bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world overall survival of patients diagnosed with recurrent versus de novo metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: O'Reilly Eileen Mary , Yu Kenneth H. , Lamarre Neil , Surinach Andy , Cockrum Paul
Published: June 2021

e16250

Background: PDAC is a lethal malignancy which accounted for the third most cancer related deaths in 2020. Patients (pts) who are initially diagnosed with stage I-III PDAC have a 5-year relative survival of 13.3 – 39.4%; those with metastatic disease at diagnosis have a 5-year relative survival of 2.9%. Limited data are published comparing the outcomes of pts with stage I-III who develop metastases (recurrent) compared to pts with de novo mPDAC (de novo). This analysis seeks to compare demographic, clinical characteristics, and survival outcomes of pts with recurrent versus de novo mPDAC in a community oncology setting. Methods: Using the Flatiron Health database, a retrospective observational study was conducted abstracting deidentified data from ≥280 US cancer clinics. Pts with mPDAC diagnosed from 01/2016 to 08/2020 with a known stage at initial diagnosis were included. Pts were stratified based on initial stage at diagnosis. Median overall survival (OS) from time of metastasis was derived using Kaplan-Meier analysis. Unadjusted and multivariable Cox proportional hazards models were used to compare survival between recurrent and de novo cohorts. Results: N = 6,543 pts analyzed; 70.1% (n = 4,586) had de novo mPDAC and 29.9% (n = 1,957) had recurrent mPDAC. Median age at time of metastasis was similar for both cohorts: 69 years (IQR: 62 – 76). The most common site of primary tumor location was head for both cohorts (recurrent mPDAC: 69.8%; de novo mPDAC: 40.3%). Approximately 45% of pts with recurrent mPDAC underwent a Whipple procedure (pre diagnosis of metastasis). A similar proportion of pts in both cohorts received treatment in the metastatic setting (recurrent mPDAC: 74.3%; de novo mPDAC: 77.3%). Pts with recurrent mPDAC had a longer median OS compared to the de novo cohort: 8.0 months (95% CI: 7.5 – 8.6) versus 6.1 (95% CI: 5.7 – 6.4) [unadjusted hazard ratio (HR): 0.79 (95% CI: 0.74 – 0.84); adjusted HR: 0.73 (0.68 – 0.78), p < 0.0001]. Conclusions: The results of this real-world study indicate that pts with recurrent mPDAC are more likely to have a head primary and to experience longer OS from time of metastasis than those with de novo mPDAC. These data suggest stratification for clinical trial enrollment for recurrent vs de novo is necessitated.
Sindilimab combined with nab-paclitaxel plus gemcitabine as first-line treatment for patients with advanced pancreatic cancer.
Authors: Zhu Huayun , Sun Xiaofeng , Pan Xuan , Wu Pingping , Chen Jia
Published: June 2021

e16257

Background: This study aimed to evaluate the efficacy and safety of Sindilimab combined with nab-paclitaxel plus gemcitabine as first-line treatment for advanced pancreatic cancer. Methods: This was a single-arm, simple-center, exploratory trial, which included advanced pancreatic cancer pts. Patients received Sindilimab combined with nab-paclitaxel plus gemcitabine. Combined chemotherapy lasted for no more than 12 cycles. Once chemotherapy intolerance occurred or at end of 12-cycle combined chemotherapy, pts with stable disease or objective response would continue to take Sindilimab as single agent until disease progression or intolerable toxicity. Response was assessed every 8 weeks. Results: 16 eligible patients were enrolled and 14 pts were evaluable for efficacy analysis. Baseline characteristics are shown in Table 2. Conclusions: This study has showed high anti-tumor efficacy and tolerant toxicity in first-line regimen for advanced pancreatic cancer. Furthermore, it is needed to be proved in update results and large scale studies. Efficacy As shown in Table 3, among 14 evaluable pts, unconfirmed ORR was 57.1% and DCR was 92.8%. 8 pts got partial response (PR), 5 pts stable disease (SD) and 1 pts progressive disease(PD) at best. PFS: The primary endpoint 6-month PFS rate was 2%(95% CI 50.4%-72.4%). Which indicated that the primary endpoint of the study was reached. And mPFS was 7.3 months(95% CI 5.9-8.1). OS: Median OS was not reached and 6m-OS rate was 85.7% (95%CI 5%-91.3%). Safety. All 16 pts were included in the safety analysis (Table 4). The overall AE incidence rate was 93.75% .≥Grade 3 irAE included GGT increased (37.5%) and peripheral neuropathy (6.25%). No TRAE led to death.[Table: see text][Table: see text][Table: see text][Table: see text]
G2M checkpoint signaling among six-cell proliferation-related pathway as a biomarker for prediction and prognosis in pancreatic cancer.
Authors: Oshi Masanori , Le Lan , Tokumaru Yoshihisa , Yan Li , Matsuyama Ryusei , Endo Itaru , Takabe Kazuaki
Published: June 2021

