bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel nanobiosensor based protease biomarkers for early detection and prognosis of pancreatic cancers.
Authors: Kasi Anup , Houghton James Kaiser , Saeed Anwaar , Williamson Stephen K. , Zambrano Obdulia Covarrubias , Bossmann Stefan H
Published: May 2020

e16787

Background: Identifying novel biomarkers for early detection and prognosis would allow for improved survival outcomes in pancreatic cancer (PC). Arginase has been implicated in tumorigenesis through its production of L-ornithine. Its aberrant expression provides metabolites for tumor proliferation. Methods: In our study, 47 patients with metastatic PC, 29 with localized PC, and 50 healthy controls were enrolled at KU Cancer Center from 2000 to 2019. Overall survival (OS) was retrospectively assessed and correlated to serum protease levels at diagnosis. Protease expression was analyzed using nanobiosensors, which utilized fluorescent nanoparticles read by Spectra Scan to measure arginase, matrix metalloproteinases (MMPs), urokinase plasminogen activator (uPA), neutrophil elastase (NE), cathepsin B (CTSB), and cathepsin E (CTSE). Survival analysis was completed by Kaplan-Meier method. Results: Protease expression in localized vs. healthy cases was significant for (CTSB [p = 1.33E-10], MMP1 [p = 6.66E-21], MMP3 [p = 1.39E-13], MMP9 [p = 2.77E-08], NE [p = 0.00015], uPA [p = 2.55E-11]) and borderline significant for arginase [p = 0.05082]. Protease expression in metastatic vs. healthy cases was significant for (CTSB [p = 7.06E-06], MMP1 [p = 3.08E-12], MMP3 [p = 2.51E-14], MMP9 [p = 1.73E-08], NE [p = 0.01430], uPA [p = 0.00024]). Further, metastatic vs. localized cancer was significant for (arginase [p = 0.00034], CTSB [p = 0.00584], MMP1 [p = 2.03E-13], NE [p = 2.29E-10], and uPA [p = 6.58E-07]. Characteristics of 21 localized PC patients are illustrated in Table. Median OS was 25m in localized PC with low Arginase expression (mean < 215) vs 17.5m in high Arginase expression (p = 0.0477). Conclusions: Expression pattern of CTSB, MMP, NE, arginase, uPA proteases showed statistical significant difference for detection of localized PC vs metastatic PC vs healthy cases. In localized PC, lower arginase expression showed a statistically significant improvement in survival vs high arginase expression. Arginase expression was borderline significant for detection of localized PC vs healthy controls, likely due to small sample. Arginase as a potential biomarker for early detection and prognosis of PC warrants validation in a larger cohort. [Table: see text]
FOLFIRINOX versus sequential 5-FU, oxaliplatin, and irinotecan-based regimens in patients with recurrent pancreatic cancer (rPDAC).
Authors: Rehman Hasan , Chi Jeffrey , Hakim Nausheen , Jose Jyothi , Moriarty Linda , Lamont Carol , Saif Wasif M.
Published: May 2020

e16791

Background: There is a paucity of data to guide treatment for rPDAC after curative resection and gemcitabine-based adjuvant chemotherapy. Our aim was to investigate whether combination treatment upfront with all active agents is better than sequential administration of these drugs in patients with rPDAC following curative therapy. Methods: We retrospectively analyzed overall survival (OS), progression-free survival (PFS), response rate (RR), and adverse events (AEs) in patients treated for rPDAC. Patients received FOLFIRNOX upfront versus sequential therapy in the following order based on patient’s presence of toxicities (FOLFOX —> FOLFIRI, FOLFOX—> liposomal irinotecan/5FU, liposomal irinotecan/5FU —> FOLFOX). Each treatment was administered per NCCN guidelines with regulated staging scans, blood work, and office visits. Data was collected about chemotherapy dose, ECOG performance status (PS), RR, PFS, OS, and AEs. Results: 55 patients were identified with ECOG PS ≤ 2 and male:female ratio 35:20. Results for FOLFIRINOX, FOLFOX followed by FOLFIRI, FOLFOX followed by liposomal irinotecan/5FU, and vice versa are as follows respectively: PFS 4.0, 3.5, 3.5, and 3.0 months; OS 8.0, 7.5, 7.0, and 8.3 months; RR 10%, (8%, 3%), (9%, 4%), and (3%, 5%). One of the patients in the mFOLFIRINOX was able to undergo metastasectomy. The table summarizes the toxicities and dose modifications seen. Conclusions: Upfront FOLFIRINOX versus sequential regimens of oxaliplatin and irinotecan-containing regimens resulted in similar PFS and OS but higher AEs as expected. However, surgery was only possible in patients receiving FOLFIRINOX. Our findings support the use of sequential treatment in rPDAC who are not potential surgical candidates. Further investigative work is warranted to optimize sequencing of active agents in this setting where prognosis has historically been poor. [Table: see text]
Early detection for pancreatic cancer in individuals at elevated-risk, using endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI) of the abdomen: Feasibility and preliminary outcomes.
Authors: Raff Joshua P. , Noyer Charles , Boxer Nicole , Sadan Sara , Costin Dan , Roayaie Sasan , Gordon Mark , Kaumaya Meghan , Hopkins Una , Cortese Marisa , Rice Melissa Rowan , Goel Sanjay
Published: May 2020

