bluuebunny/crossref_metadata_2025 huggingface dataset:
Urine exosome gene expression assay net benefit analysis in a large pooled cohort.
Authors: McKiernan James M. , Tutrone Ronald F. , Donovan Michael Joseph , Torkler Phillipp , Noerholm Mikkel , Alter Jason , Skog Johan
Published: February 2020

287

Background: Over-diagnosis of indolent prostate cancer (PCa), supports the need for non-invasive tools that can differentiate low-grade (≤ Gleason score 6, GS 6) from high-grade (≥ GS 7). We examined the clinical benefit of ExoDx™ Prostate (IntelliScore) (EPI) results in a pooled cohort over a range of probabilities using net benefit analysis. Methods: A pooled dataset of two prior validation cohorts and additional cases from a large group practice provided a large data set (N=1,212) for net benefit analysis. The pooled population consisted of men > 50 years, scheduled for initial biopsy and with a PSA measurement. Urine specimens were collected at enrollment using a provided urine collection device and the EPI tests were run at a CLIA-certified central laboratory at Exosome Diagnostics, Waltham, MA. The clinical decision value of the urine exosome gene expression assay (EPI) was assessed using net benefit analysis and compared EPI results with standard of care information across a range of probabilities for which a patient might decide on a prostate biopsy. The net benefit is determined by adding the true positive results and subtracting the false negatives across different biopsy probability thresholds. Results: The ExoDx IntelliScore or EPI assay (green) demonstrated superior clinical benefit when compared to the Prostate Cancer Prevention Trial (PCPT) prostate cancer risk calculator or PSA. Conclusions: In this new analysis of a large pooled cohort, the EPI exosome gene expression assay had the highest clinical net benefit across the 10% - 50% decision threshold compared to decision support methods currently used in the clinic.
Clinical utility of biomarkers 4K score, SelectMDx and ExoDx with MRI for the detection of high-grade prostate cancer.
Authors: Fasulo Vittorio , de la Calle Claire Marie , Cowan Janet E. , Herlemann Annika , Chu Carissa , Gadzinski Adam John , Au Yeung Reuben , Saita Alberto , Cooperberg Matthew R. , Shinohara Katsuto , Carroll Peter , Nguyen Hao Gia
Published: February 2020

307

Background: Although adoption of new biomarkers and MRI has become widespread, their utility when deciding to biopsy is unclear. We aim to evaluate and compare 4K, SelectMDx, ExoDx and their added value when combined with prostate MRI in the detection of high-grade prostate cancer (HG PC) and avoidance of unnecessary biopsies. Methods: Patients referred for consideration of prostate biopsy at UCSF between 2016-2019 were enrolled and had either 4K, SelectMDx or ExoDx testing with/without MRI. Logistic regression and AUC were used to determine the performance of each biomarker in detecting HG PC (≥Gleason grade (GG) 3+4). In the subgroup of patients that underwent biopsy, with PSA 2.5-10 and negative DRE, we determined the number of avoided unnecessary biopsies (with GG 3+3 cancer or no cancer) and missed HG PC for each biomarker with/without MRI. Results: A total of 896 patients were enrolled, 457 were biopsied. Mean age was 65.5 years, median PSA was 6.32. Logistic regression showed that having an abnormal biomarker score or PI-RADS 4/5 on MRI (P4/5) was strongly associated with finding HG PC: 4K OR 12.9 (CI 4.58-36.1), ExoDx OR 14.7 (CI 3.31-65.3), SelectMDx OR 3.62 (CI 1.44-9.11), P4/5 OR 6.20 (CI 3.93-9.79), TRUS ≥T2a OR 4.33 (CI 2.78-6.75), PSAD >0.15 OR 4.01 (CI 2.59-6.20), p<0.01). Combining biomarker and P4/5 lesion on MRI increased AUC for detecting HG PC. In the biopsy subgroup, a normal 4K or ExoDx test missed only 4-5% HG PC, while an abnormal test resulted in avoiding 14-20% unnecessary biopsies. Combining MRI with ExoDx or 4K missed 0-1.43% HG PC but avoided only 7-9% unnecessary biopsies (Table). Conclusions: 4K and ExoDx outperformed MRI and SelectMDx but combining the biomarkers with MRI resulted in the best predictive ability for detecting HG PC. Negative MRI avoided more biopsies than a normal 4K or ExoDxbut missed more aggressive cancers. Our data suggest that MRI alone is not sensitive enough to detect all HG PC and that 4K or ExoDx testing alone could be sufficient when deciding to proceed with biopsy.[Table: see text]
Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy.
Authors: Gupta Shilpa , Sonpavde Guru , Weight Christopher J. , McGregor Bradley Alexander , Gupta Sumati , Maughan Benjamin Louis , Wei Xiao X. , Gibb Ewan , Thyagarajan Bharat , Einstein David Johnson , Dechet Christopher B. , Lowrance William Thomas , Murugan Paari J , Kilbridge Kerry L. , Agarwal Neeraj , Davicioni Elai , Eckstein Markus , Mossanen Matthew , Preston Mark A. , Konety Badrinath R.
Published: February 2020

