tbuckley/cabot-search huggingface dataset:
IFN-α, IFN-γ, IL-2 combined with TNF-α for predicting efficacy of PD-1 inhibitors combination therapy in patients with solid cancers.
Authors: Penghui Xing, Jinyan Zhang, Rongfeng Liu, Junyan Wang, Ming Ma, Lixing Wang, Wenjing Jiao, Junguo Shao, Yuxiang Wang, Hongtao He, Baoen Shan, Jian Shi
Journal: Journal of Clinical Oncology (2021)

2584 Background: PD-1 inhibitors have transformed the treatment landscape for patients (pts) with many advanced malignancies. Combination therapy with PD-1 inhibitors for cancer is a trend. However, Biomarkers for the efficacy of combination therapy remains unknown. In order for the benefited population to be screened out, biomarkers need to be established. we will conduct the following study, to explore the IFN-α, IFN-γ, IL-2 combined with TNF-α for predicting efficacy of PD-1 inhibitors combination therapy. Methods: Using postoperative without lesions as control group (n=7). Pts with lesions as the experimental group (n=66). 27 of 66 pts received chemoradiotherapy (group A), 39 of 66 pts received PD-1 inhibitors combined with therapy (group B). IFN-α, IFN-γ, IL-2, TNF-α in peripheral blood of all pts were measured using flow cytometry. Results: 1) There was significant difference in proportion above normal concentrations (ANCs) of IFN-α between two groups (57.1% vs 43.5%, P&lt;0.05), but there was no significant difference in IFN-γ, IL-2 and TNF-α between two groups (IFN-γ 57.1% vs 52.2%, IL-2 14.3% vs 5.8%, TNF-α 42.9% vs 43.5%, P&gt;0.05). 2) The normal ratios of IFN-α, IFN-γ and TNF-α in group B was significantly higher than that in group A (IFN-α 64.1% vs 51.9%, IFN-γ 59% vs 37%, TNF-α 69.2% vs 44.4%, P&lt;0.05). The proportion ANCs of IFN-α, IFN-γ, and TNF-α were lower in group A (IFN-α 35.9% vs 63%, P&gt;0.05; IFN-γ 41% vs 63%, P&lt;0.05; TNF-α 30.8% vs 55.6%, P&lt;0.05). However, the proportion ANCs of IL-2 detection was lower (7.4% vs 5.1%). 3) In group B, 21 of 39 pts were evaluable. ORR was 52.4% (11/21) and DCR was 85.7% (18/21). The proportion ANCs of IFN-α, IFN-γ and TNF-α in the pts with PR was higher than that with SD (IFN-α 37.5% vs 28.6%, IFN-γ 37.5% vs 28.6%, TNF-α 50% vs 38.8%, P&lt;0.05). 4) We found that the coincidence rate of IFN-α+ IFN-γ and IFN-α+ IFN-γ+TNF-α was higher in group B (Table). Conclusions: Our results suggest that the proportion ANCs of IFN-α, IFN-γ, and TNF-α in the pts with lesions were lower than that without lesions, it may be the decrease of immune function with lesions. There was positive correlation between proportion ANCs of IFN-α, IFN-γ and TNF-α and efficacy in these pts. IL-2 was not used as a routine detection indicator. The coincidence rate of IFN-α, IFN-γ combined with TNF-α was higher, it may help predict the outcome of PD-1 inhibitors combination therapy in pts with solid cancers, and helpful to screen the benefit population. Further study is needed.[Table: see text]
Anti PD-(L)1 in KRAS mutant advanced nsclcs: A meta-analysis of randomized controlled trials.
