CAB and 1 pt on BSC. 14 pts have died of disease (8 on CAB; 6 on BSC).Median OS was 5.6 months (95% confidence interval (CI) 0.7-15.2) for CAB pts and 8.2 months (95% CI 1.0-8.8) for BSC pts. Median PFS was 4.4 months (95% CI 0.7-9.4) for CAB pts and 4.1 months (95% CI 1.0-6.8) for BSC pts. Conclusions: It has been hard to recruit these poorly patients within a single centre, but CAB-B1 successfully reached the efficacy target for the 1st stage, showing that there could be a role for CAB in these pts. Clinical trial information: NCT01668459.
The clinical role of purified protein derivative skin test reaction in patients with non-muscle invasive bladder cancer treated with bacillus-Calmette Guerin.
Authors: Kikuchi Eiji , Niwa Naoya , Hayakawa Nozomi , Mizuno Ryuichi , Oya Mototsugu 
Published: September 2018

4545 Background: We investigated the association between purified protein derivative (PPD) skin test reaction prior to BCG therapy and clinical outcomes, both oncological outcomes and occurrence of side effects, in BCG-naïve non-muscle invasive bladder cancer (NMIBC) patients. Methods: A total of 288 NMIBC patients who received PPD skin test prior to BCG therapy were included. The PPD skin test reaction was categorized into three groups: positive, slightly positive, and negative. The presence of an induration was positive. If an induration was absent, an erythema 10 mm or more and less than 10 mm corresponds to slightly positive and negative, respectively. Results: Sixty-six (22.9%), 149 (51.7%), and 73 (25.3%) patients had positive, slightly positive, and negative PPD skin test results, respectively. The 5-year recurrence-free survival rate of patients with a positive PPD skin test was 89.4±4.1%, which was significantly higher than that of patients with slightly positive (65.5±4.2%, p = 0.001) and negative (56.4±6.6%, p < 0.001) results. Multivariate Cox regression analysis demonstrated that a positive PPD skin test was independently associated with tumor recurrence (Hazard ratio of 0.213, p < 0.001) but not with stage progression. The occurrence rate of major side effects in patients with a positive BCG skin test (33.3%) was significantly higher than that in patients with slightly positive (26.8%) and negative PPD skin tests (13.7%). The incidence rate of fever persisting beyond 2 days or fever of ≥38°C in patients with a positive PPD skin test (18.2%) was significantly higher than that in patients with slightly positive (8.7%) and negative PPD skin tests (4.1%). Conclusions: NMIBC patients with a positive PPD skin test and who were treated with BCG therapy had a significantly lower tumor recurrence rate and higher incidence of major side effects such as fever persisting beyond 2 days or fever of ≥38°C. Our findings suggest that PPD skin test prior to BCG therapy can predict clinical outcomes following BCG therapy and provide useful information regarding who would experience a strong therapeutic effect for BCG therapy and BCG-related major side effects.
Oncological outcomes of intravesical gemcitabine and docetaxel for select patients with high grade recurrent NMIBC.
Authors: Milbar Niv , Kates Max , Chappidi Meera R. , Schoenberg Mark P. , Bivalacqua Trinity 
Published: September 2018