439

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) in MIBC improves survival which correlates with pathologic response (PaR) at radical cystectomy (RC). The combination of immunotherapy and NAC may improve PaR and outcomes in MIBC. We tested the efficacy and safety of nivolumab (N) with gemcitabine-cisplatin (GC) as neoadjuvant therapy for MIBC in our phase II trial (NCT03294304). Methods: Eligible pts with MIBC (cT2-T4a, N≤1, M0) who were candidates for RC were enrolled. Pts received C (70mg/m2) IV on D1, G (1000mg/m2) on D1,D8 and N (360 mg) IV on D8 every 21 days for 4 cycles followed by RC within 8 weeks. The primary endpoint was PaR (≤pT1,N0). Secondary objectives were safety of GC+N and PFS at 2 years. The correlative objectives based on pre-treatment biopsies were correlation of PaR with 1) WGS 2) molecular subtypes of BC; 3) PD-L1 expression; 4) baseline TILs, CD3, CD8 and CD56.. Evaluable pts. should have received at least 1 dose of N. PaR will be summarized by the PaR rate as estimated by the sample proportion with exact 95% confidence intervals. We specified a null PaR of 0.35 and an alternative hypothesis of 0.55; we will reject the null hypothesis if at least 20 of 41 pts. have a PaR. Results: Between Feb 2018 and June 2019, 41 pts. were enrolled (cT2N0 90%, cT3N0 7%, cT4N1 3%); 2 patients refused surgery but were included in ITT population. PaR was observed in 27/41 pts. (65.8%), including pts with N1 disease. The combination was safe with manageable toxicities and no deaths from treatment. Majority of AEs were from GC; the overall rates of grade 3-4 AEs was 20%, majority being neutropenia, thrombocytopenia and renal insufficiency. Immune related AEs were seen in 3 patients, 2 had "adenitis" which wasymptomatic,1 pt developed Guillian Barre Syndrome after surgery, which resolved with IVIG; and none of them required steroids. There was no delay in time to RC and no unexpected surgical complications from treatment. Patients are being followed for progression and survival. Correlative work is ongoing. Conclusions: Neoadjuvant N+GC is safe and effective in MIBC with significant pathologic downstaging rates and no added toxicities or delay to surgery. Clinical trial information: NCT03294304.
Medical oncologists’ first-line treatment preferences in metastatic urothelial carcinoma.
Authors: Apolo Andrea B. , Cambron-Mellott M. Janelle , Beusterien Kathleen , Seal Brian S. , Maculaitis Martine C. , Bernstein Andrew , Epperson Megan , Jeffress Mara Lisa , Doleh Yunes
Published: February 2020

449

Background: Immunotherapy and combination platinum chemotherapy are effective treatment options with different adverse events (AEs) for patients (pts) with metastatic urothelial carcinoma (mUC). This study quantified treatment preferences based on perceived benefit-risk trade-offs associated with first-line (1L) therapy among medical oncologists (MOs). Methods: MOs completed a cross-sectional online survey assessing treatment preferences for 3 pt groups: cisplatin (cis)-eligible (elig) PD-L1 high, cis-ineligible (inelig) PD-L1 high, and cis-inelig PD-L1 low. Three discrete choice experiments (DCEs) showed a series of tasks where MOs chose between 2 alternative treatment profiles varying on 7 attributes identified as important in qualitative research: overall survival (OS), overall response rate (ORR), all grades (G) neuropathy, G3/4 nausea/vomiting, colitis, pneumonitis, and neutropenia. Hierarchical Bayes models were used to estimate preference weights for each attribute. Results: A total of 210 MOs, averaging 16 years in practice (65% community [C], 35% academic [A]), participated. PD-L1 testing was available to most MOs, 87.5% (C) and 74.3% (A). In cis-elig PD-L1 high and cis-inelig -PD-L1 low pts, the order of relative importance was: OS, ORR, G3/4 nausea/vomiting, G3/4 neutropenia, G3/4 pneumonitis, all G neuropathy, and G3/4 colitis. In cis-inelig PD-L1 high pts, improved OS was most important but decreasing G3/4 nausea/vomiting was more important than improving ORR. In cis-elig PD-L1 high, cis-inelig PD-L1 high, and cis-inelig PD-L1 low pts, to accept increases in AEs, MOs require OS increases of 2.0, 3.0, and 2.5 months (G3/4 nausea/vomiting by 21%); 1.6, 1.8, and 2.0 months (G3/4 neutropenia by 23%); 0.9, 0.4, and 1.1 (G3/4 pneumonitis by 3%); and 0.9, 0.6, and 0.7 months (all G neuropathy by 5%), respectively. Conclusions: OS and ORR are key drivers for MOs in the choice of 1L therapy for pts with mUC. MO selection of therapy is governed by platinum eligibility, PD-L1 status, and a desire to limit AEs. Future 1L treatments for mUC pts need to provide a substantial OS benefit in exchange for a higher risk of AEs, especially in cis-inelig PD-L1 low pts, whom are perceived as having poor outcomes.
Real-world outcomes in patients (pts) with metastatic urothelial carcinoma (mUC) who received first- or second-line immunotherapies (IO) in the United States (US).
Authors: Boyd Marley , Annavarapu Srinivas , Doshi Gurjyot K. , Imai Kentaro , Sbar Eric , Godwin James Luke , Li Haojie , Sonpavde Guru
Published: February 2020