e16798

Background: There are no accepted guidelines for testing individuals at elevated risk for developing pancreatic duct adenocarcinoma (PC). We initiated a prospective screening and surveillance program for individuals at elevated risk for PC. Methods: Eligibility for the Pancreatic Cancer Early Detection Protocol (PCEDP) was based on germ line status and/or family history of PC, provided that the imparted risk was either five times that of the general population or 7.5% lifetime risk for developing PC. Testing was continued alternating between Endoscopic Ultrasound (EUS) and Magnetic Resonance Imaging (MRI) of the abdomen. Objectives were was to analyze the number, type, and location of pancreatic conditions found and their associations with genetic or family history; and to evaluate the outcomes and/or complications that may have resulted from our testing. Results: From April 2014 through October 2019 we received 238 queries, out of which 75 individuals (31%) enrolled in the PCEDP. Eligibility was based upon individual’s germ line only (45%), family history only (32%), and both (23%). Germ line mutations were observed in 34 (BRCA2), 9 (BRCA1), 4 (ATM), 3 (PALB2), and 3 (CDKN2A) individuals. Median age at consent was 57, 60% were female,and88%, 4%, 3%, and 1% self-identified as Caucasian, African American, Hispanic, and Asian, respectively. 133 EUS procedures and 83 MRIs have been performed. No serious adverse events occurred. Standard Insurance approved and paid for the vast majority of tests. Four individuals withdrew (5%) and three (4%) were lost to follow up. Ten individuals (13%) were found to have abnormal findings in the pancreas and therefore met an endpoint of the study, including seven anechoic cysts and three suspected intraductal papillary mucinous neoplasms (IPMN). All individuals with endpoints were recommended to continue surveillance with EUS. Eight of the ten endpoints were found on baseline EUS, one one from baseline MRI, and one was found on the 3rd EUS. One of the individuals with a 2.5cm IPMN seen on baseline EUS underwent a subsequent distal pancreatectomy, with pathology revealing high grade dysplasia. Conclusions: Screening and surveillance for PC using EUS alternating with MRI was feasible and well tolerated in our population of individuals with an elevated risk. Baseline EUS was successful in detecting 10/75 = 13% of enrollees with some abnormal pancreatic finding, including one requiring intervention with a high grade pre-malignant IPMN.
Deaths among pancreatic cancer in-hospital, and the utilization of palliative care.
Authors: Kasi Anup , Al-Rajabi Raed Moh'd Taiseer , Saeed Anwaar , Sun Weijing , Abbasi Saqib
Published: May 2020

e16803

Background: Pancreatic cancer has a dismal 5 year survival of 5-10%. Deaths commonly occur in-hospital as they present with acute complications. The purpose of this study is characterize this population compared to all pancreatic deaths, identify causes for admission, trends in palliative care utilization and its effect on costs and patient stay. Methods: From the years of 2002 to 2014, admissions for patients with a diagnosis of pancreatic cancer were identified using the National Inpatient Sample. Annual trends in death were compared to overalls deaths using SEER data. Trends in hospital length of stay (LOS) and total charges (TC) were assessed, as well as utilization of palliative care. The effect of palliative care utilization on hospital LOS and TC were also identified. Results: 97,389 (weighted) patient deaths occurred from 2002 to 2014, with 7,634 in 2002, compared to 7,200 in 2014. Compared to total overall deaths of 38,026 and 42,047 respectively. Signifying 25% (2002) to 21% (2014) total patients expiring in an in-patient setting. The most common billed primary diagnosis was sepsis at 15.5%, followed by acute renal failure and fluid disorder (12.5%) and liver failure (5.3%). Overall length of stay trended down from 9.0 days to 7.5 days (p < 0.001). And total charges for admission increased from $36,704 to $88,063 (p < 0.001). Palliative care consults increased from 12% in 2002 to 45% in 2014. In 2014, the TC for deaths among those who received palliative care consults was $52,612 (p < 0.001 when compared to all deaths). LOS among these patients also decreased from 7.5 days to 6.2 days. When looking at patients with sepsis who did not die, a palliative care consult decreased costs from $86,738 to $74,544 (p < 0.001). LOS was not significantly different at 8.8 days compared to 8.5 days (p = 0.15). Conclusions: A quarter of patients with pancreatic cancer die in an in-hospital setting. Palliative involvement decreased health care resource utilization. In reviewing patients who developed sepsis without in-hospital mortality, a palliative care consult decreased total charges of admission.
Studying the interrelation between the HPV infection status and the morphological features of bladder cancer.
Authors: Zykova Tatiana A. , Shevchenko Alexey N. , Khomutenko Irina A. , Filatova Elena V. , Shevyakova Elena A. , Velikorodnaya Lilia A. , Dimitriadi Sergey N , Kit Oleg I.
Published: May 2020