4546 Background: Bacillus Calmette-Guerin (BCG) unresponsive patients with Non-Muscle Invasive Bladder Cancer (NMIBC) who prefer bladder preservation over Radical Cystectomy (RC) or are poor surgical candidates may be offered intravesical therapies. 2nd line intravesical Gemcitabine (GEM) combined with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH). Our objective was to evaluate JHH experience with GEM/DOCE, and specifically to address appropriate endpoints for 2nd-line therapies in NMIBC. Methods: 33 patients who received full induction courses of GEM/DOCE since 2011, per the protocol adapted from Michael O’Donnell at U. Iowa, were identified in the IRB-approved JHH NMIBC database. Multivariable logistic regression determined factors associated with LG and HG recurrence. Cox proportional hazard models evaluated risk factors for disease free survival (DFS) and HG recurrence-free survival (HG-RFS). Results: Median DFS was 6.5 months with 42% 1-year and 24% 2-year DFS. Median HG-RFS was 17.1 months with 56% 1-year and 42% 2- year HG-RFS. Median HG-RFS among patients who initiated GEM/DOCE with HG pathology was 15.7 months, with 51% 1-year HG-RFS and 34% 2-year HG-RFS. Within initial HG-NMIBC presentation, 46% (13/28) had HG recurrence. 80% (4/5) of patients with initial LgTa had LG recurrence and 20% (1/5) had HG recurrence. There were no significant predictors for HG-RFS or DFS. There were 5 LG recurrences, and 16 HG recurrences, with 6 progressions among these. 7 patients underwent RC at a median of 14.9 months. Conclusions: GEM/DOCE is a well-tolerated alternative to immediate RC for highly selected patients with HG-NMIBC. As anticipated, including LG recurrence as an endpoint made GEM/DOCE appear less efficacious. However, since standard of care for LG recurrence is further intravesical therapy and recurrence does not result in worse cancer outcomes, it may not be an appropriate endpoint. Future studies of 2nd line therapies for NMIBC should identify endpoints based on clinically meaningful outcomes of interest.
Myeloid derived suppressor cells (MDSC) and inflammatory biomarkers in metastatic urothelial carcinoma (mUC).
Authors: Ornstein Moshe Chaim , Diaz-Montero C. Marcela , Rayman Patricia A. , Elson Paul , Haywood Samuel , Kim Jin Sub , Pavicic Paul G , Finke James , Rini Brian I. , Stephenson Andrew J. , Lamenza Marcelo , Dann Priscilla , Schach Kim , Devonshire Sarah , Ko Jennifer S , Fergany Amr Farouk , Ernstoff Marc S. , Hoimes Christopher J. , Garcia Jorge A. , Grivas Petros 
Published: September 2018

4548 Background: MDSC are potent immunosuppressive cells with prognostic implications in many solid tumors. We previously reported significant correlations between MDSC and clinicopathologic features in localized UC. We hypothesized that different MDSC populations may correlate with inflammatory biomarkers and clinicopathologic features in mUC. Methods: Peripheral blood samples were collected from 46 mUC pts. MDSCs were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations & clinicopathologic factors. Results: Of 46 pts:78% men, median age at diagnosis 69 (31-83), 33% never smokers, 76% pure UC, 76% bladder primary, 28% prior intravesical therapy, 35% prior neoadjuvant chemotherapy, 56% prior cystectomy, 83% overweight/obese. G-MDSC was the predominant subset in WB (43%) and PBMC (39%), although M-MDSC were almost equally predominant in PBMC (35%). There was a correlation between the WB and PBMC values of T-, I-, and M- MDSC (p≤0.05). Higher % WB I-MDSC correlated with lower blood neutrophil/lymphocyte ratio (NLR) (p = 0.009), while higher WB G-MDSC and %PBMC G-MDSC were associated with higher NLR (p = 0.03 and p = 0.02, respectively). Higher I-MDSC / G-MDSC ratio was associated with lower NLR (r = -0.35, p = .02) and with various clinicopathologic parameters. Conclusions: HigherI-MDSC / G-MDSC ratio correlates inversely with NLR, which is considered an inflammatory biomarker and had prognostic value in other studies. The mechanism of MDSC interaction with inflammatory response in mUC pts merits evaluation and is being investigated in a larger cohort of UC pts on chemotherapy or immunotherapy (with longer follow up).
Everolimus (EVE) exposure as a predictor of toxicity (Tox) in renal cell cancer (RCC) patients (Pts) in the adjuvant setting: Results of a pharmacokinetic analysis for SWOG S0931 (EVEREST), a phase III study (NCT01120249).
Authors: Synold Timothy W. , Plets Melissa , Tangen Catherine M. , Heath Elisabeth I. , Palapattu Ganesh S. , Mack Philip C. , Stein Mark N. , Meng Maxwell V. , Lara Primo , Vogelzang Nicholas J. , Thompson Ian Murchie , Ryan Christopher W. 
Published: September 2018