e16264

Background: Given the poor survival and severe side effects of treatments for pancreatic cancer, prognostic and predictive biomarkers to guide management are in urgent need. We hypothesized that the cell proliferation-related pathway is associated with drug response and survival in pancreatic cancer. Methods: Six hallmark cell proliferation-related gene sets (G2M checkpoint, E2F targets, MYC targets V1 and V2, mitotic spindle, p53 pathway) defined by MSigDB in gene set variant analysis (GSVA) was evaluated in 3 independent cohorts, TCGA-PDAC ( n = 176), GSE57495 ( n = 63), and GSE62452 ( n = 69). Results: Although G2M and E2F correlated strongly with each other (Spearman’s r = 0.976), Mitotic and p53 pathway scores correlated highly with the other cell function gene sets. All pathways were significantly associated with high expression of MKI67 and with proliferation score (all p > 0.001), but none with pathologically complete resection (R0). Mitotic spindle pathway alone associated with high cytolytic activity ( p = 0.020). All pathways were significantly associated with high expression of KRAS and TP53 genes and with high rate of KRAS gene alteration except for MYC v1. G2M, E2F, and p53 pathways were significantly associated with high rate of TP53 gene alteration ( p = 0.026, 0.011, and 0.07, respectively). Interestingly, different pathway correlated with AUC of different agents, such as gemcitabine (mitotic: r=0.706 [ p = 0.01]), paclitaxel (MYC v2: r = -0.636 [ p < 0.05]), apatinib (mitotic: r = -0.556 [ p = 0.03]), palbociclib (E2F: r =0.675 [ p < 0.01]), and sorafenib (G2M: r = -0.593 [ p = 0.03]), for pancreatic cancer. Among all six pathways, only G2M was significantly associated with worse patient survival consistently in all 3 cohorts. Conclusions: Each proliferation-related pathway was predictive of the unique agent, and the G2M score predicts survival of pancreatic cancer.
Efficacy of olaparib therapy in metastatic pancreatic ductal adenocarcinoma (PDAC) with homologous recombination deficiency (HRD).
Authors: Tan Elaine , Hicks James Kevin , Blue Kirsten , Kim Richard D. , Carballido Estrella M. , Kim Dae Won
Published: June 2021

e16266

Background: Pancreatic cancer is one of the deadliest malignancies, with a 5 year OS of around 3%. Up to 3% of unselected patients (pts) with (PDAC) have the BRCA 1/2 mutation, while up to 15% possess HRD (ARID1A, ATM, BAP1, BARD1, BRIP1, CHEK1/2, FANCA, PALB2, RAD50, RAD51). PARP inhibitors, like olaparib, demonstrate clinical benefit in metastatic PDAC with BRCA mutations (mBRCA) and may have a role in those with HRD. The objective of this study is to determine the role of PARP inhibition in PDAC with HRD. Methods: This was a retrospective chart review of metastatic PDAC pts with germline (g) or somatic (s) mBRCA or HRD who received olaparib. An analysis of PFS and OS was performed for PDAC pts with mBRCA vs. HRD. Results: Forty-six pts with metastatic pancreatic cancer were identified to have mBRCA (n = 13) or HRD (n = 23) and received olaparib in our database. Median age was 73 years for mBRCA and 66 years for HRD. Five pts received olaparib as maintenance therapy after disease control with platinum: 2 mBRCA and 3 HRD pts. Six pts with mBRCA and 7 pts with HRD were platinum naïve prior to olaparib. Zero pts with mBRCA and 3 pts with HRD received olaparib after disease progression on platinum. The median (med)PFS for mBRCA vs. HRD was 6.1 months vs. 2.8 months (HR 0.5, 95% CI: 0.2-1.1, p = 0.07). The medOS for mBRCA vs. HRD was 7.7 vs. 5.3 months (HR 0.7, 95% CI: 0.2-1.9, p = 0.4). Of those with mBRCA who received olaparib, prior cisplatin exposure (n = 8) vs. cisplatin naïve (n = 5) led to medPFS of 6.1 vs. 7.8 months (HR 1.8, 95% CI 0.5-6.7, p = 0.3) and medOS of 6.8 months vs. 9.5 months (HR 1.5, 95% 0.3-6.4, p = 0.6). Six pts with HRD including gCHEK2 c.407T > C, gCHEK2 c.1461+1 G > A, gPALB2 gain (exon 11), sFANCI p.N1252S, sATM p.V2716A, sARID1A Q944fs*14 were noted to have disease control of at least 3 months on olaparib. Only one of these pts received olaparib as maintenance therapy after platinum. The medPFS was 6.1 months and medOS was not reached. One pt with HRD (sFANCI N1252S) had progressive disease on platinum prior to olaparib, but had stable disease > 5 months with olaparib. Conclusions: Our study suggests olaparib may have anticancer activity in PDAC with certain HRD. In addition, olaparib may have a role outside maintenance therapy in PDAC with mBRCA. Prospective studies are needed to confirm these findings.
Early detection of pancreatic cancers by novel nanobiosensor-based protease biomarkers using hierarchical decision structure.
Authors: Kasi Anup , Sun Weijing , Ehsan Sumia , Covarrubias Jose , Eschliman Kayla , Neri Raul , Agarwal Deepesh , Zambrano Obdulia Covarrubias , Bossmann Stefan H , Natarajan Bala
Published: June 2021

e16273

Background: There is a critical need to develop fast, reliable, and cost-effective methods for the detection of pancreatic cancer (PC) at the earliest stage to maximize the impact of treatment. To-date, early detection of PC is close to impossible due to the location of the pancreas and the absence of characteristic symptoms in early cancer stages. Methods: Our team of clinicians and scientists has established a fast and reliable nanobiosensor technology that comprises iron/iron oxide nanoparticles attached to a protease or arginase activatable FRET pair (tetrakis (4- carboxyphenyl) porphyrin (TCPP) /cyanine 5.5). Arginase and seven proteases (MMP1, 3, and 9, cathepsin B, and E, urokinase plasminogen activator, and neutrophil elastase) were identified using the Gene Expression Omnibus (GEO) web tool based on their different expression pattern in pancreatic cancer patients, pancreatitis and healthy control subjects. Protease/arginase activities were measured in serum after 1h of incubation. Based on this data, a novel engineering approach to improved early stage detection of pancreatic cancer is reported here. This study was funded by American Cancer Society Institutional Research Grant (IRG‐16‐194‐07), awarded to the University of Kansas Medical Center. Results: In our study, 159 patients were enrolled at KU Cancer Center from 2000-2019, 47 with metastatic PC, 36 with localized PC, 26 pancreatitis and 50 healthy controls using KUCC Biospecimen Repository. The problem of early stage detection of pancreatic cancer can be modeled as a multi-class classification problem. Conventional classification approaches provide at most 77% accuracy for the dataset under consideration. A new hierarchical decision structure with specific feature engineering at each step is introduced here to improve the performance of the classifier. The fundamental premise of this information fusion-based framework involves tailoring the statistically most significant features with appropriate weights to execute an efficient binary classification task at each hierarchical step. An overall accuracy of 95% was achieved for the detection of patients with early pancreatic cancer (see table). Conclusions: Because of the dire survival statistics of pancreatic cancer, detection at the earliest possible time by means of a liquid biopsy will offer the greatest benefit. Novel nanobiosensor based protease biomarkers achieved high accuracy in early detection of pancreatic cancers by applying hierarchical decision structure. Our results need validation in a larger cohort. Predicted true class considering the following combination of classification methods: Step1 – kNN*, step2 – kNN*, step3 – RFC* (Accuracy = 94.97%).[Table: see text]
Accuracy of an urine-based liquid biopsy genetic test in detecting renal pelvic cancer.
Authors: Xu Yansheng , Shi Min , Liang Yiming , Li Hongzhao , Ma Xin , Zhang Xu , Che Dongxue , Guo Weihua
Published: June 2021