e17003

Background: The etiological role of human papillomavirus (HPV) in the development of squamous cell carcinoma of the cervix and larynx is considered proven. At the same time, there are conflicting data in the literature on the role of HPV in the development of bladder cancer (BC). The aim of the present study was to evaluate the prevalence of HPV infection in patients with BC, identifying the relationship between the status of infection and the morphological characteristics of the tumor. Methods: The study included 46 patients (10 women and 36 men) with morphologically confirmed urothelial cancer. Samples of urine, tumor tissue and a healthy bladder mucosa were examined. HPV DNA was determined by real-time PCR. Results: 28 (60.9%) patients were infected with high-risk HPV, including 6 (60.0%) women and 22 (61.1%) men. In 14 (30.4%) patients, HPV DNA was found in the tissue of the bladder mucosa: in 6 (13.0%) cases it was only in tumor tissue, in 4 (8.7%) only in healthy mucosa, in 4 (8.7%) simultaneously in healthy and tumor tissue. HPV DNA was detected in urine in 22 (47.8%) patients. The simultaneous presence of HPV DNA in the tissue of the bladder mucosa and urine was found in 8 (28.6%) HPV-positive patients. Single HPV infection was found in 20 (71.4%) patients, two types were found in 8 (28.6%). When analyzing type diversity, it was found that HPV16 infected 14 (38.9%) patients; HPV18, 31, 39 and 56 were determined in 4 (11.1%) cases each; 33, 52 and 59 types in 2 (5.6%) cases. Chronic inflammation was noted in 12 (26.1%) patients, 6 (50.0%) of them were HPV-positive. Among HPV-positive patients, invasive cancer was registered in 18 (64.3%), non-invasive cancer in 10 (35.7%) patients. Among HPV-negative patients, these rates were 14 (77.8%) and 4 (22.2%), respectively (p > 0.05). In the group of HPV-positive patients, tumors with a low degree of differentiation were found in 16 (57.1%), moderate in 6 (21.4%), high in 6 (21.4%). Among HPV-negative patients, these indicators were 4 (22.2%), 12 (66.7%) and 2 (11.1%), respectively (p > 0.05). Conclusions: HPV infection was detected in 60.9% of patients, including tumor tissue infection in 21.7% of patients. The most common HPV type was HPV16. There was no statistically significant difference between HPV-positive and negative tumors.
Combined OX40 agonist and PD-1 inhibitor immunotherapy improves the efficacy of vascular targeted photodynamic therapy in a urothelial tumor model.
Authors: Alvim Ricardo , Nogueira Lucas , Georgala Petrina M , Somma Alexander , Nagar Karan , Thomas Jasmine , Ledbai Souhil , Hudges Christopher , Scherz Avigdor Joshua , Zanganeh Saeid M , Kim Kwanghee , Coleman Jonathan
Published: May 2020

e17004

Background: In patients with low-grade, small upper tract urothelial carcinomas (UTUC), as well as those in whom preservation of kidney function is critical, local ablative therapies such as vascular targeted photodynamic (VTP) therapy have emerged as a means of reducing treatment-related morbidity. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. Methods: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. Results: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and metastasis and prolonged survival to a much greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. Conclusions: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.
Effect of neoadjuvant chemotherapy on health-related quality of life in patients with muscle invasive bladder cancer: Results from JCOG0209, a randomized phase III study.
Authors: Nishiyama Naotaka , Kitamura Hiroshi , Hinotsu Shiro , Tsukamoto Taiji , Shibata Taro , Mizusawa Junki , Kobayashi Takashi , Miyake Makito , Kojima Takahiro , Nishiyama Hiroyuki
Published: May 2020

e17006

Background: Although neoadjuvant chemotherapy (NAC) provides survival benefits in muscle-invasive bladder cancer (MIBC), the impact of NAC on health-related quality of life (HRQoL) has not been investigated by a randomized trial. The purpose of this study is to compare HRQoL in patients with MIBC who received NAC followed by radical cystectomy (RC) or RC alone based on patient-reported outcome data. Methods: Patients were randomized to receive 2 cycles of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) followed by RC or RC alone. HRQoL was measured using the Functional Assessment of Cancer Therapy – Bladder (FACT-BL, version 4) questionnaire before the protocol treatments, after NAC, after RC, and one year after registration. Results: A total of 99 patients were analyzed. No statistically significant differences in postoperative HRQoL were found between the arms. In the NAC arm, the scores after NAC were significantly lower than the baseline scores in physical well-being, functional well-being, FACT-General total, weight loss, diarrhea, appetite, body appearance, embarrassment by ostomy appliance, and total FACT-BL. However, there was no difference in scores for these domains, except for embarrassment by ostomy appliance, between the two arms after RC and one year after registration. Conclusions: Although HRQoL declined during NAC, no negative effect of NAC on HRQoL was apparent after RC. These data support the view that NAC can be considered as a standard of care for patients with MIBC regarding HRQoL. Clinical trial information: C000000093.
Pembrolizumab and concurrent radiation is an effective regimen for muscle invasive bladder cancer.
Authors: Gupta Niraj K. , Reichard Chad A. , Large Michael , Leagre Christopher A. , Ney Kenneth , Liebross Robert H. , Ramsey John , Dugan Thomas , Tumati Vasu , Yadav Rina , Heckman Patrick , Tutterrow Rachelle , Schmidt Kristen
Published: May 2020

e17020

Background: Neo-adjuvant chemotherapy with Gemcitabine and Cisplatin followed by radical cystectomy is the standard of care in muscle invasive bladder ca. Some patients, usually older patients or those with poor PS with bladder ca are either cisplatin in-eligble or medically unfit for radical cystectomy. We share our experience using a combination of Pembrozulimab and concurrent radiation in cisplatin in-eligible patients with muscle invasive bladder cancer. Methods: Patients with muscle invasive bladder ca underwent TURBT followed by treatment with Pembrolizumab 200 mg IV every three weeks for 4 cycles concurrent with radiation treatments. Radiation treatments were started 1 week after starting pembrolizumab. A total of 64-65 Gy was given to the bladder and pelvis. All patients underwent a cystoscopy to assess local response and imaging studies to rule out distant metastases. Results: Between June 2018 and October 2019, 9 patients with locally advanced, cT2-cT4 urothelial ca were treated. Male to female ratio 7 to 2. Median age was 76 years, range was 71-90. Reasons were not using cisplatin were, renal-insufficiency, 7 pts. and pt refusal in 2 pts. ECOG PS was 1 in 6 patients and 2 in 3 pts. All patients finished radiation treatments. All but one patient finished 4 cycles of pembrolizumab. One patient declined the last dose. Grade-3/4 I/O inhibitor AEs were seen in 2 patients, One had pneumonitis and other had elevation of LFTs. None of the patients was found to have distant mets on the scans done after 4 cycles of Pembrolizumab. A complete response, by cystoscopy (histology/cytology) was seen in 7/9 (77%) of the patients. The other 2 pts. with PR declined cystectomy and have continued on immunotherapy without any evidence of progression. Conclusions: A combination of Pembrolizumab concurrent with radiation treatments is an effective option and can be safely administered in cT2-T4 bladder cancer. It is an attractive option for cis-ineligible patients. The feasibility and efficacy of this combination needs to be further explored in larger studies
Heterogeneity of PD-L1 expression between primary and metastatic bladder cancer tumors and therapeutic implications between the immune cell score and combined positivity score.
Authors: Schulz Gerald Bastian , Todorova Rumyana , Rodler Severin , Grimm Tobias , Staehler Michael D. , Mayr Doris , Stief Christian G. , Casuscelli Jozefina
Published: May 2020