457

Background: Benefit of IO (PD1 and PD-L1 inhibitors) for mUC was observed in clinical trials but real-world evidence for benefit and clinical outcomes is limited. Methods: This was a retrospective study of adult pts with mUC who initiated IO regardless of PD-L1 expression in the first- (1L cohort) or second-line (2L cohort) setting between 5/1/2016-1/31/2019 in the US Oncology Network (USON), a network of community oncology practices. Descriptive and Kaplan-Meier analyses to evaluate baseline characteristics, treatment patterns and clinical outcomes were conducted using data from USON’s electronic heath record. Results: Among 393 pts in the 1L cohort, median (range) age at IO initiation was 77 (42, 90+), 74% were male, 69% were White, and 19.1% and 4.1% had ECOG performance status (PS) 2 and 3/4, respectively. Among the 366 pts in the 2L cohort, median (range) age at IO initiation was 70 (29, 90+), 74% were male, 71% were White, and 19.7% and 1.4% had ECOG PS 2 and 3, respectively. Median (range) follow-up durations from IO initiation were 4.2 (0, 34.1; 1L cohort) and 4.1 (0, 31.3; 2L cohort) months (mo), during which time 43.1% (1L cohort) and 44.4% (2L cohort) of pts died. Median overall survival (OS) from IO initiation (95% confidence interval [CI]) was 10.6 (9.7, 13.2) mo for the 1L cohort and 9.4 (7.1, 11.5) mo for the 2L cohort; 1-year survival probabilities (95% CI) were 46.6% (40.1%, 52.8%; 1L cohort) and 43.4% (36.8%, 49.8%; 2L cohort). By the end of the follow-up, 48.1% of 1L pts and 47.8% of 2L pts were alive and did not advance to next line of therapy, and 13.5% of 1L and 13.4% of 2L cohort pts advanced to the next line of therapy. Median (95% CI) treatment durations were 2.6 (2.1, 2.9) and 2.8 (2.2, 3.5) mo for the 1L and 2L cohorts, respectively; 6-mo ongoing treatment probabilities (95% CI) were 26.6% (22.2%, 31.2%; 1L cohort) and 31.4% (26.4%, 36.4%; 2L cohort). Conclusions: OS of pts in the real world receiving 1L and 2L IO appears consistent with clinical trial results, although survival follow-up is limited. A minority of pts received post-IO therapy. Future research should examine influence of pt characteristics and PD-L1 expression on treatment choice and outcomes.
Real-world outcomes in patients with locally advanced or metastatic urothelial carcinoma receiving taxane monotherapy following platinum and anti-PD-1/L1 therapy.
Authors: Hepp Zsolt , Shah Sonali , Tan Katherine , Balakrishna Shreya
Published: February 2020

458

Background: There are currently limited options for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) following progression on platinum chemotherapy and anti-programmed death 1/death-ligand 1 (PD-1/L1) therapy. Further, limited data are available from clinical trials or real-world studies on outcomes in this population. This retrospective analysis investigated clinical outcomes in patients treated with taxane monotherapy, a commonly used and NCCN guideline-recommended option in this setting. Methods: Patients aged ≥18 years with histologically-confirmed diagnosis of la/mUC on or after 2011, ≥2 clinical visits, and sufficient relevant unstructured data were included from the de-identified nationwide Flatiron Health electronic health record-derived database. The study cohort included patients treated with taxane monotherapy (docetaxel, paclitaxel, or nab-paclitaxel) following anti-PD-1/L1 therapy and who have received prior platinum containing chemotherapy. Baseline characteristics, overall survival (OS), real-world progression-free survival (rwPFS) based on clinician documentation of disease status, and real-world response (rwR) based on clinician-confirmed radiologic assessments were reported. Patients were followed until death, data cutoff, or loss to follow up. Results: Among 276 patients treated following anti-PD-1/L1 therapy and who met all of the inclusion/exclusion criteria, 72 were treated with taxanes and also had documented prior platinum chemotherapy. Patients were mostly male (75%) and Caucasian (74%), with a mean age of 73 years. 65% had > 2 sites of metastasis at index (start date of taxane). Post index, median OS = 7.6 months (95% CI 5.2, 14.4) and median rwPFS = 2.9 months (95% CI, 2.4, 4.0). Among the 50 patients with ≥1 rwR assessment, confirmed rwR = 18% (95% CI: 9%, 32%). Conclusions: In the real-world setting, limited responses to taxanes and short duration of PFS and OS were observed in patients with la/mUC previously treated with a platinum and anti-PD-1/L1 therapy. There is a need for more effective therapies to improve clinical outcomes for this patient population.
Practice trends and attitudes of medical oncologists on new therapies in urothelial carcinoma.
Authors: Rosenthal Kristen , Galsky Matt D. , Milowsky Matthew I. , Howson Alexandra , Quill Timothy A. , Obholz Kevin
Published: February 2020

472

Background: Treatment options for patients with metastatic urothelial carcinoma (mUC) have dramatically changed. The goal of this study was to assess the worldwide impact and use of new therapeutic developments in clinical practice. Methods: The study consisted of qualitative telephone interviews (3/25/19-4/5/19) and a quantitative online survey (3/20/19-5/27/19) with questions designed to determine current practice trends and specific challenges faced by clinicians. Participants were recruited via email and answers were compared with those of experts and guideline recommendations. Results: A total of 30 US-based clinicians completed the interviews and 491 participants (US, n = 156; ex-US, n = 335) completed the online survey. Most participants (69%) treated ≤ 10 patients with UC per month. For newly diagnosed mUC, many participants failed to select appropriate first-line therapy based on creatinine clearance (CrCl) and PD-L1 expression (Table). Only 58% of clinicians correctly selected SoC cisplatin-based chemotherapy for eligible patients based on CrCl. For cisplatin-ineligible patients, 60% of clinicians indicated use of an immune checkpoint inhibitor (ICI) despite low PD-L1 expression. Many clinicians were also unfamiliar with novel agents. Only 56% recognized the mechanism of action (MoA) of erdafitinib, an FGFR inhibitor approved during the survey period, and 31% recognized the MoA of enfortumab vedotin, an investigational agent with FDA breakthrough therapy designation. About 40% of US clinicians and < 20% of ex-US clinicians indicated confidence to use these agents in clinical practice if available. Conclusions: This study highlights the need for ongoing education on the optimal use of novel therapeutic strategies to care for patients with mUC. [Table: see text]
Relationship between hyperphosphatemia with infigratinib (BGJ398) and efficacy in FGFR3-altered advanced/metastatic urothelial carcinoma (aUC).
Authors: Lyou Yung , Grivas Petros , Rosenberg Jonathan E. , Hoffman-Censits Jean H. , Quinn David I. , Petrylak Daniel Peter , Galsky Matt D. , Vaishampayan Ulka N. , De Giorgi Ugo , Gupta Sumati , Burris Howard A. , Rearden Jessica , Ye Yining , Wang Hao , Moran Susan , Daneshmand Siamak , Bajorin Dean F. , Pal Sumanta K.
Published: February 2020