e16500

Background: Renal pelvis cancer is accounting for about two-thirds of upper tract urinary carcinoma. Lesions in renal pelvis often lead to a differential diagnosis that requires ureteroscopic biopsy. Besides causing discomfort and pain, ureteroscopy prior to surgery increases risk of tumor implantation and recurrence. Although urine cytology and FISH were applied, more effective non-invasive diagnostic method is imperative for diagnosis of renal pelvic cancer. Methods: A total of 141 patients with one or more lesions in renal pelvis detected by ultrasound were enrolled. 50-ml first-void urine sample was collection before ureteroscopic biopsy and was analysis by Genetron uro-18 genes panel, by which mutations in 17 genes and methylation status of ONECUT2 were analysis using high-throughput sequencing. If mutations and/or ONECUT2 methylation were detected in urine sediment DNA, the patients were considered as high risk of renal pelvis cancer. The results of the urine-based liquid biopsy genetic test were compared with pathology report and urine FISH results of urinary cells. Results: According to pathological analysis with ureteroscopic biopsy, 42 out of 141 patients (29.7%) were diagnosis with renal pelvic cancer: 13 low-grade, 24 high-grade, 5 equivocal. For 33 renal pelvic cancer patients with FISH testing result of urinary cells, only 54.5% (18/33) samples were positive. By Genetron uro-18 genes test, 95 patients (67.4%) were classified as high risk and 46 (32.6%) patients were low risk. The overall specificity was 88.0% (88/95) and overall sensitivity was 92.9% (39/42), which is significant higher than FISH test of urinary cells. Conclusions: With high specificity and sensitivity, Genetron uro-18 genes test could be incorporated in renal pelvic cancer diagnosis, especially for patients with a ultrasound detectable lesions. Ureteroscopy prior to surgery could be reduced, which may lead to decrease risk of tumor implantation and recurrence.
The process of urinary bladder cancer recurrence in 33 patients with 113 tumors, analyzed by changes in IHC features of 80 pairs of subsequent tumors.
Authors: Kurbel Sven , Dmitrovic Branko , Matić Mate , Vrbanec Damir
Published: June 2021

e16507

Background: The aim was to define IHC changes between the two subsequent urinary bladder cancers (UBC). Methods: IHC data on EGFR, HER2, HER3, Ki-67, MLH1, MSH2, MSH6 and PMS2 in 113 UHC from 24 male and 9 female patients (1 to six recurrences) were used. Except for the Ki-67 value, other markers were stratified: “0” for no positive cells; “1” < = 10% positive cells; “2” 1%-30% positive cells; and “3” 31%-100% positive cells. Data of consecutive tumors were paired in 80 processes of recurrence (PoR). Changes between the latter and the former tumor were calculated: in +/- % for Ki-67 values, and as integer sums of absolute changes in expression for HER markers and for Lynch markers. EM clustering was applied for recognition of relevant IHC changes. Results: Three aspects were tested: the speed of recurrence, was it the first, or later recurrence and whether PoRs depended on the total number of tumors in that patient. Early and late PoRs clustered along the Lynch score, while the intermediate clustered along the delta Ki-67 value. The first PoRs clustered along the HER score and all subsequent PoRs depended on the Lynch score. Conclusions: Even in this limited group of patients Lynch and HER markers showed complex differences between early and late recurrent tumors. The speed of the recurrence and changes of IHC features depended mainly on the rate of change in Lynch markers, suggesting that they should be tested as predictors of UBC recurrence.[Table: see text]
Parameters of local cellular immunity in patients with bladder cancer.
Authors: Belyakova Lyubov I. , Sagakyants Aleksandr B. , Shevchenko Alexey N. , Filatova Elena V. , Bondarenko Elena S. , Shulgina Oksana G. , Khvan Viktor K. , Shvyrev Dmitry A. , Khomutenko Irina A.
Published: June 2021