e17041

Background: Heterogeneity of PD-L1 expression between primary and metastatic tumors has been reported for different cancer entities. In metastatic bladder cancer (BC), this might have an impact on therapeutic algorithms. For cisplatin-ineligible patients, first-line immune-checkpoint inhibitor therapy is recommended based on the PD-L1 expression assay employed, namely immune cell (IC) or combined positive score (CPS). Here, we compared the CPS and IC scores in bladder tumors (BT) and matched metastatic lymph nodes (LN). Methods: From our institutional database we identified patients with urothelial BC and lymphatic spread on pathologic examination of radical cystectomy specimens. Both CPS and IC were assessed by PD-L1 immunohistochemistry in the BT and matched LN metastases. Positive scores were in accordance to the respective cut-offs (CPS ≥10 and IC ≥2). Key clinicopathological parameters were correlated with CPS and IC scores. Differences between the two scores and between primary BT and LN metastasis were compared. CPS and IC scores both between and within the bladder tumour and LN metastasis were tested for correlation. Finally, the prognostic impact of the CPS and IC score was assessed. Pearson’s chi-squared test, Wilcoxon-test and Log-rank test were employed. Results: We included 108 patients (73.1% males, 26.9% females) with LN-positive urothelial BC. There was no correlation between age, gender, T-stage, number of positive lymph nodes and either CPS or IC scores. CPS was significantly more often positive in BT specimens (43.5%, n = 47/108) compared to LN samples (35.6%, n = 37/104) (p = 0.004). IC score was also significantly more often positive in BT specimens (28.7%, n = 31/108) compared to LN samples (21.2%, n = 22/104) (p = 0.013). There are significantly more CPS positive vs. IC positive cases when assessing PD-L1 expression in BT (p < 0.001). CPS and IC score positively correlated within both BT (r = 0.682, p < 0.001) and LN (r = 0.648, p < 0.001). CPS (r = 0.778, p < 0.001) and IC (r = 0.692, p < 0.001) positively correlated between the bladder tumour and LN. PD-L1 expression had no impact on oncological prognosis. Conclusions: PD-L1 expression measured by CPS correlates with IC scores in BC. There are, however, significant and clinically relevant differences between the BT and LN as well as between the two assays. Besides the implication for checkpoint-inhibitor therapy, PD-L1 expression does not seems to be prognostic in BC.
Patterns and predictors of referral among patients with muscle-invasive bladder cancer: A real-world study.
Authors: Clement Jessica Mary , Lu Zengqi , Pan Qi , Swede Helen , Mehta Rajni , Wang Xiaoyan
Published: May 2020

e17051

Background: The multidisciplinary treatment of muscle-invasive bladder cancer (MIBC) has demonstrated considerable challenges in widespread clinical adoption. Despite guidelines recommending multidisciplinary, utilization of neoadjuvant chemotherapy for bladder cancer treatment remains low in the real-world settings. This study aims to examine the real-world referral patterns from urology to medical oncology and/or radiation oncology and the factors that associated with the referral following a diagnosis of MIBC. Methods: Following approval of involved IRBs, investigators followed a common protocol under the auspices of the Rapid Case Ascertainment at the Yale Cancer Center and performed manual chart review of MIBC patients diagnosed in the state of Connecticut from 2004 – 2015 and treated at investigator-affiliated hospitals. Information on medical history, radical or partial cystectomy, chemotherapy, radiation therapy, initial treating physician, and referrals to additional providers were recorded. This data set was linked to the Surveillance, Epidemiology, and End Results (SEER) database for demographic information. Logistic regression analysis adjusted with demographics (i.e. gender, race) and medical histories (i.e. prior cancers) was conducted to identify factors associated with referral. Results: Of the 665 patients whose initial treating physician was urologist, only 291 (43.8%) were referred to a medical oncologist and/or a radiation oncologist. Independent factors associated with lack of referral included: older age (OR = 0.994 for every incremental year, P-value: 0.0055), and greater Charlson comorbidity score (OR = 1.064. P-value: 0.015). Patients with kidney diseases and diabetes were less likely to be referred. Conclusions: Lack of referral to medical oncology and/or radiation oncology is a critical barrier to the use of optimal multidisciplinary therapy. Referral decision made by urologists is impacted by a patient’s age and overall health condition. [Table: see text]
Association of lymph node count and survival after primary retroperitoneal lymph node dissection (RPLND) for testicular nonseminomatous germ cell tumor (NSGCT).
Authors: Patel Hiren V. , Srivastava Arnav , Kim Sinae , Singer Eric A. , Kim Isaac Yi , Jang Thomas L
Published: May 2020