Authors: Thierry Landre, Gregoire Justeau, Jean-baptiste Assié, Kader Chouahnia, Chérifa Taleb, Christos Chouaid, Boris Duchemann
Journal: Journal of Clinical Oncology (2021)

9025 Background: KRAS comprise the most frequently found oncogene driver mutation in non-small cell lung cancer (NSCLC), accounting for 20-25% of these patients. Single-agent Anti PD-(L)1 clinical efficacy against KRAS mutant NSCLC is a topic of debate. Methods: This meta-analysis examined randomized-trial data comparing first-or second line Anti PD-(L)1 +/- chemotherapy (CT) vs CT alone for KRAS mutant advanced NSCLCs. Outcome measures included overall survival (OS) and progression-free survival (PFS). Analyses were computed using the Cochrane method of collaboration for meta-analyses, with Review Manager software (RevMan version 5.3; Oxford, UK). Results: We analyzed 3 trials in first line (IMPOWER-150, KEYNOTE-189 and KEYNOTE-042), as well as 3 trials in second line (OAK, POPLAR and CHECKMATE-057) including 1313 NSCLCs (386 KRAS mutant and 927 KRAS wild-type tumor). Anti PD-(L)1 +/- CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.59 [0.49-0.72]; p &lt; 0.00001) and PFS (0.58 [0.43-0.78]; p = 0.0003) compared to CT alone in KRAS mutant NSCLCs. Survival benefits occured in both first and second line. Survival benefits observed in KRAS wild-type NSCLCs were (0.87 [0.76-0.99]; p = 0.03) and (0.79 [0.56-1.11]; p = 0.17) respectively. OS benefit in KRAS mutant was significantly superior compared to OS benefit in KRAS wild-type (p = 0,001). Conclusions: Anti PD-(L)1 (+/- CT) appears superior to CT alone both for mutant and wild-type KRAS in advanced NSCLCs for OS and PFS with higher magnitude of benefit in KRAS mutated group for OS.
A phase 1 study of neoadjuvant chemotherapy followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in pancreatic cancer.
Authors: Andrew Stewart Poklepovic, Emma Charlotte Fields, Dipankar Bandyopadhyay, Mary Beth Tombes, Maciej Kmieciak, William P. McGuire, Sarah W. Gordon, Brian J. Kaplan, Jennifer Lynn Myers, Khalid Matin, Bhaumik Patel, Sejal Kothadia, Paul Dent
Journal: Journal of Clinical Oncology (2021)

e16268 Background: The multi-kinase inhibitor sorafenib (S) and HDAC inhibitor vorinostat (V) demonstrated synergism against preclinincal pancreatic cancer (PaCa) models. The combination of S &amp; V also potently radiosensitized pancreatic cancer cells and enhanced the activity of gemcitabine (G). This led to a phase 1 trial to determine the doses and schedule appropriate for phase 2 study of S &amp; V with weekly G and intensity modulated radiotherapy (IMRT) as neoadjuvant treatment of PaCa following chemotherapy. Methods: Using a 3+3 dose-escalation design, adult patients with resectable, borderline resectable, unresectable, and lymph node positive PaCa were enrolled to 6 dose levels. Enrolled patients had completed at least 8w of neoadjuvant chemotherapy prior to IMRT. The schedule of administration was weekly 200mg/m2 G weekly during IMRT, S &amp; V were dosed either 3x or 5x weekly during IMRT. Primary endpoint was to identify the dose and schedule for S &amp; V with G based chemoradiation. Key secondary endpoints included antitumor activity, R0 resection rate, OS. Correlative studies to evaluate a variety of biomarkers and Nanostring expression analysis on pre- and post-therapy tumor specimens were also performed. Results: 22 patients were enrolled and 21 treated at 6 dose levels. Due to thrombocytopenia limiting drug exposure, the trial was modified to reduce G to 200mg/m2/wk and S &amp; V to 3 d/wk instead of 5 d/wk. 13 patients were eligible for surgery, and 9 had R0 resections. Conclusions: Our findings indicate that the study regimen was well tolerated, typical toxicities of S (hand foot syndrome) were not observed with intermittent dosing. Uncomplicated cytopenias limited drug exposure, which was improved with intermittent S&amp;V dosing. The RP2D of the combination is S (400mg po BID 3d/wk), V (200mg po qd 3d/wk), G 200mg/m 2 IV weekly, with IMRT (50.4 Gy over 28 fractions, 5d/wk). Antitumor activity was observed across dose levels, with an encouraging R0 resection rate. These results warrant further investigation of combining S and V with G and IMRT as neoadjuvant treatment of PaCa following chemotherapy. Analyses of correlative studies and OS are underway. Clinical trial information: NCT02349867. [Table: see text]
Cost-effectiveness of zanubrutinib versus ibrutinib in adult patients with Waldenström macroglobulinemia in the United States.