e16508

Background: Bladder cancer (BC), which accounts for 4.5% of the total cancer incidence, is the cause of frequent severe disability and a significant deterioration in the quality of life of patients. BC development is determined by a number of factors, involving the immune system; however, its role is poorly understood. The purpose of the study was to determine characteristics of parameters of the cellular immunity in patients with non-muscle invasive BC. Methods: The study included 14 patients with newly diagnosed stage I BC. Patients were divided into two groups: with low-grade tumors (LG), n = 7, mean age 57 years; with high-grade tumors (HG), n = 6, mean age 60 years. All patients underwent transurethral resection of the bladder, and tumor tissues (TT, size up to 1.5 cm) and perifocal tissues (PT, at least 0.5 cm from the tumor) were obtained. The specimens were disintegrated to obtain the cell suspension. The relative numbers of the main populations of leukocytes and T- and B-lymphocytes, as well as some subpopulations of T-lymphocytes, were determined using the BD FACSCanto II flow cytometer and a panel of antibodies according to the manufacturer's instructions (Becton Dickinson, USA). Results: Reduction of lymphoid tissue infiltration by 78% was observed in TT in HG patients, compared to the LG group; levels of CD8+ lymphocytes, CD3+CD4-CD8- and CD3+CD4+CD8+ cells, NK- and B-lymphocytes were lower by 27%, 33%, 51%, 45% and 62%, respectively. Levels of Treg in HG TT were 32% lower than in LG. The numbers of activated CD4+, CD8+ cells were unchanged, but TT infiltration by naive lymphocytes of both populations was increased by 28% and 31%, respectively. In HG PT, a decrease in the total number of lymphocytes by 27% was observed, together with higher levels of CD3+CD4+CD8+ cells and NK- and B-lymphocytes by 200%, 213% and 31%, respectively. Conclusions: BC patients with various tumor grades demonstrate different distributions of lymphocyte populations in tumor and perifocal tissues; the functional activity of these cells can both contribute to the disease development and determine the risk of recurrence.
Cancer stem cells as markers of bladder cancer recurrence.
Authors: Belyakova Lyubov I. , Sagakyants Aleksandr B. , Shevchenko Alexey N. , Filatova Elena V. , Khvan Viktor K. , Khomutenko Irina A. , Shvyrev Dmitry A. , Ulianova Elena P. , Bondarenko Elena S. , Novikova Inna A.
Published: June 2021

e16511

Background: Bladder cancer (BC) is an urgent problem of oncology in the world, and without appropriate and timely treatment it can lead to severe disability and a significant deterioration in the quality of life of patients. BC accounts for 4.5% of the total cancer incidence. Cancer stem cells (CSCs) are actively involved in the development of recurrent malignant tumors, and also play an important role in the development of chemotherapy and radioresistance of tumor cells. CSCs in BC are poorly studied. Our purpose was to determine the CSC numbers in patients with non-muscle invasive BC. Methods: The study included 7 patients with newly diagnosed stage I BC, G2, intermediate prognosis according to the EORTC scoring system. All patients underwent transurethral resection of the bladder, and tumor tissues (TT, size up to 1.5 cm) and perifocal tissues (PT, at least 1.0 cm from the tumor) were obtained. The specimens were disintegrated to obtain the cell suspension, and the CSC percentages were determined using the FACS Canto II flow cytometer with monoclonal antibodies to CD45-APC-Cy7, CD24-FITC, and CD133–PE according to the manufacturer's instructions (BD, USA). Numbers of cells with CSC markers (CD24+, CD44+, CD133+, CD24+CD44+, CD44+CD133+) were calculated as the percentage from the total number of CD45--cells. The results of statistical processing were presented as the arithmetic mean and the standard error of the arithmetic mean. The significance of differences between the samples was assessed using the Mann-Whitney’s nonparametric test. Results: The numbers of CD45--cells were similar in TT and PT (61.3±5.8 and 71.8±12.6). The relative numbers of cells with CSC phenotypic markers, such as CD24, CD44, were 77% and 58% higher in TT than in PT: 18.3±3.5 vs. 4.3±2.1 and 15.5±5.3 vs. 6.5±0.8, respectively; p≤0.05. The number of CD133+ cells was 83% higher in PT compared to TT - 41.6±12.1 vs. 22.7±7.6. The numbers of CD44+CD24+ and CD44+CD133+ cells in TT were higher than in PT by 80% and 63%, respectively: 10.3±4.9 vs. 2.1±0.4, 9.0±4.5 vs. 3.3±0.9, p≤0.05. CD44-CD24+ CD133+ cells were not detected in PT. Conclusions: The results indicate the peculiarities of the distribution of CSCs in TT and PT, which can be used to predict the risk of the disease recurrence and/or progression, and also help to evaluate results of the treatment.
Opioid use in locally advanced or metastatic urothelial carcinoma patients and matched non-cancer controls.
Authors: Grewal Simrun Kaur , Hepp Zsolt , Liu Yutong , Fuldeore Rupali , Sesterhenn Steve , Chang Nancy N. , Galsky Matt D.
Published: June 2021

e16517

Background: There are currently no published data on the patient experience with pain and pain medication use among the locally advanced or metastatic urothelial carcinoma (la/mUC) population. In this study, we quantified opioid use, as a proxy for pain, in patients with la/mUC and in matched non-cancer controls, using real-world data. Methods: We performed a retrospective claims analysis of adults diagnosed with UC who initiated ≥1 la/mUC therapy between 5/2016-6/2019 using the IBM MarketScan databases. Non-cancer controls were identified in 2 steps: 1) exact match on age/gender at index, 2) nearest neighbor propensity score matching (1:3 ratio) based on age, gender, region, insurance type, index year, enrollment time, and major comorbidities. Index was the date of first la/mUC therapy; index for controls was aligned to claims activity for matched patients with la/mUC. Baseline was the 6 months pre-index; follow-up was from index until disenrollment, death or study end (12/2019). Analyses examined the proportion of opioid users, number of opioid prescriptions, and daily morphine equivalent dose (MEQ). Results: A total of 1,293 patients with la/mUC and 3862 controls were included; mean (standard deviation [SD]) age at index was 64.1 (11.9) years for the la/mUC cohort and 64.8 (12.0) for controls, and most were male (60.2% and 61.3%, respectively). Mean (SD) follow-up was 15.1 (8.9) and 15.5 (8.6) months, respectively. A higher proportion of patients with la/mUC used opioids than controls during both baseline and follow-up (Table). Among opioid users, trends in opioid use were similar between the cohorts during baseline, with differences during follow-up (Table). At baseline, 63.6% (n=822) of patients with la/mUC had ≥1 opioid prescription which decreased during first-line (1L) treatment to 38.8% (n=502) and subsequently increased to 47.0% (n=159 of 338) during second-line (2L) treatment. The mean (SD) number of opioid prescriptions also increased during later therapy lines (1L: 0.92 [0.99], 2L: 1.37 [1.24]) along with increases in mean (SD) daily MEQ (1L: 69.8 [274], 2L: 133 [586]). Conclusions: This study underscores the impact of pain among patients with la/mUC, which is common at diagnosis, higher than matched controls, and worsens as the patient progresses. Improved disease control with more effective therapies may reduce pain in this population. [Table: see text]
Outcomes of patients (pts) with advanced urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICIs): Associations with age, race, sex and smoking history.
Authors: Makrakis Dimitrios , Talukder Rafee , Carril Lucia , de Kouchkovsky Ivan , Park Joseph J , Bilen Mehmet Asim , McKay Rana R. , Agarwal Neeraj , Zakharia Yousef , Devitt Michael E. , Pinato David James , Hoimes Christopher J. , Gartrell Benjamin Adam , Tripathi Abhishek , Bamias Aristotelis , Drakaki Alexandra , Murgic Jure , Di Lorenzo Giuseppe , Grivas Petros , Khaki Ali Raza
Published: June 2021