e17052

Background: RPLND for clinical stage (CS) I & IIA/B NSGCT has both staging and therapeutic implications. Single center studies have reported on the impact of lymph node count on outcome after 1° RPLND for men with NSGCT. However, this has yet to be corroborated in a nationally representative dataset. Methods: Using the National Cancer Database, patients who received a 1° RPLND from 2004-2014 for CS I & IIA/B NSGCT were identified. The analytic cohort was stratified according to LN count (≤20, 21-40, and > 40 LNs). Sociodemographic characteristics were compared among groups. The Kaplan-Meier method was calculated and pairwise comparisons performed. Based on sensitivity analyses to determine LN cutoff that impacts survival, subsequent analysis compared patients with ≤20 and > 20 LNs resected. Multivariate analysis using stepwise regression was used to determine factors associated with receipt of an RPLND with > 20 LNs resected. Results: Of 1,376 men who received 1° RPLND for Stage I or IIA/B NSGCT, 35.6%, 27.4%, and 14% had ≤20, 21-40, and > 40 LNs resected, respectively. LN count was associated with overall survival (OS), with 95%, 97%, and 98% 8-year OS for men with LN count ≤20, 21-40, and > 40 LNs, respectively. OS in men with ≤20 vs 21-40 (p = 0.018) and > 40 LNs (p = 0.042) resected differed significantly. However, no significant difference was observed when 21-40 vs > 40 LNs were resected (p = 0.677). Therefore, subsequent analysis compared those who had ≤20 and > 20 LN resected, and OS between these two groups differed significantly (Figure). Multivariate analysis demonstrated that patients with private insurance, surgery having been performed at an academic center or in the Northeast, and those with pT2 disease were more likely to have > 20 LNs resected at the time of RPLND. Conclusions: Lymph node count after 1° RPLND for NSGCT is significantly associated with overall survival, with more favorable survival seen in those who receive an RPLND with > 20 LNs resected when compared to ≤20 LNs.
Standard-dose salvage chemotherapy in patients with refractory metastatic germ-cell tumors (mGCT) progressing after high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplant (PBSCT).
Authors: Agrawal Vaibhav , Althouse Sandra K. , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: May 2020

e17061

Background: About 40% of patients with relapsed GCT will progress after HDCT and PBSCT and are generally incurable with further standard dose chemotherapy. We previously evaluated standard dose cisplatin combination chemotherapy in 15 patients following progression from HDCT and observed only a single brief PR ( JCO 18(6), 1181-1186.). We report results of non-platinum standard-dose chemotherapy regimens in refractory mGCT. Methods: Pts with mGCT who progressed after HDCT+PBSCT at Indiana University from 2004-2019 were evaluated. Kaplan-Meier methods and log-rank tests were used to analyze PFS and OS for the regimen directly following HDCT. Results: 78 pts with refractory mGCT were reviewed. 64 pts. (82%) received paclitaxel+gemcitabine (TG), 10 pts. (13%) received daily oral etoposide (E), and 4 pts. (5%) received oxaliplatin-based (O) regimens (oxaliplatin+gemcitabine or oxaliplatin+bevacizumab). Median age was 29 (range, 16-57). Primary site was testis in 62, retroperitoneum in 6, mediastinum in 9. Metastatic sites included retroperitoneal LNs (62), pulmonary (58), liver (23), bone (6), and brain (21). IGCCCG risk was good in 16, intermediate in 5, and poor in 57. HDCT was utilized as 2nd line setting in 72 pts, and ≥3rd line in 6 pts. Median time from HDCT to progression was 4 months (upper limit 16.6 months). PS and OS data is shown in the table, with superior outcomes in TG compared to O and E (p < 0.001). Maintenance oral etoposide after HDCT was administered in 44% (n = 28) of all patients who later progressed and received TG. Among 12 patients (19%) with 12-month PFS on TG, the median overall PFS was 18.3 months with 2 patients alive at the time of last follow-up. The primary site was testis in 11 patients, 67% (n = 8) were platinum refractory, and 83% (n = 10) were IGCCCG poor risk. 10 patients achieved a PR to TG, and two patients achieved CR. Conclusions: Salvage standard-dose chemotherapy with paclitaxel+gemcitabine after progression on HDCT is superior to oral etoposide or oxaliplatin-based regimens and should be the preferred regimen in patients with refractory mGCT. [Table: see text]
Baseline and early change of neutrophil to lymphocyte ratio (bNLR and ΔNLR) as prognostic factors in metastatic renal cell carcinoma (mRCC) treated with Nivolumab: Final results of the Meet-URO 15 (I-BIO-REC) study.
Authors: Rebuzzi Sara Elena , Buti Sebastiano , Maruzzo Marco , De Giorgi Ugo , Sbrana Andrea , Zucali Paolo Andrea , Fantinel Emanuela , Procopio Giuseppe , Merler Sara , Fratino Lucia , Baldessari Cinzia , Ricotta Riccardo , Massari Francesco , Banna Giuseppe Luigi , Soraru' Mariella , Santoni Matteo , Cortellini Alessio , Bersanelli Melissa , Signori Alessio , Fornarini Giuseppe
Published: May 2020