576

Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 inhibitor with significant clinical activity in aUC bearing FGFR3 alterations. A common adverse event is hyperphosphatemia, a class effect associated with FGFR1 inhibition. We sought to better understand the relationship between hyperphosphatemia and response to infigratinib in patients with aUC. Methods: Eligible patients had aUC with activating FGFR3 mutations/fusions and had received prior platinum-based chemotherapy, unless contraindicated. Patients received infigratinib 125 mg orally daily (3w on/1w off) until disease progression or unacceptable toxicity. Calcium and phosphate levels within normal limits were required at enrollment. Efficacy was assessed by overall response rate (ORR) and disease control rate (DCR) based on RECIST 1.0 criteria. All patients received prophylaxis with the oral phosphate binder sevelamer. Hyperphosphatemia was defined as serum phosphorous >5.5 mg/dL, consistent with the threshold for action in the protocol. Results: Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on ≥1 post-baseline lab test. Efficacy findings in patients with vs without hyperphosphatemia were: ORR 33.3% (95% CI 20.4–48.4) vs 5.3% (95% CI 0.1–26.0), mPFS 4.9 months (95% CI 3.65–5.98) vs 1.84 months (95% CI 1.28–3.48), and mOS 8.74 months (95% CI 5.72–13.67) vs 7.62 months (95% CI 2.53–15.57). Median treatment length was 4.1 vs 1.4 months and mDOR was 5.0 vs 3.7 months for patients with vs without hyperphosphatemia, respectively. A landmark analysis at the 1-month mark was performed, and hyperphosphatemia (Y/N) was determined based on lab tests within the first month. The differences in efficacy outcomes were still observed. Conclusions: Hyperphosphatemia is a well-described class effect and pharmacodynamic biomarker of FGFR inhibitors, including infigratinib, and is generally reversible/easily managed with diet and phosphate binders. Our data support prior observations with FGFR inhibitors, suggesting that hyperphosphatemia is associated with treatment response and is not negatively associated with treatment length. Clinical trial information: NCT01004224.
Combination of dual immune checkpoint inhibition (ICI) with stereotactic radiation (SBRT) in metastatic renal cell carcinoma (mRCC) (RADVAX RCC).
Authors: Hammers Hans J. , Vonmerveldt Dendra , Ahn Chul , Nadal Rosa Maria , Drake Charles G. , Folkert Michael Ryan , Laine Aaron Michael , Courtney Kevin Dale , Brugarolas James , Song Daniel Y. , Hannan Raquibul , Carducci Michael Anthony
Published: February 2020

614

Background: Dual ICI with nivolumab/ipilimumab (N/I) has become a standard of care (SOC) for patients (pts) with mRCC. Since the failure to respond to ICI may be due to a lack of immune recognition, novel vaccination approaches and stimulation of the innate immune system (e.g. stimulator of interferon genes (STING) agonists) are being pursued in clinical trials. Because preclinical studies using SBRT have demonstrated the a.) release of tumor antigens, b.) STING pathway activation and c.) synergy with ICI, we have conducted a study to explore the safety and efficacy of this approach in mRCC pts. Methods: Pts with clear cell mRCC were screened and enrolled at two sites (UT Southwestern and Johns Hopkins). Prior treatment with tyrosine kinase inhibitors (TKI) and IL2 were allowed. Enrolled pts received standard of care dosing with Nivolumab (3 mg/kg) and Ipilimumab (1mg/kg) IV q3weeks followed by nivolumab monotherapy. SBRT was administered to 1-2 disease sites with a dose of 50 Gy in 5 fractions between the first and the second dose of N/I. The primary goals of this exploratory study were to determine the safety and tolerability as well as the objective response rate (ORR) by RECIST 1.1 of non-irradiated lesions. Results: A total of 29 pts were screened and 25 pts were enrolled. 11 (44%) of pts received at least one prior systemic therapy: 4 (16%) pts received IL2 and 7 (28%) TKI therapy. The cohort was primarily intermediate and poor risk pts (favorable risk n = 2 (8%), intermediate risk n = 20 (80%), poor risk n = 3 (12%)). 10 (40%) pts required immune suppressive therapy with prednisone for classic immune related adverse events as seen with dual ICI. Radiation pneumonitis limited to the radiation field (grade 2) was seen in 2 pts and responded promptly to oral steroids. At the time of analysis, partial responses (PR) were observed in 14/25 patients with an ORR of 56%. Additional analyses including duration of response, progression free survival and overall survival will be presented. Conclusions: Dual ICI with SBRT showed an acceptable safety and encouraging antitumor activity in mRCC warranting further investigations. Clinical trial information: NCT03065179.
Tivozanib as first-line treatment of metastatic renal cell carcinoma: A real-world outcome review in North-West of England, United Kingdom.
Authors: Wong Sam , Prasad Kellati , Waddell Tom , Charnley Natalie , Wong Helen , Law Andrea , Parikh Omi , Pillai Manon , Griffiths Richard , Chow Shien
Published: February 2020