e16526

Background: ICIs have altered the therapeutic landscape in pts with aUC and new biomarkers are needed to better predict response and outcomes with ICIs. It is unclear whether demographics, such as race, age, sex and history of smoking, are associated with outcomes with ICIs. We hypothesized that specific demographic groups (sex, age, race, smoking history) would be associated with outcomes with ICIs in aUC. Methods: We performed a retrospective cohort study across 25 institutions. Data collected included demographic and clinicopathologic factors, response and outcomes. We calculated observed response rate (ORR), Progression-Free Survival (PFS) and overall survival (OS) for specific demographic groups. We built multivariable models (logistic regression for ORR; Cox regression for PFS and OS) with all demographic groups to assess outcomes. Analysis was done for the overall population and stratified by treatment line (first line [1L]; salvage [2+L]). The stratified analysis was also adjusted for known prognostic risk scores (internally developed for 1L; Bellmunt for 2+L); p-value < 0.05 was significant. Results: We identified 1026 pts; 754, 744 and 780 were included in OS, ORR and PFS analysis. Overall, median age at ICI initiation was 70; 26% female; 75% White, 11% Hispanic, 5% Black, 8% other; 69% had smoking history; 28% with mixed histology; 17% with upper tract UC. In the unstratified analysis, age 65-74 (vs < 65) was significantly associated with higher ORR (32% vs 22%) and median PFS (5 vs 3 mo HR 0.8); otherwise no significant difference was noted among groups for ORR, PFS, OS in both the stratified and unstratified analyses (Table). Conclusions: We did not identify significant associations between age, sex, race or smoking history and ORR, PFS, OS with ICIs in pts with aUC. Limitations include retrospective nature, lack of randomization, possible selection and confounding factors. Further research is required to identify prognostic and predictive biomarkers for ICI therapy in aUC.[Table: see text]
Impact of clinicopathological features on survival in patients treated with immune-based combinations for metastatic urothelial carcinoma: A meta-analysis of randomized clinical trials.
Authors: Mollica Veronica , Rizzo Alessandro , Santoni Matteo , Marchetti Andrea , Rosellini Matteo , Massari Francesco
Published: June 2021

e16534

Background: Immune checkpoint inhibitors (ICIs) have recently revolutionized the treatment landscape of metastatic urothelial carcinoma (mUC). Nonetheless, little is known regarding the impact of clinicopathological features in this setting. We performed a meta-analysis aiming to evaluate the predictive value of ECOG-PS, age, gender, liver metastases, and histology in randomized controlled trials (RCTs) comparing ICI-based combinations versus chemotherapy in mUC patients. Methods: We retrieved all the relevant RCTs through PubMed/Med, Cochrane library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible studies included RCTs comparing ICI-based combinations versus chemotherapy alone in mUC patients. The primary endpoint was overall survival (OS), measured as hazard ratio (HR) with corresponding 95% confidence interval (CI). All statistical analyses were performed using R studio software. Results: Overall, 1032 mUC patients were included in the analysis. Compared with chemotherapy, ICI-based combinations significantly decreased the risk of death in several clinicopathological subgroups, including no liver metastases (HR, 0.84; 95% CI, 0.74-0.95) and ECOG-PS 0 patients (HR, 0.84; 95% CI, 0.72-0.97). Similarly, ICI-based combinations were associated with prolonged OS in mUC patients who were < 65 years old (HR, 0.82; 95% CI, 0.72-0.95), as well as in male (HR, 0.90; 95% CI, 0.82-0.99) and female patients (HR, 0.81; 95% CI, 0.68-0.97). Conversely, a non-statistically significant benefit was observed for chemotherapy alone in mUC patients with liver metastases (HR, 1.06; 95% CI, 0.86-1.31). Conclusions: According to our results, the magnitude of benefit of ICI-based combinations over chemotherapy in mUC was consistent across a number of clinicopathological subgroups, while a proportion of patients could respond to chemotherapy alone.Despite several limitations affect our analysis, we believe these results could guide in everyday treatment decision-making, also assisting in the design and interpretation of future clinical trials on ICIs in mUC.
Cabozantinib versus other TKIs after CPI treatment in the real-world management of patients with mRCC.
Authors: Marteau Florence , Harrow Brooke , McCarthy Christine , Wallace Joel , Monnette Alisha , Wang Yunfei , Doshi Gurjyot K.
Published: June 2021