e17081

Background: Biomarkers to select mRCC patients most likely to benefit to immunotherapy are needed. The retrospective multicentre Meet-URO-15 study evaluated the prognostic role of peripheral blood cells in mRCC patients treated with Nivolumab. Methods: Complete blood count was assessed at the first four cycles of Nivolumab. The primary endpoint was median overall survival (mOS) according to bNLR. NLR was defined as neutrophil / lymphocyte (cutoff = 3) and ΔNLR the difference between NLR at 2nd cycle and bNLR (median as cutoff = 1.1). Results: From October 2015 to October 2019, 470 patients started Nivolumab as 2nd (67%), 3rd (22%) and > 3rd (11%) line. Median age was 66 years, 71% were male and 83% had clear cell histology. Baseline IMDC group was favorable in 25%, intermediate in 63% and poor in 12%. Lymph-nodes, visceral and bone metastases were present in 54%, 91% and 36%. mOS and progression-free survival (PFS) were 34.8 and 7.5 months. Overall response rate (ORR) and disease control rate (DCR) were 30% and 61%. bNLR was available in 404 patients: bNLR < 3 (54%) correlated with statistically significant longer PFS [11.4 vs 5.4 months; HR 1.69 (1.33-2.15)] and OS [46.2 vs 17.2 months; HR 2.37 (1.72-3.26)] (both p< 0.001), with similar ORR (35% vs 30%, p= 0.28) but higher DCR (71% vs 52%, p< 0.001). ΔNLR was available in 360 patients: ΔNLR < 1.1 (73%) correlated with a statistically significant improvement of PFS [11.2 vs 4.9 months; HR 1.53 (1.16-2.03), p= 0.03], OS [Not Reached vs 19.7 months; HR 1.83 (1.28-2.61), p= 0.001], ORR (37% vs 23%, p= 0.011) and DCR (68% vs 53%, p= 0.008). Multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation of bNLR and ΔNLR with OS, PFS and DCR. Conclusions: Our study showed the statistically significant correlation of lower bNLR and early ΔNLR with longer OS, PFS and higher DCR in mRCC patients treated with Nivolumab.
Real-world safety and efficacy data of patients with synchronous metastatic renal cell carcinoma (mRCC) treated with nivolumab and ipilimumab (N+I) and the primary tumour (PT) in place.
Authors: Meerveld-Eggink Aafke , Graafland Niels , Wilgenhof Sofie , Van Thienen Johannes V. , Grant Michael , Szabados Bernadett , Abu-Ghanem Yasmin , Boleti Ekaterini , Blank Christian U. , Haanen John B. A. G. , Powles Thomas , Bex Axel
Published: May 2020

e17083

Background: Following CARMENA and SURTIME, upfront cytoreductive nephrectomy (CN) is no longer standard of care. Intermediate and poor risk patients (pts) receive systemic therapy with the PT in place with the option to perform deferred CN in responding pts. This practice has been adopted after the recent shift to immune checkpoint inhibitor combination in frontline for mRCC. We assessed the safety and efficacy of this approach in a real-world population. Methods: A retrospective analysis of a clinical audit from 3 institutional datasets of pts treated with first-line N+I and the PT in place. Pts and tumour characteristics, International Metastatic RCC Database Consortium (IMDC) risk, overall response rate (ORR) in the PT and metastatic sites, time to response (TTR) of the PT, PT- and immune related- (ir) adverse events (AE), deferred CN rate, progression free- (PFS) and overall survival (OS) were assessed. Results: Of 41 pts treated with N+I and the PT in place, 46.3% were IMDC poor risk and 51.2% had > 3 metastatic sites. After a median follow-up of 5.9 (2-10.3) months, 29 had at least 1 CT scan from baseline. Of those, 7 (24.3% [95% confidence interval [CI] 0.10-0.43]) had a partial response (PR) of the PT with a median TTR of 5.3 (2.5-8.6) months. Mean and median PT reduction were 16.9% (+7.6 to -70.3%) and 10% from a baseline mean tumour size of 9.5 (3.8-16.1) cm. Pts with a PT reduction > median (n = 14) had a PR at metastatic sites in 86% (CI 0.57-0.98) and no progressive disease (PD). Pts with PT reduction < median (n = 14) had PR in only 21% and PD at metastatic sites in 57% (CI 0.28-0.82). None of the PT progressed. There was no complete response (CR) at metastatic sites . No CN was performed; 5 pts (12%) developed hematuria grade 1-3, requiring embolisation in 2 (4.9%). Grade 3-4 irAE were observed in 22% of pts. Median PFS and OS are 8.6 months and not reached. Conclusions: N+I with the PT in place is safe and PT reduction is associated with response at metastatic sites. Most PT responded by 6 months. No CR at metastatic sites were observed (compared to a 9% CR rate in the pivotal trial) in this real-world population with a relatively high percentage of poor-risk pts. Furthermore, no deferred CN has been performed, neither for near-CR at metastatic sites nor for PT symptoms.
Exploration of Chinese early-onset renal cancer predisposed genetic features.
Authors: Gong Yu , Zhou Yifan , Zhang Bei , Bai Yuezong , Guo Jianming
Published: May 2020