Authors: Jorge J. Castillo, Keri Yang, Rongzhe Liu, Yu Wang, Aileen Cohen, Todd M. Zimmerman, Qian Zhao, Gijs van de Wetering, Xin Gao, Boxiong Tang
Journal: Journal of Clinical Oncology (2021)

e18856 Background: The efficacy of zanubrutinib and ibrutinib was examined in the randomized ASPEN trial (NCT03053440) in adult patients with Waldenström macroglobulinemia (WM). This analysis assessed the cost-effectiveness (CE) of zanubrutinib vs ibrutinib in this population from a US payer perspective. Methods: A 3-state (pre-progression, post-progression, and death) partitioned survival model was used to estimate the life years (LYs), quality-adjusted life years (QALYs), and costs for each treatment over a 30-year lifetime horizon. Overall survival (OS), progression-free survival (PFS), and time-to-discontinuation (TTD) curves were fitted using parametric distributions to extrapolate long-term outcomes. Selection of the parametric models for each outcome and treatment was based on assessments of 1) the proportional hazard assumption, 2) goodness-of-fit, and 3) clinical plausibility of extrapolated mean OS and associated hazard patterns (based on literature and US clinical expert input) and the alignment between PFS and TTD. Background US mortality was accounted for in the model. Utilities were based on the ASPEN EQ-5D data and literature. Costs (2020 US$) included drug (wholesale acquisition cost from RED BOOK) and adverse event management (Healthcare Cost and Utilization Project) for zanubrutinib and ibrutinib, routine care, and terminal care. Sensitivity analyses were conducted to evaluate the impact of parameter uncertainty. All outcomes were discounted at 3% annually. Results: In the base case analyses using the dependent exponential model for all outcomes over a 30-year time horizon, zanubrutinib led to 0.94 LY and 0.84 QALY gained with an additional total drug cost of $11,132. This additional cost was primarily driven by patients staying on zanubrutinib treatment longer as zanubrutinib has longer time to treatment failure. However, this is partially offset by zanubrutinib’s lower monthly drug acquisition, reduced cost of routine care (–$2,935) and terminal care (–$2,964) than ibrutinib. The incremental cost-effectiveness ratio (ICER) of zanubrutinib is $13,205 per QALY gained. The deterministic sensitivity analyses showed that ICER was most sensitive to the monthly costs of routine care. The probabilistic sensitivity analyses showed that the mean probabilistic ICER was $16,804, and that the probability of zanubrutinib being cost-effective was 61% at a willingness-to-pay threshold of $100,000 per QALY gained. Varying the time horizon to 5, 10, or 15 years consistently led to zanubrutinib being dominant (i.e., greater QALYs but lower costs). Conclusions: Zanubrutinib appears to be cost-effective compared with ibrutinib for the treatment of patients with WM in the US.[Table: see text]
Analysis of metabolism-related gene signature for prognosis prediction of clear cell renal cell carcinoma.