e16539

Background: Checkpoint inhibitors (CPIs) are a treatment option for patients with metastatic renal cell carcinoma (mRCC), but there is limited clinical data on the efficacy of targeted therapies following CPI treatment. Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets multiple receptor kinases implicated in tumorigenesis. In the US, cabozantinib is approved for use in patients with advanced RCC including after CPI treatment. Methods: This retrospective observational cohort study (NCT04353765) evaluated outcomes associated with cabozantinib or other TKIs (axitinib, lenvatinib, pazopanib, sorafenib, sunitinib) in patients with mRCC following CPI treatment. Eligible patients initiated TKI therapy between May 1, 2016 and Sep 31, 2019 and had received a CPI as their last systemic treatment prior to TKI therapy. Patients were identified from the US Oncology Network iKnowMed electronic health record database through structured queries and a targeted chart review. The following real-world outcomes were assessed: 6-month response rate (RR6months; primary); overall response rate (ORR); overall survival (OS); time to treatment discontinuation (TTD); rates of dose reductions, and discontinuation due to adverse events (AEs). The p value for RR6months (χ2 test) was used to test for non-inferiority. Results: Eligible patients ( n = 247) had a mean (SD) age of 65.9 (10.5) years and 74.1% were male; 75.7% ( n = 187) received cabozantinib and 24.3% ( n = 60) received other TKIs. All patients had intermediate or poor MSKCC score; more poor-risk patients received cabozantinib than other TKIs (28.9% vs 20%). Outcomes data are shown in the Table. Compared with other TKIs, cabozantinib was associated with a significantly higher RR6months and ORR, and TTD was twice as long with cabozantinib. Discontinuation due to AEs was more frequent with other TKIs than with cabozantinib, although this was not statistically significant; 21.7% of discontinuations occurred during the first 3 months of treatment. AEs leading to discontinuation were consistent with the known safety profile of the products. Conclusions: In this mRCC population receiving routine care in the US, cabozantinib was used more frequently than other TKIs after CPI treatment. Cabozantinib was an effective and well tolerated option post-CPI, with a high response rate in the real-world setting.abozantinib was associated with a significantly higher response rate and a lower discontinuation rate due to AEs; TTD was double that of other TKIs. Clinical trial information: NCT04353765. [Table: see text]
Does concurrent COX inhibition and immune checkpoint blockade improve clinical outcome in patients with metastatic renal cell carcinoma?
Authors: Zhang Yumeng , Adashek Jacob J. , Kumar Premsai , Skelton William Paul , Li Jiannong , Chahoud Jad , Manley Brandon J , Spiess Philippe E.
Published: June 2021

e16558

Background: Cyclooxygenase (COX) inhibition is postulated to restore the immune environment and synergizes with immune checkpoint inhibitors (ICI). The concurrent use of COX inhibitors (COXi) and ICI was associated with longer disease control in metastatic melanoma and non-small cell lung cancer. However, its role in mRCC remains unclear. Methods: We retrospectively reviewed 194 patients with mRCC treated with ICI (PD-(L)1 inhibitors +/- CTLA-4 inhibitors or TKIs) at Moffitt Cancer Center between 6/2014-7/2019. Concurrent use of COXi (aspirin [ASA] or NSAIDs) was defined as at least 3 weeks of COXi use during the first ICI course. Clinical characteristics of both arms were compared using Chi-squared or Kruskal-Wallis Rank Sum test. Time to progression (TTP) and Overall survival (OS) were compared using Kaplan Meier’s estimates. Univariate and multivariate Cox proportional hazards model was performed to evaluate the association between clinical factors, TTP, and OS. Results: Of 194 patients, 126 patients (64.9%) took COXi. Median age was 59.7 years and 80.4% were male. COXi arm had fewer patients with < 1 year from diagnosis to systemic treatment (45.9% vs 69.5%, p = 0.006) and more advanced age (median: 66 years vs 60 years, p = 0.01). IDMC risk group, number of prior therapies, neutrophil to lymphocytes ratio were similar between both arms. Median TTP was 8 months (m) for COXi arm and 12m for ICI only (HR 1.38; 95% CI [0.98, 1.94]). Median OS was 27m for COXi arm and 33m for ICI only (HR 1.05, 95% CI [0.69, 1.59]). Early mortality rate (within 3m of ICI treatments) were similar between both arms. Conclusions: In contrast to melanoma and lung cancer, concurrent use of COXi and ICI did not improve TTP and OS in patients with mRCC. The dual blockade showed a trend for shorter TTP. Further validation studies with larger cohorts are needed to confirm this finding.[Table: see text]
Thirty day readmissions and outcomes following radical nephrectomy in renal cell carcinoma: A nationwide analysis.
Authors: Shrivastava Trilok , Salazar Miguel , Prado Victor , Gauto Estefania , Baral Binav , Upadhyay Shristi , Elsebaie Maha A.T.
Published: June 2021