4566 Background: S0931 is assessing recurrence-free survival in RCC pts randomized to receive EVE versus placebo for one year following nephrectomy. To date, there has been a higher than expected dropout rate due to bothersome tox. Previous reports have shown an association between EVE trough levels and both tox and disease response in RCC pts. Therefore, we have assessed EVE trough levels to evaluate the relationship between measured exposure and probability of tox. This analysis has been approved by the DSMC. Methods: Patients received 10 mg daily EVE or placebo for nine 6-week cycles. Pre-dose whole blood samples collected pre-cycle 2 and pre-cycle 3 were analyzed for EVE. Pts with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. When both trough levels were available, results were averaged. Pts were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the following adverse event outcomes using EVE trough as a predictor; any grade 3+ tox, grade 2+ triglycerides, grade 2+ hyperglycemia, grade 2+ oral mucositis, grade 2+ rash, and premature stopping of EVE. Hazard and odds ratios were adjusted for age, BMI and performance status. Results: This study reached its accrual goal and closed on 9/15/2016 with 1545 (775 EVE) randomized patients. A total of 386 pts are included in this preliminary analysis. Median EVE trough was 12.8 ng/mL (range 3.1, 75.6) per 10 mg dose. Event rates for tox were: any grade 3+ tox = 46%, grade 2+ triglycerides = 33%, grade 2+ hyperglycemia = 15%, grade 2+ oral mucositis = 34%, grade 2+ rash = 15%, and premature stopping of EVE = 40%. The risk of grade 2+ triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.95; p = 0.001 and OR = 3.48; p < 0.001). The risk of grade 2+ rash was increased in Q2 and Q4 vs Q1 (OR = 2.95; p = 0.02 and OR = 3.20; p = 0.01). There was also a trend towards an increased risk of any grade 3+ tox in Q3 vs Q1 (OR = 1.72; p = 0.07). Conclusions: This analysis has identified significant associations between EVE exposure and the probability of tox. EVE analysis is ongoing and the final results will be presented. Clinical trial information: NCT01120249.
Effects of pazopanib (PAZ) and sunitinib (SUN) dose modification on safety and efficacy in patients with metastatic renal cell carcinoma (mRCC) from COMPARZ.
Authors: Bjarnason Georg A. , Kollmannsberger Christian K. , Ahmad Qasim , Dezzani Luca , Elmeliegy Mohamed , Han Jackie , Nathan Paul D. 
Published: September 2018

4574 Background: COMPARZ was a randomized, controlled, open-label, phase 3 trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in patients (pts) with mRCC (NEJM 2013;369:722). We evaluated the relationship between dosing, safety, and efficacy in PAZ- and SUN-treated pts who did or did not undergo dose reduction or interruption resulting from adverse events (AEs) and other reasons. Methods: The AEs and median progression-free survival (mPFS) of PAZ and SUN were evaluated for pts with no, any, 1, and ≥2 dose reductions or dose interruptions lasting ≥7 days. Results: Similar percentages of pts in the PAZ and SUN groups had a dose interruption (44% vs 49%, respectively) or reduction (44% and 51%, respectively). The incidence of AEs in pts from the PAZ and SUN groups with dose modifications was higher compared to those with no dose modifications. Longer mPFS was observed in pts with dose modification (Table). Pts treated with PAZ or SUN with no dose reductions had mPFS of 7.3 months (mos) and 5.5 mos, respectively, whereas pts with any dose reduction had mPFS of 12.5 mos and 13.8 mos, respectively. Similarly, pts treated with PAZ or SUN with no dose interruptions lasting ≥7 days had mPFS of 8.2 mos and 5.6 mos, respectively, whereas those with any dose interruption lasting ≥7 days had mPFS of 12.6 mos and 13.8 mos, respectively. Pts with 2 or more dose interruptions or reductions had mPFS > 16 mos with both SUN and PAZ. Conclusions: Consistent with previous data for SUN, the current analyses showed longer mPFS with PAZ and SUN when dose modification is required to manage toxicity, suggesting that pts are not disadvantaged by such dose reductions or interruptions. Pts not requiring dose modification may have sub-optimal therapeutic drug exposure. Clinical trial information: NCT00720941. [Table: see text]