Authors: Dalong Cao, Yuchen Liao, Guoqiang Wang, Shangli Cai, Guohai Shi
Journal: Journal of Clinical Oncology (2021)

e16580 Background: Clear cell renal cell carcinoma (ccRCC) is characterized by a dysregulation of changes in cellular metabolism. However, the prognostic value of metabolism-related genes in ccRCC have not been systematically profiled. In this study, a candidate prognostic gene signature of metabolism in ccRCC was explored. Methods: The clinical and gene expression profiles of ccRCC patients were downloaded from the TCGA, GEO and three clinical trials (CheckMate 009, CheckMate 010, CheckMate 025), and the metabolism-related gene set was downloaded from MSigDB. Differential expression analysis and LASSO Cox regression with binomial deviance minimization criteria were applied to identify and build a metabolism-based signature. The prognostic significance of the signature was further evaluated with the Receiver Operating Characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analysis was performed to evaluate the impact of each variable on OS. Furthermore, the prediction power of the signature has been validated using different ccRCC cohort. Results: In this study, a signature of 8 metabolism-related genes (ANGPT2, ATP6V1B1, CACNA1E, CD163L1, EPN2, HOXD11, PROS1, SHOX2) was constructed as being significantly associated with overall survival (OS) among patients with ccRCC, which differentiated ccRCC patients into high- and low-risk subgroups. The Kaplan-Meier (KM) analysis showed that the survival rate of the low-risk patients was significantly higher than that of the higher-risk patients (hazard ratio (HR) in training set, 0.25 [95% CI, 0.14-0.44; P &lt; 0.001]; testing set, 0.28 [95% CI, 0.10-0.76; P = 0.008]; validation cohort (clinical trials), 0.47 [95% CI, 0.33-0.68; P &lt; 0 .001]; validation cohort (GSE29609), 0.25, [95% CI, 0.08-0.88; P = 0 .01]). ROC curve analysis of the prognostic signature showed that the areas under curve (AUC) for the 1-, 3-, and 5-year OS in all cohort were more than 0.70 (AUC of the signature for 3 year in the training set and validation cohort were 0.816 and 0.708, respectively, and 0.807 and 0.702, respectively, for the 5- year OS). Further more, a nomogram based on the signature was constructed and showed an accurate prediction for prognosis in ccRCC. Conclusions: Taken together, we identified the key metabolism-related genes and constructed a robust prognostic signature for the prognostic predictor of ccRCC patients, which maybe help personalized management of ccRCC patients.
HGG-10. THE BLOOD-BRAIN BARRIER IN DIPG: INVESTIGATING REGION-SPECIFIC DIFFERENCES IN PERMEABILITY
Authors: Caitlin Ung, Dannielle Upton, Maria Tsoli, David Ziegler
Journal: Neuro-Oncology (2021)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is the most aggressive pediatric high-grade glioma with median survival of only 12 months from diagnosis. Current therapies are essentially palliative. The blood-brain barrier (BBB) is a major obstacle, limiting delivery of effective chemotherapeutics into the brain. We hypothesized that tumors in the brainstem region have a BBB less permeable than tumors in other brain regions. We have confirmed the presence of an intact BBB in three orthotopic models of DIPG by Evans Blue extravasation assay. Immunohistochemical staining of CD13+ pericytes and CD34+ endothelial cells in healthy mouse brain compared to orthotopic DIPG model showed higher levels of both components in brainstem compared to cortical region. Single-cell RNA sequencing experiments are currently being undertaken to investigate region-specific differences in BBB cell populations and the impact of DIPG on signaling pathways that govern permeability. To determine if tumor location impacts therapeutic outcome, we performed in vivo efficacy studies with DIPG orthotopically injected into cortical region or brainstem region and treated with SAHA, HDAC inhibitor, or temsirolimus, mTOR inhibitor. Temsirolimus or SAHA was ineffective at extending survival in mice injected with DIPG in the brainstem compared to control. However, temsirolimus led to a significant improvement in survival in mice injected with DIPG cells in cortical region (median survival 85 days) compared to control (median survival 69 days (P≤0.01)). This suggests that the same tumor in cortical region may respond to systemic therapy that is ineffective in the brainstem and that the intact BBB in the brainstem is a major reason for treatment failure in DIPG. In conclusion, the BBB in the brainstem and in the presence of DIPG may be altered, changing signaling pathways that affect permeability. Understanding the brainstem cerebrovasculature may potentially lead to a novel strategy to treat DIPG as well as other brain tumors.