e16560

Background: Nephrectomy is one of the primary treatments of Stage I-III renal cell carcinoma (RCC), which is usually associated with low rates of serious morbidity and mortality. However, a fraction of patients gets readmitted after the surgery for numerous reasons which can impact their overall prognosis. Methods: We conducted a retrospective cohort study using the 2017 National Readmission Database of adult patients with RCC readmitted within 30 days after an index admission for nephrectomy. We aimed to identify the 30-day readmission rate, mortality, resource utilization, and independent predictors of readmission. Results: A total of 25,307 patients with RCC underwent nephrectomy. The 30-day readmission rate was 8.7%. The top five causes for readmission were sepsis, AKI, STEMI, surgical infections & metastatic disease. Patients requiring readmission were less likely to be discharged home (56.5 vs 81.8%), have private insurance (27.2 vs 34.7), obesity (14.7 vs 20.6%), hypertension (30.9 vs 47.1%), and be admitted to a teaching hospital (75.8 vs 79.2%). They were more likely to be insured with Medicare (58.3 vs 53.3%), have lower income (28.7 vs 26.3%), type 2 diabetes (32.4 vs 26.7%), CKD (44.1 vs 20.7%), malnutrition (9.2 vs 2.1%), undergo chemotherapy (5.2 vs 1.9%). Readmission was associated with higher in-hospital mortality (1.5 vs. 0.1%), CVA (0.6 vs 0.3%), AKI (29.6 vs 16.9%) and pleural effusion (7.8 vs 1.8%). They were also more likely to require mechanical ventilation (3.5 vs 1.8%), parenteral nutrition (1.2 vs 0.4%) and hemodialysis (11.9 vs 4.5%). The in-hospital economic burden of readmission was $128 million in total charges and $31.8 million in total costs. Independent predictors of readmission were disposition to a short-term hospital or skilled nursing facility, length of stay, need for mechanical ventilation and transfusion of blood products, having type 1 diabetes, malnutrition, pleural effusion, and CKD. Younger age and private insurance were associated with preventing readmission. Conclusions: Readmissions after nephrectomy in patients with RCC are associated with increased in-hospital mortality rate and pose a high health care economic burden. We identified few risk factors and patient characteristics associated with post-surgical readmissions; however, further in-depth studies are needed to find preventable risk factors.[Table: see text]
Sunitinib in metastatic clear cell renal cancer (CCRC): A real life Chilean single institution experience.
Authors: Orlandi Luis J. , Galaz Pedro Pablo , Holloway Robert Melo , Linares Belkys Melina , Garcia Vicente Larrain
Published: June 2021

e16562

Background: The introduction of biologic and immunologic therapy has produced a profound change in the management of metastatic CCRC but there is no definitive indication on drug selection and therapeutic sequences based on efficacy, toxicity, costs and access. Methods: We report 50 consecutive stage IV CCRC patients treated at our Institution from 12/2007 to 11/2020 with sunitinib at recommended dosage. Median age at stage IV diagnoses was 62.5 months (39 to 79). Sex distribution was 5 women (10%) and 45 (90%) men. Under MSKCC criteria 35 patients were medium + high risk (70%) and 15 (30%) low risk. Results: On an intent to treat basis the complete + partial response rate was 56% (28/50) for the entire group , 45.7% (16/35) for the high-risk group and 80% (12/15) for the low-risk group. Actuarial 5 year survival was 24% for the entire group, 11.4% for the high-risk group and 53.3% for the low -risk group. We explored the effect of metastases-free time on survival. We found that 15 patients were metastatic at the moment of initial diagnoses versus 26 patients who developed metastatic disease at 12+ months after primary tumor diagnoses. Mean survival was 32.7 months (1 - 97) for the first group and 49.5 months (6 - 156) for the second group (p<0.5). Subsequent therapies consisted of pazopanib (25 patients), axitinib (17 patients), everolimus (9 patients), nivolumab (6 patients) and cabozantinib (1 patient). Secondary reactions consisted of emesis (20%), diarrhea (16%), asthenia (14%), skin dispigmentation (12%), mucositis (10%), disgeusia (10%), dermatitis (10%), neutropenia (8%), hand and foot syndrome (4%). Conclusions: Sunitinib is a good choice in low-risk metastatic CCRC and we adopted this regimen as standard therapy in this group of patients at our Institution.
FDG-PET avidity as a prognostic biomarker for overall survival in renal cell carcinoma.
Authors: Ferdinandus Justin , Maríc Ines , Darr Christopher , Kesch Claudia , Hilser Thomas , Fendler Wolfgang Peter , Herrmann Ken , Hadaschik Boris A. , Grünwald Viktor
Published: June 2021

e16564

Background: Positron emission tomography with (18F)-fluorodeoxyglucose (FDG-PET) is not considered a standard of care (SOC) in renal cell carcinoma (RCC) because of its variability in metabolic activity. We investigated the rate of PET-positivity in our institutional cohort and tested whether PET-positivity had prognostic value in metastatic (m)RCC. Methods: Patients with FDG-PET imaging at any time during the course of disease were identified from medical records. PET-positivity was defined according to PERCIST criteria and a five-point rating scale analogue to Deauville Scoring was used to stratify PET-avidity. Tracer uptake of the hottest lesion was measured as SUVmax. Clinical parameters and PET-positivitywere correlated with overall survival (OS). Kaplan-Meier plots, log-rank analyses, kendall rank correlation, univariate and multivariable cox regression models were employed, where appropriate. Results: A totalof 90 patients was analyzed. The median age was 64.0 (34.0-83.0) and 56 (62.2%) patients had clear cell RCC. Metastatic disease was present in 64 (71.1%) and 22 (24.4%) patients received ongoing medical treatment. 72 (80.0%) patients had prior nephrectomy. PET-positivity occurred in 57 (63.3%) patients, with similar rates among metastatic (41/64; 64%) and non-metastatic patients (16/26; 62%). PET-positive patients had shorter median OS compared to PET-negative patients (38.5 months (CI95:24.5-NR) vs. not reached (CI95: 69.6-NR), P= 0.0013). A weak correlation was found between PET-Uptake and histologic grade (Kendall’s tau 0.22; P= 0.03). Prior nephrectomy, presence of primary lesions, presence of distant metastases, histologic grade and PET-positivity were significant predictors of OS in univariate regression. In multivariable analysis, only PET-positivity remained significant (HR 4.1 (CI95: 1.1-15.4), P= 0.04). Conclusions: RCC is a metabolically active cancer, which in the majority of patients is suitable for FDG-PET diagnostic procedures. PET-positivity was an independent prognostic factor for OS in RCC, indicating its putative clinical use. Further studies to define the role of FDG-PET imaging in RCC are ongoing.
Bone-targeted therapy in patients with renal cell carcinoma bone metastases undergoing palliative surgery.
Authors: Garmezy Benjamin , Brozovich Ava , Feng Lei , Deveza Lorenzo , Satcher Robert L.
Published: June 2021