638

Background: Tivozanib is a selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor and has been shown to offer PFS and tolerance advantage compared to sorafenib among patients with mRCC. In this retrospective review, we aim to investigate the real world efficacy and tolerance of tivozanib delivered in four cancer hospital in the Northwest of England. Methods: mRCC patients started tivozanib in first line setting were identified and reviewed. Primary outcomes of interest include overall response rate (ORR), survival (OS, PFS where possible) and treatment tolerance. Results: A total of 113 patients were identified between March 2017 and May 2019. Median follow up was 200 days (15-792). 26% were switched from other prior TKI due to intolerance. 28%, 48% and 24% had Favourable (F), Intermediate (I) and Poor(P) IMDC risk category respectively. ORR was 29% (CR 0%, PR29%, SD38%, PD26%, NE 7%). Median PFS (after 53 events) was 9 months (F = NR, I = 7 months, P = 3 months p value < 0.0001) with estimated 6 and 12 months OS of 80% and 67 % respectively. At cut-off, 26/32 with F IMDC risk remaining on treatment c.f. 24/54 (I) and 6/27 (P). Median treatment received was 5 cycles and 65% still on full dose at end of observation. Dose reduction was necessary in 31% while treatment was stopped in 15% due to toxicity. 46% received subsequent therapy post- progression. The commonest adverse events were fatigue (32%, G3 0%), diarrhoea (15%, G3 1.7%), mucositis (15%, G3 < 1%), and anorexia (7%, G3 1.7%). Conclusions: Preliminary findings from this review suggests similar clinical efficacy of tivozanib compared to agents such as pazopanib or sunitinib in real-world setting particularly among patient with Favourable IMDC category however longer follow up is required to fully evaluate this. Treatment is well tolerated with low incidence of severe grade toxicities and may be a good monotherapy option in patient of Favourable IMDC category unsuitable for combination therapies.
Real-world evidence of cabozantinib in metastatic renal-cell carcinoma (mRCC): Results from the Canadian Kidney Cancer Information System (CKCis).
Authors: Zhang Hanbo , Basappa Naveen S. , Joy Isaiah , Ghosh Sunita , Lalani Aly-Khan A. , Hansen Aaron Richard , Heng Daniel Yick Chin , Castonguay Vincent , Kollmannsberger Christian K. , Winquist Eric , Wood Lori , Bjarnason Georg A. , Breau Rodney H. , Pouliot Frederic , Kapoor Anil , Graham Jeffrey
Published: February 2020

682

Background: Cabozantinib is a multitargeted tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in mRCC randomized trials. Less is known about the activity of cabozantinib in patients (pts) exposed to immuno-oncology (IO) agents. We explored the real-world effectiveness of cabozantinib, including in pts who had progressed on IO therapy. Methods: Using CKCis, a prospective Canadian database, pts treated with cabozantinib monotherapy as second-line or later were identified. Baseline clinical and treatment characteristics were collected. Rates of partial response (PR), stable disease (SD), progressive disease (PD) and disease control (DCR, PR+SD) were determined along with median time to treatment failure (mTTF) and median overall survival (mOS). Results: A total of 156 pts were identified. Median age was 62 years (range 21-84), 74% of pts had clear-cell histology, and 54% had > 3 sites of metastases (12% in CNS, 47% in bone). At time of cabozantinib start, 34% had KPS score < 80. Outcomes are described below. Conclusions: The effectiveness of cabozantinib observed in this real-world population was consistent with results from clinical trials. Cabozantinib also appears to provide benefit to mRCC pts who have progressed on prior IO therapy, and should be incorporated into contemporary treatment algorithms. Further follow up is ongoing.[Table: see text]
Development of a predictive model of PSA response to a switch from prednisone to dexamethasone in metastatic castrate-resistant prostate cancer patients biochemically progressing on abiraterone.
Authors: Barua Reeta , Phillips Cameron , Arciero Vanessa Sarah , Zhang Liying , Rahmadian Amanda , Delos Santos Seanthel , Parshad Shruti , Emmenegger Urban
Published: February 2020

88

Background: Abiraterone acetate (AA) is typically administered with prednisone (P) to prevent symptoms of mineralocorticoid excess in patients with metastatic castrate resistant prostate cancer (mCRPC). After biochemical progression on AA + P, there is a sizeable subset of patients who have a renewed PSA response when switched from P to dexamethasone (D). The purpose of this study was to delineate clinical and pathologic factors that are predictive of a PSA response to such a steroid switch. Methods: We performed a retrospective analysis of 87 patients switched from AA+P to AA+D at Sunnybrook Odette Cancer Centre (Toronto, ON, Canada) between December 2012 and September 2018. Information on demographics, disease characteristics, previous treatments and performance status was collected. Response to the P to D switch maneuver was defined as a decrease in PSA by ≥30% within 12 weeks of the intervention (PSA30). Univariate logistic regression analyses were used to create a prediction model for each covariate tested, and R2 was applied for the measure of fit.Using multivariable logistic regression analysis and a backward stepwise selection procedure, we sought to identify patient and/or disease characteristics associated with a PSA30. Results: 38/87 patients (44%) experienced a PSA30. Univariate analysis showed that a favourable ECOG performance status, no prior docetaxel and no prior enzalutamide use were associated with a PSA30. On multivariable logistic regression analysis both favourable ECOG performance status and no prior enzalutamide use remained associated with a PSA30 (Table). Conclusions: A considerable proportionof patients with mCRPC who biochemically progress on AA+P have a renewed PSA response when changed to AA+D.Patients with a favourable ECOG performance status and no prior enzalutamide use are more likely to respond to such a steroid switch. Further prospective studies are needed to validate our findings.[Table: see text]
A multicenter phase IIb trial to evaluate the efficacy and tolerability of ModraDoc006/r in subjects with metastatic castration-resistant prostate cancer (mCRPC), suitable for treatment with a taxane (NCT04028388).
Authors: Vaishampayan Ulka N. , De Wit Edwin J. , Shore Neal D. , Dreicer Robert , George Daniel J. , Boccia Ralph V. , Curti Brendan D. , Geczi Lajos , Csõszi Tibor , Vogelzang Nicholas J.
Published: February 2020