Trends in primary gallbladder cancer incidence and incidence-based mortality in the United States, 1973 to 2015.
Authors: Soon Khai Low, Dimitrios Giannis, Nguyen Dinh Thuong, Nguyen Hai Nam, Abdulmueti Alshareef, Dimitrios Moris, Shin Yin Lee, Mohammad Ammad Ud Din, Nguyen Tien Huy
Journal: Journal of Clinical Oncology (2021)

e16133 Background: Primary gallbladder carcinoma (GBC) is the most common biliary tract cancer with poor survival despite aggressive treatment. The purpose of our study was to investigate the trends of GBC incidence and incidence-based mortality (IBM), as well as to identify the factors responsible for any observed changes. Methods: GBC cases diagnosed between 1973 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results database (SEER) database. Incidence and IBM rates age-adjusted to the 2000 US standard population were calculated and were stratified according to population and tumor-associated characteristics. Joinpoint Regression Analysis program was used to calculate the annual percent changes (APCs) for trend analysis. Results: Among the 10,792 patients with GBC, there was a predominance of white (81%) and female (71%) patients. The overall incidence rate was 1.086 (95% CI: 1.065 to 1.106) and the overall IBM rate was 0.995 (95% CI: 0.976 to 1.015). GBC incidence decreased by 1.645% (95% CI: 1.448 to 1.842, p &lt; 0.001) per year, but the decreasing trend was only statistically significant from 1973 to 2002, after which the incidence rates stabilized. Conversely, IBM decreased by 1.689% (95% CI: 1.217 to 2.159, p &lt; 0.001) per year from 1980 to 2015; the degree of decline in IBM rates during 1997-2015 (-1.194, 95% CI: -1.680 to -0.705, p &lt; 0.001) was lower compared to that during 1980-1997 (-3.132, 95% CI: -3.682 to -2.578, p &lt; 0.001). Mortality rates of GBC decreased in all age groups and in all races except for African American. There was a significant decrease in IBM in all SEER stages of GBC, except for distant stage GBC. Conclusions: GBC incidence and IBM rates have been decreasing over the last 40 years. However, the decrease in incidence and IBM appeared to have plateaued in the last two decades. The roles of increasing widespread use of laparoscopic cholecystectomy and use of newer treatment modalities, such as adjuvant chemotherapy and radiation, need to be investigated further.[Table: see text]
Diagnostic performance of Gallium-68 prostate-specific membrane antigen (PSMA) PET/CT imaging in early-relapsed prostate cancer: Phase 3, prospective, multicenter study (IAEA-PSMA study).