e17087

Background: The population of early-onset renal cancer patients is increasing in China and they need early genetic screening test to give risks management. In order to avoid the bias of focusing on the patients younger than 45 years old without comparing the genetic features of the patients over 45y and to find more biomarkers, we explored both germline and somatic variations of patients without age limitation. Methods: Ages at confirmed diagnoses and renal tissue samples were collected from 701 patients. The next generation sequencing (NGS) was performed using validated commercial panels containing over 300 genes or WES. Variations were classified into four groups: germline-MUT/ VLM (pathogenic or very like pathogenic mutations), germline-VOUS (variations of unknown significance), somatic-MUT/ VLM and somatic-VOUS. Statistical analysis was performed by t-test (single tail), and p≤ 0.05 was considered statistically significant. Results: In 701 renal cancer patients, with the median age of 55 (12, 86) years old, 114 (16.26%) patients confirmed diagnoses under 45y. The germline MUT/ VLM of 21 genes (FH, VHL, CHEK2, BRCA2, FLCN, ATM, TSC2, SDHB, MUTYH, SDHA, FANCA, RAD50, APC, BARD1, JAK2, LRP1B, TP53, FANCD2, PALB2, MSH6 and CDH1) were observed, more than previous studies. As two aggressive potential predisposed genes in early-onset renal cancer, VHL and FH were studied comprehensively. There were 29 (4.14%) and 369 (52.6%) patients carried FH variations and VHL variations (either germline or somatic), respectively. The median age of patients harbored VHL germline MUT/ VLM was 33.5 (23, 52), significantly lower than other groups (Table). Interestingly, in 6 patients harboring VHL germline MUT/ VLM, 3 of them carried large region deletion. The median age of FH germline-MUT/ VLM group was 33 (21, 59), significantly lower than patients carried germline VOUS (Table). In addition, germline variations or copy number variations of SDHB gene or germline variations of FLCN gene might be associated with early onset. However, the patients No. was small to give conclusion. Conclusions: Genetic test of FH and VHL genes might be necessary in early screening of renal cancer in China. The role of variations of SDHB and FLCN genes and large region deletion needs more explorations. [Table: see text]
Impact of treatment line on outcomes with salvage ipilimumab + nivolumab in metastatic renal cell carcinoma (mRCC).
Authors: Kotecha Ritesh , Lee Chung-Han , Knezevic Andrea , Shah Neil J. , Carlo Maria Isabel , Feldman Darren R. , Patil Sujata , Motzer Robert J. , Voss Martin H
Published: May 2020

e17092

Background: With the approval of ipilimumab plus nivolumab (I+N) and other immune checkpoint blockade (ICB) based combinations in the first-line setting, the role of I+N for salvage is of high interest for treatment sequencing, yet data is limited. Methods: We conducted a retrospective review of mRCC patients (pts) treated with I+N in the second-line (2L) and beyond settings at MSKCC between 2013-2019. Pt demographics, treatment history and toxicity were compiled. IMDC-risk status was calculated at I+N therapy start. Time to treatment failure (TTF) was defined as earliest date of clinical progression, therapy change or death, and overall survival (OS) was estimated by Kaplan-Meier method. Results: 36 pts received I+N in the 2+L setting, including 31/36 with clear-cell histology. Evaluable IMDC-risk at I+N start was favorable in 1/35 and intermediate-poor in 34/35 pts. The most common 1L therapies were anti-VEGF (22/36) and VEGF + ICB (6/36). 11/36 pts had ICB treatment exposure prior to I+N therapy. I+N therapy in the 2L, 3L and 4L was in 21/36, 8/36 and 7/36 pts, respectively, and 7/36 pts continue I+N at data cut-off. 8/36 pts discontinued I+N due to toxicity, 20/36 pts discontinued therapy due to disease progression, and 1 pt discontinued per pt preference. Cohort median OS was 14.8 months (95%CI: 4.2-44). Overall median TTF was 5.0 months (95%CI: 2.9-14.4), and TTF per 2L, 3L and 4+L was 8.3, 8.9 and 2.5 months, respectively. The number of patients who completed all 4 I+N induction cycles in the 2L, 3L, and 4+L was 11/21 (52%), 5/8 (63%), and 1/7 (14%). The number of patients who subsequently received nivolumab maintenance therapy after induction was 16/21 (76%) in the 2L, 1/8 (13%) in the 3L, and 0/7 (0%) in 4+L. Conclusions: With emerging treatment options for mRCC, this study reveals activity and safety for I+N in 2+L settings. In this limited cohort, completion of induction ipilimumab and use of maintenance nivolumab decline in later-line settings, suggesting limitations as salvage therapy. [Table: see text]
Predictors of successful randomized phase III studies in the treatment metastatic renal cell carcinoma: A meta-analysis.
Authors: Lin Justin , Zhong Xiaobo , Galsky Matt D. , Oh William K. , Tsao Che-Kai
Published: May 2020

e17105

Background: The success of randomized phase III therapeutic trials (RP3TT) to reach their primary endpoint is critical given the enormous resources required to conduct such studies. In an era of accelerated therapeutic development in advanced kidney cancer, we aim to identify factors in such studies associated with a positive endpoint (PE) to better understand how to optimize trial design. Methods: Using PubMed and ClinicalTrials.gov, we identified all published RP3TT in patients with metastatic renal cell carcinoma between 1/2007-9/2019. Studies were considered PE if the primary endpoint was reached, and negative endpoint (NE) if otherwise. Studies were categorized as either first line only (FLO) or second line and beyond (SLB), with adjuvant and consolidation therapy studies excluded. We collected components of study design and baseline patient characteristics and analyzed with multivariate logistic regression to evaluate the associations between each factor and PE RP3TT. Results: Of the 65 studies evaluated, only 22 RP3TT (14 FLO, 8 SLB) were found to have published data and were included, with 14 PE and 8 NE. For all studies, those with larger enrollment size (OR = 1.008, 95% CI [1.001-1.015], p = 0.021) and clear cell requirements (OR = 0.077, 95% CI [0.007-0.901], p = 0.041) were associated with PE. After adjusting for sample size, only larger enrollment size remained significant (OR = 1.007, 95% CI [1.001-1.014], p = 0.032). Other baseline patient demographic and clinical characteristic variables were not associated with PE RP3TT. Subgroup analysis of only FLO or SLB studies also did not yield any significant associations with PE RP3TT. Conclusions: Higher enrollment size was identified as factor associated with PE in RP3TT. Incomplete trial data reporting was evident, particularly in earlier studies. Further efforts are needed to better characterize factors in order to optimize clinical trial design in this disease. [Table: see text]
Dynamic changes in full blood count (FBC) occurring in patients treated with immune checkpoint inhibitors (ICIs) to predict responses in patients with metastatic renal cell carcinoma (mRCC).
Authors: Abu Ghanem Yasmin , Choy Julia , Jackson-Spence Francesca , Jovaisaite Agne , Grant Michael , Bex Axel , Powles Thomas , Szabados Bernadett
Published: May 2020