TPS268

Background: Docetaxel IV and prednisone is a standard of care in mCRPC with demonstrated overall survival benefit. ModraDoc006 is a novel oral tablet formulation of docetaxel and to enhance bioavailability, it is co-administered with ritonavir (/r), an inhibitor of cytochrome p450 3A4 and P-glycoprotein. The oral combination, denoted as ModraDoc006/r, could be preferable due to patient convenience and elimination of infusion reactions and prophylactic steroids administration. Due to its weekly administration and exposure levels, increased efficacy may be demonstrated. Methods: The study is an open label 1:1 randomized phase 2b trial of ModraDoc006/r bi-daily QW versus docetaxel IV 75 mg/m2 Q3W. Thirty (30) mg ModraDoc006 combined with 200 mg /r in morning and 20 mg ModraDoc006 with 100 mg /r in evening is administered on days 1, 8 and 15 of a 21 day cycle. Safety and preliminary efficacy of ModraDoc006/r have been established in a phase Ib trial in mCRPC pts. All patients will receive 5 mg oral prednisone twice daily. Treatment is continued until progression, unacceptable toxicity or patient wish. mCRPC pts with measurable disease per RECIST 1.1, suitable for docetaxel therapy, are eligible. No prior treatment with taxanes is allowed. Primary objective is objective response rate (ORR) as assessed by investigators. Secondary objectives include PSA response, PSA-PFS, time to skeletal related events and progression, duration of response, disease control rate and safety assessments. Patient reported outcomes and health-related quality of life will be captured with treatment satisfaction and FACT-P questionnaires. It is expected that ModraDoc006/r will be at least as effective as docetaxel IV. A sample size of 50 evaluable pts per arm will evaluate an estimated ORR of 25% in each arm, with a 5% two-sided alpha and power of 83.7%. Conclusions: ModraDoc006/r represents an advance in prostate cancer therapeutics with convenience of oral administration, reduced myelosuppressive toxicity and potential improved efficacy over IV docetaxel. Clinical trial information: NCT04028388.
Phase III study of perioperative pembrolizumab (pembro) plus neoadjuvant chemotherapy (chemo) versus placebo plus neoadjuvant chemo in cisplatin-eligible patients (pts) with muscle-invasive bladder cancer (MIBC): KEYNOTE-866.
Authors: Siefker-Radtke Arlene O. , Steinberg Gary D. , Bedke Jens , Nishiyama Hiroyuki , Fang Xiao , Kataria Ritesh , Homet Moreno Blanca , Hoimes Christopher J.
Published: February 2020

TPS599

Background: MIBC prognosis is poor, despite standard neoadjuvant cisplatin-based chemo. PD-1/PD-L1 pathway inhibition is an effective first-line option for cisplatin-ineligible pts and a second-line option for platinum-based chemo pretreated pts. Neoadjuvant chemo + pembro, a PD-1 inhibitor, recently showed encouraging pathologic complete response rates, in cisplatin-eligible patients with MIBC (NCT02365766), warranting further investigation. Methods: KEYNOTE-866 (NCT03924856) is a randomized phase 3 study to assess efficacy and safety of chemo+perioperative pembro versus chemo+perioperative placebo for pts with MIBC. An estimated 790 patients will be randomly assigned 1:1 to neoadjuvant pembro+chemo (4 cycles) followed by adjuvant pembro after radical cystectomy+pelvic lymph node dissection (RC+PLND, 13 cycles) or neoadjuvant placebo+chemo (4 cycles) followed by adjuvant placebo after RC+PLND (13 cycles). Pts will receive neoadjuvant and adjuvant pembro 200 mg IV Q3W; neoadjuvant chemo will be gemcitabine 1000 mg/m2+cisplatin 70 mg/m2 IV Q3W. Pts will be stratified by tumor PD-L1 status (combined positive score [CPS] ≥10 vs CPS <10), disease stage (T2 vs T3/4), and region of treatment (Unites States vs Europe vs most of world). Adults (≥18 y) with histologically confirmed MIBC (T2-T4aN0M0) who are cisplatin-eligible, are clinically nonmetastatic (N0M0), and have an ECOG PS 0 or 1 will be enrolled. Pts are required to provide tumor tissue for histology and PD-L1 analysis. Pts will not be permitted to have previously received systemic antineoplastic treatment for MIBC or radiotherapy to the bladder. Imaging by CT/MRI will be performed Q12W for up to 96 wk after cystectomy, at discontinuation, and during follow-up starting at 3 y (Q24W). Primary end points are pathologic complete response and event-free survival in all pts and pts with PD-L1 CPS ≥10. Secondary end points are OS, disease-free survival, and pathologic downstaging rate in all pts and pts with PD-L1 CPS ≥10, and safety. Accrual began June 13, 2019. Clinical trial information: NCT03924856.
A phase I trial to assess the biologic effect of CBM588 (Clostridium butyricum) in combination with nivolumab plus ipilimumab (nivo/ipi) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Bergerot Paulo Gustavo , Dizman Nazli , Ruel Nora , Frankel Paul Henry , Hsu Joann , Pal Sumanta K.
Published: February 2020