e16572

Background: RCC bone metastases (RCCBM) are found in 20-39% of patients and are becoming more prevalent. RCCBM cause significant morbidity and often require surgical intervention. Current bone-targeted therapies include bisphosphonates and denosumab. Previous literature has suggested that bisphosphonates do not improve survival or reduce skeletal related events and little has been published about the effect of denosumab. Here we present experience describing outcomes and therapeutic effect in patients with RCCBM following palliative surgery for bone metastasis. Methods: We performed a retrospective analysis of 226 patients with RCCBM who underwent orthopedic surgery at MD Anderson Cancer Center between 11/2005 – 8/2019. The Kaplan-Meier method and log-rank test were used to estimate and evaluate survival differences. Results: Patient characteristics included: median age 58.2, male 66.4%, clear cell histology 93.5%, metastatic at presentation 57.9%, nephrectomy 79.8% (63.9% prior to orthopedic intervention), received radiation to the surgical site (pre-op: 13.0%, post-op: 41.4%). First orthopedic intervention: resection arthroplasty 37.2%, curettage and intramedullary nailing (IMN) 18.6%, IMN 16.4%, open reduction internal fixation 15.0%, amputation 2.7%, 10.2% other. Pre-op therapy: bisphosphonate 12.4%, denosumab 5.8%, both 2.7%, none 79.2%. Post-op therapy: bisphosphonate 18.1%, denosumab 13.7%, both 0.9%, none 67.2%. With a median follow up of 3.1 years after first orthopedic intervention, median overall survival (OS) was 2.7 yr (95% CI 2.1 – 3.6). Progression free survival (PFS) was calculated from time of first surgery to either first progression or death; median PFS was 5.2 months (95% CI 4.6 – 7.5). Pre-op or post-op bone-targeted therapy was not significantly associated with PFS (yes vs no: Pre-op: median 3.4 vs 6.3 mth, p=0.42; Post-op: median 4.3 vs 5.8 mth, p=0.61) or OS (Pre-op: 2.1 vs 2.9 yr, p=0.45; Post-op: 2.4 vs 3.2 yr, p=0.18). Post-op denosumab compared to bisphosphonate was associated with increased PFS (9.6 vs 3.8 mth, p=0.03) and OS (3.3 vs 1.6 yr, p=0.02). However, post-op denosumab vs no bone-targeted therapy was not significantly associated with increased PFS (9.6 vs 5.8 mth, p=0.42) or OS (3.3 vs 3.2 yr, p=0.85). Of note, post-op bisphosphonate vs no bone-targeted therapy was associated with reduced PFS (3.8 vs 5.8 mth, p=0.04) and OS (1.6 vs 3.2 yr, p=0.01). Conclusion: Addition of bone-targeted therapy did not significantly improve PFS or OS in patients with RCCBM undergoing orthopedic intervention. Post-op denosumab was associated with better PFS and OS compared to bisphosphonates and bisphosphonates were associated with worse PFS and OS compared to no bone-targeted therapy. Patient selection for therapy may be an important source of bias. Prospective research is needed to clarify the role and selection of bone-targeted therapy in RCCBM patients.
Inpatient outcomes of pathological fractures in metastatic prostate cancer.
Authors: Ahuja Kriti , Lingamaneni Prasanth , laswi hisham , Kumi Dennis Danso , Chhabra Navika , Darweesh Omnia , Batra Kunnal
Published: June 2021

e17007

Background: Bone is a frequent site of metastasis in prostate cancer and is involved in 88% of patients with metastatic prostate cancer. Metastasis to bone increases the risk of pathological fractures, which are associated with increased morbidity and mortality. We performed a retrospective analysis on inpatient outcomes of pathological fractures in prostate cancer metastatic to bone in comparison to men with osteoporotic fractures. We also examined the disposition of these patients. Methods: We queried the Nationwide Inpatient Sample between 2016 and 2018 to retrospectively identify adult males with osteoporotic fractures and those with pathological fractures secondary to metastatic prostate cancer. We used T-test and chi-square test to compare means of continuous variables and compare proportions of categorical variables respectively. Multivariate analysis of predictors of mortality, length of stay, hospitalization costs and disposition in this group were performed. Results: A total of 22,800 fractures, combining osteoporotic fractures and pathological fractures due to metastatic prostate cancer were identified, of which the latter accounted for 13.6%. Patients with pathological fractures secondary to metastatic prostate cancer were younger (mean age 73.5 vs 77.5 years, p < 0.0001) and more likely to be black (16.4% vs 4.6%, p < 0.0001) or Hispanic (8.4% vs 5.1%, p < 0.0001). Adjusting for demographic variables and comorbidity burden, pathological fractures in patients with prostate cancer metastasis to the bone were not associated with a significant increase in mortality (aOR 1.46, 95% CI 0.82-2.60, p = 0.20) or length of hospital stay. However, they did have higher hospitalization costs by $2,610 per admission (p = 0.01). Patients with pathological fractures secondary to prostate cancer are less likely to be discharged to a nursing facility (aOR 0.50, 95% CI 0.40-0.62, p < 0.001) and are more likely to be transitioned to home health care (aOR 1.49, 95% CI 1.20-1.84, p < 0.001). Conclusions: Pathological fractures secondary to prostate cancer are less frequent than osteoporotic fractures in men and are not independent predictors of mortality or length of stay. This is in keeping with the relatively indolent course of prostate cancer. However, there is an increased cost of hospital stay associated with pathological fractures in metastatic prostate cancer. Interestingly, these patients are more likely to be discharged with home health care and are less likely to go to a nursing facility, making disposition a crucial aspect in the care of these patients.