e17110

Background: ICI transformed the treatment of 1L mRCC, yet early clinical predictors of response are still unknown. Methods: Retrospective database analysis from Barts Cancer Institute, London was carried out. Patients with treatment naïve mRCC were identified and grouped according to their 1L treatment: 1: VEGF inhibitor 2: IO/IO 3: IO/VEGF Data on hemoglobin, neutrophil-to-lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR) at baseline, 6weeks and 12weeks after treatment initiation was correlated with outcome. Results: Between Jan 2014 - Dec 2019; 28, 29 and 21 patients received 1L VEGF, IO/IO or IO/VEGF respectively. Patient receiving 1L VEGF inhibitors showed a decrease in Hb levels both in responding and non-responding groups (significant group effect: F(1,6) = 6.6, p = 0.04); significant time effect:F(2,12) = 12.4, p = 0.001). Group x time interaction was not significant. NLR levels decreased both in responding and non-responding groups over time (significant time effect: F(2,12) = 16.7, p = 0.001. PLR levels in non-responders increased over time, whereas in responding group, PLR levels steadily decreased over 6 and 12 weeks (significant time effect: F(2,12) = 0.3, 0.044). Patients receiving IO/IO combination therapy; within the non-responder group, Hb levels didn’t change significantly whereas in the responding group Hb levels increased significantly and overtook Hb levels of non-responding group (P = 0.001). NLR levels significantly decreased in the responding group (0.041) and a similar trend was observed at 12 weeks with a decrease in PLR among non-responders, with a significant group affect (F(1,5) = 0.18, 0.035). In patient treated with 1L IO/VEGF, among non-responders Hb levels increased slightly, only to return to baseline levels again at 12 weeks after treatment initiation. Whereas, Hb levels in the responding group increased significantly in both 6weeks and 12weeks after starting therapy. Significant time effect:F(2,20) = 3.65, p = 0.044. NLR levels in the responding group presented a steady decrease over time with a significant group and time effect. Both responders and non-responders experienced an increase in PLR over time. However, while PLR decreased at 12 weeks among responders, it continued to increase among non responders (significant time effect: F(2,20) = 0.3, 0.03), (significant group effect: F(1,10) = 0.05, 0.005) and significant interaction: F(2,20) = 0.1, 0.01) Conclusions: Close monitoring of FBC changes may predict response to ICI.
The effect of antibiotic use on immune-checkpoint inhibitor efficacy in patients with advanced urothelial carcinoma.
Authors: Khan Mohammad , Radakovich Nathan , Rini Brian I. , Mian Omar Y. , Ornstein Moshe Chaim , Gupta Shilpa
Published: May 2020

e17116

Background: There is emerging evidence that antibiotic (Abx) use may be associated with poor response to immune-checkpoint inhibitors (ICIs) in patients (pts) with some solid tumors. However, this has not been studied in metastatic urothelial carcinoma (mUC). We examined the effect of Abx use on outcomes in pts receiving ICIs for mUC. Methods: We retrospectively reviewed adult pts receiving ICIs for mUC treated at Cleveland Clinic between 2015 and 2020. Pts included in the study received > / = 3 cycles of ICI therapy with either azetolizumab or pembrolizumab. Abx use was defined as at least 3 days of Abx in the 60 days preceding or following ICI initiation. PFS and OS were estimated using the Kaplan-Meier method and a Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CI). Results: A total of 69 pts with mUC receiving ICI therapy were included. The Abx-treated group consisted of 22 pts (32%) and the Abx-untreated group was 47 pts (68 %). 30 pts had Abx 60 days prior to ICI initiation and 20 patients had Abx within 60 days of ICI initiation. Abx use 60 days prior to ICI was not associated with PFS (HR = 0.91, 95% CI = 0.42-1.95) or OS (HR = 0.52, 95% CI = 0.33-1.68). Abx use during the first 60 days of ICI use was associated with decreased PFS (HR = 2.23, 95% CI = 1.03-4.86) but not OS (HR = 2.01, 95% CI = 0.89-4.53). Notably, there was no effect on response rates. The most commonly used Abx prior to treatment were: fluoroquinolones (30%); cephalosporins (26%); non-cephalosporin beta lactams (17%); and trimethoprim-sulfamethoxasole (13%). The most commonly used Abx after treatment initiation were: fluoroquinolones (17% of patients); cephalosporins (13%); non-cephalosporin beta lactams (12%); and trimethoprim-sulfamethoxasole (9%). Our study was insufficiently powered to address the effect of different antibiotic classes on outcomes. Conclusions: In our study, Abx use within first 60 days of treatment with ICIs was associated with decreased PFS and a trend toward decreased OS in pts with mUC but not in pts receiving Abx 60 days prior to ICI therapy. While the numbers are small, this is the first report exploring the effect of Abx on ICI response in mUC and further studies in larger databases are warranted.