TPS764

Background: The combination of the immune checkpoint inhibitors (ICIs) nivo/ipi is standard of care for pts with intermediate/poor-risk clear cell RCC. Although data are encouraging, less than 50% of pts will exhibit partial or complete response with nivo/ipi, and approximately 20% of pts will progress through this regimen. Studies have shown that response to ICIs may be modulated by the gut microbiome (Routy et al Science 2018), and that certain gut bacteria (e.g., Bifidobacterium spp) may predispose pts to response (Caitano et al ASCO GU 2017). CBM588 is a strain of Clostridium butyricum, a Gram-positive bacillus which produces short-chain fatty acids. It promotes the growth of commensal gut bacteria like Bifidobacterium, Lactobacillus and Bacteroides spp, and has been shown to enhance Th1 cells and IL-10 production with immunomodulatory effects. Here, we present the study design of an ongoing phase I trial to assess the biologic effect of CBM588 in combination with nivo/ipi in pts with mRCC. Methods: This is a single institution phase I trial. Pts will be randomized to one of two treatment arms. The experimental arm will receive the standard dose/schedule for nivo/ipi (3 mg/kg / 1 mg/kg Q3w for 12w, followed by nivo alone Q4w) plus CBM588 (60 mg PO 3x/d). The control arm will receive nivo/ipi at standard dose/schedule. Key eligibility criteria include intermediate/poor-risk mRCC, no concurrent antibiotic therapy and no prior systemic treatment. The primary objective is to determine the biologic effect of CBM588 + nivo/ipi in the modulation of the gut microbiome, measured by the change in Bifidobacterium spp and Shannon index (a measure of microbiome diversity). Secondary objectives include clinical efficacy (progression free survival by RECIST 1.1) and assessment of systemic immune-modulation effects through the analysis of circulating Tregs, MDSCs, and circulating cytokines/chemokines. Stool samples and serum correlatives will be collected on weeks 1 and 13 of treatment. A two-group t-test with a one-sided type I error of 0.05 will be used to assess the study primary endpoints. Clinical trial information: NCT03829111.
To Address Burnout in Oncology, We Must Look to Teams: Reflections on an Organizational Science Approach
Authors: LeNoble Chelsea A. , Pegram Riley , Shuffler Marissa L. , Fuqua Tranaka , Wiper Donald W.
Published: February 2020

PURPOSE:

Despite decades of effort, burnout among physicians remains elevated compared with that of other working populations, and it yields catastrophic consequences, including medical errors and physician suicide. Burnout leaves oncologists feeling like they are alone, but this is not the case—it affects everyone. To effectively address burnout, it is not enough to look only at oncologists; instead, we must include all those involved in the delivery of cancer care. With this aim, we present an overview of the organizational science strategies and initial evidence for the value of a comprehensive, team-focused approach to addressing oncology provider burnout.

METHODS:

We describe the development of a team-focused burnout intervention approach, implemented for oncology providers, which focuses on the importance of encouraging communication and psychological safety to reduce feelings of isolation and fragmentation. We discuss the initial findings from 1 such team-based initiative currently underway within an academic medical center, presenting data from 409 cancer care providers embedded in 30 oncology units participating in this intervention approach.

RESULTS:

Preliminary results demonstrate that units that integrated a team-focused intervention for burnout reported significantly higher levels of teamwork and lower levels of burnout. We also describe lessons learned and recommendations for implementing this type of intervention on the basis of best practices from organizational science.

CONCLUSION:

This approach can positively affect the delivery of cancer care, interprofessional relationships among oncology staff, and the well-being of both patients and providers. Treating physician burnout alone will treat 1 symptom of the overall issue of burnout in oncology. As burnout pulls oncology clinicians apart, our solution must be to bring them together.
An unsupervised learning method for reconstructing cell spatial organization with application to the DREAM Single Cell Transcriptomics Challenge
Authors: Chen Yang , Mao Disheng , Zhang Yuping , Ouyang Zhengqing
Published: February 2020

Single cell RNA sequencing (scRNA-seq) data analysis is important for building a global transcription landscape of all cell types in tissues, tracing cell lineages, and reconstructing cell spatial organizations. In this article, we propose an unsupervised learning method to predict spatial positions and gene expression of individual cells in Drosophila embryos using a small number of driver genes. Specifically, we develop a two-stage clustering approach, and compute a probability matrix of the spatial positions of single cells. This method is applied to dataset in the DREAM Single Cell Transcriptomics Challenge. The comparison with the “gold standard” suggests that our method is effective in reconstructing the cell positions and gene expression patterns in spatial tissues.
Rectal gonorrhoea and chlamydia among men who have sex with men in coastal Kenya
Authors: Ngetsa Caroline J. , Heymann Marc W. , Thiong'o Alex , Wahome Elizabeth , Mwambi John , Karani Clara , Menza Nelson C. , Mwashigadi Grace , Muturi Margaret W. , Graham Susan M. , Mugo Peter M. , Sanders Eduard J.
Published: February 2020

Background: Men who have sex with men (MSM) have a higher prevalence of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections compared to the rest of the population, often remaining undiagnosed. In Kenya, prevalence of rectal CT and NG infection and NG antimicrobial sensitivity are poorly described.

Methods: MSM who reported receptive anal intercourse (RAI) were recruited from an ongoing human immunodeficiency virus acquisition and treatment study in coastal Kenya in 2016-2017. Rectal swabs were collected at two time points 6 months apart to estimate prevalence and incidence of CT/NG infection using a molecular point-of-care assay. Participants positive for CT or NG were treated according to national guidelines. NG culture and antimicrobial susceptibility testing was performed. Participant and risk behaviour characteristics were collected and association with baseline CT/NG prevalence assessed by multivariable regression analysis.

Results: Prevalence of CT/NG in 104 MSM was 21.2% (CT 13.5%, NG 9.6%, dual infection 1.9%) at baseline and 25.9% in 81 MSM at follow-up (CT 14.8%, NG 14.8%, dual infection 3.7%). CT/NG incidence was estimated at 53.0 (95% CI, 34.5-81.3) per 100 person-years. Most CT/NG positive participants were asymptomatic: 95.5% at baseline and 100% at follow-up. CT/NG infection was associated with being paid for sex [adjusted odds ratio (aOR)=6.2, 95% CI (1.7-22.9)] and being in formal employment [aOR=7.5, 95% CI (1.1-49.2)]. Six NG isolates were obtained at follow-up; all were susceptible to ceftriaxone and cefixime and all were resistant to penicillin, tetracycline and ciprofloxacin.

Conclusions: There is a high prevalence and incidence of asymptomatic rectal CT and NG in MSM reporting RAI in coastal Kenya. MSM who were paid for sex or had formal employment were more likely to be infected with CT/NG suggesting increased risk behaviour during transactional sex. Antimicrobial susceptibility results suggest that current antibiotic choices in Kenya are appropriate for NG treatment.
Platform Pricing and Investment to Drive Third-Party Value Creation in Two-Sided Networks
Authors: Tan Burcu , Anderson Edward G. , Parker Geoffrey G.
Published: February 2020

Many two-sided platforms, such as eBay, iOS, Android, and Twitter, invest in developer integration tools, such as modular interfaces, interactive development environments, application programming interfaces, and help desks, in order to reduce the cost and improve the functionality of third-party content developed for the platform. Although these integration tools are crucial to platform success, they are costly to create, and therefore, managers need to understand where and when to deploy them. In particular, when the necessary integration investment is high, the advice to subsidize one side of a two-sided market while charging the other may not hold. This means that integration investment should be carefully coordinated with market pricing decisions. In general, higher levels of investment by hardware/software platforms into integration become desirable when the platform (1) has access to a large pool of content providers and consumers, (2) is able to develop integration tools that are highly effective in reducing third-party development costs, and (3) operates in high-consumer value markets. However, there are nuances. For example, business to business platforms can make investments in integration to facilitate participation by both sides of the market. We find that such investments are complements, not—as one might expect—substitutes.
Calculative Trust and Interfirm Contracts
Authors: Susarla Anjana , Holzhacker Martin , Krishnan Ranjani
Published: February 2020

Interfirm contracts are plagued by opportunism arising from exchange hazards that increase the seller’s gains from holdup in fixed price contracts. These exchange hazards are higher when the seller can engage in unverifiable deliberate obfuscation. Although cost-plus contracts reduce holdup losses, they suffer from cost inefficiency. Past research has underscored the importance of trust as a control instrument to mitigate losses from exchange hazards, especially social relational trust that develops from past experiences. However, trust can also be calculative when it develops from the expectation of future economic gains to the buyer-seller dyad. We identify two dyadic mechanisms that generate calculative trust and curtail the likelihood of cost-inefficient behavior in cost-plus contracts. These mechanisms include future potential and bilateral reputation capital for cost containment. Analysis using probit estimations on 149 information technology outsourcing contracts for the period 1998 to 2005 suggests that calculative trust increases the likelihood of cost-plus contracts. Thus, calculative trust can mitigate inefficiencies in interfirm contracts.

This paper was accepted by Shiva Rajgopal, accounting.
Polynomial Jump-Diffusion Models
Authors: Filipović Damir , Larsson Martin
Published: February 2020

We develop a comprehensive mathematical framework for polynomial jump diffusions in a semimartingale context, which nest affine jump diffusions and have broad applications in finance. We show that the polynomial property is preserved under polynomial transformations and Lévy time change. We present a generic method for option pricing based on moment expansions. As an application, we introduce a large class of novel financial asset pricing models with excess log returns that are conditional Lévy based on polynomial jump diffusions.
High-tech scan to aid diagnosis of hypertension
Authors: Palmer Sarah Jane
Published: February 2020

In this monthly feature, Sarah Jane Palmer delves into topical news, the latest research and what the experts are saying on subjects related to cardiology and cardiac nursing practice.
Chronic diarrhoea due to bile salt malabsorption: nurse-led assessment, medical treatment and dietary management
Authors: Adio Jitka , Burch Jennie
Published: February 2020

Bile salt malabsorption (BSM) occurs when bile salts, which are secreted in the small bowel to aid digestion of fats and vitamins, are not sufficiently re-absorbed in the terminal ileum. Consequently, an excess of bile salts enters the colon, causing chronic explosive diarrhoea, associated with abdominal cramps, flatulence and urgent, frequent and unpredictable bowel habits. BSM affects around 1% of the population, often occuring in ileal Crohn's disease or after ileal resection. Diagnosis begins with a nurse-led assessment, including blood and stool tests, to exclude other potential organic causes of chronic diarrhoea. BSM can then be confirmed and classified with a75Se-homocholic acid taurine (SeHCAT) scan. BSM can be treated medically with bile salt sequestrants, including colestyramine sachets, which are approved but have an unpleasant taste, and colesevelam tablets, which are more tolerable but more expensive and not yet approved. However, long-term sequestrant use can impact absorption of vitamins and other medications. BSM can also be managed with a low-fat diet, which is cost-effective and can reduce the amount of bile secreted. Nurses should provide patient education to ensure adherence and safe use.
Newly qualified health visitor: Safeguarding the ‘unseen’ child
Authors: Boddy Bethany
Published: February 2020

Bethany Boddy considers the need for holistic assessment of appointments where children were not present, and the importance of considering that a child was not brought, rather than did not attend