Authors: Juliano J Cerci, Stefano Fanti
Journal: Journal of Clinical Oncology (2021)

5078 Background: Biochemical recurrence (BCR) is a clinical challenge in prostate cancer (PCa) patients with impact on defintion of subsequent therapies. The use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) presents better accuracy than standard imaging practice. This phase3, prospective, multicentric, international study evaluates the diagnostic performance and clinical impact of PSMA-PET/CT in evaluating BCR in PCa. Methods: Patients with PCa who have undergone primary definitive treatment and with rising PSA were recruited in the study. Overall 17 centers from 15 countries (Azerbaijan, Brazil, Colombia, India, Israel, Italy, Jordan, Lebanon, Malaysia, Mexico, Pakistan, Poland, South Africa, Turkey, and Uruguay) were involved. Images and data were centrally reviewed; data were collected for PSMA site of findings, positivity rate, defined as the percentage of patients with a positive 68Ga-PSMA PET/CT taking into account the composite standard: pathology, correlative imaging, PSA response, with at least 6 mo. clinical follow-up, and impact on patient management by determining changes in the treating physician’s documented clinical plans before and after 68Ga-PSMA PET/CT. Results: Were enrolled 1198 patients and presented final data from 1004 patients. 68Ga-PSMA PET/CT was positive in 654/1004 patients (65.1%); lesions were identified as: prostate/prostatic bed only in 13.7% cases; pelvic lymph nodes only 20.5%, and with any metastatic disease in 27.0%. There was a correlation between PSMA-PET/CT positivity and Gleason score (p&lt;0.001): detection rate was 371/613 (60.5%) in patients with Gleason 7, 130/196 (66.3%) in Gleason 8, 140/180 (77.8%) in Gleason 9 and 13/15 (86.7%) in Gleason 10. There was also significant correlation between lesions identification and PSA values (p&lt;0.001): detection rate was 21/41 (51.2%) for PSA &lt;0.2, 84/188 (44.7%) for PSA between 0.2-0.5, 124/232 (53.4%) for PSA 0.5-1.0, 158/235 (67.2%) for PSA ≥1 and &lt;2, 171/206 (83.0%) for PSA ≥2 and &lt;4, and 96/102 (94,1%) in PSA 4 to 10. Also, treatment was modified based on PSMA results in 56.8% of patients. The 68Ga-PSMA PET/CT positivity was consistent and not statistically different among the countries. Conclusions: This is the largest multicenter trial on 68Ga-PSMA PET/CT detected local and metastatic recurrence in most men with BCR. 68Ga-PSMA PET/CT results changed the recommended treatment approaches in the majority of patients. This study confirms the reliability of PSMA PET in BC and the worldwide feasibility of such approach.
Side effects of extended interval dosing of checkpoint inhibitors among patients during COVID-19 pandemic at the Moncton and the Miramichi hospitals.
Authors: Mahmoud Abdelsalam, Rana Sughayar, Glenn Myers, Mrudula Avileli, Maged Salem
Journal: Journal of Clinical Oncology (2021)

e14550 Background: Since the COVID-19 pandemic started, managing cancer patients who are more vulnerable than the rest of the population has been a concern. One of the strategies to decrease cancer patient visits to the Oncology Clinic was by the use of an extended dosing schedule of immune checkpoint inhibitors. The goal of the present study is to record and describe patients’ experiences with irAEs on the modified treatment schedules. Methods: The study included cancer patients getting their treatment at the cancer care clinics at The Moncton Hospital and the Miramichi Hospital, and who switched to receiving either a modified dose of Pembrolizumab or Durvalumab. These participants were asked to complete a short survey that covered important data in their diagnosis and treatment, as well as the type of cancer diagnosed and which drug they were prescribed for treatment. Participants were also asked about the presence of any possible immune-related symptoms from a list of possible AEs since their last treatment visit, and to indicate (A) how often the symptom was experienced, and (B) how severe the symptom was. Results: Twenty-one patients filled out the questionnaire half of whom were females. Most of the patients had lung cancer and were on pembrolizumab. All the patients interviewed developed at least one new symptom after the change in the dose was introduced. The most frequent symptoms reported were itchy skin and fatigue and they were severely experienced. However, very few of the symptoms experienced required a physician consult or hospitalization. Most of the participants welcomed the change in the dose to protect them from COVID-19 and were mainly indifferent as to whether they get the low dose more frequently or the higher dose less frequently. Conclusions: This study has highlighted the frequency and severity of irAEs with the use of extended dosing schedule of immune checkpoint inhibitors. Future research should have more patients to validate this outcome and look for the causes behind the increased incidence and severity of irAEs with higher dose less frequent intervals of these immunotherapies.[Table: see text]
Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood–brain barrier
Authors: Jin Kim, Kyung-Tae Lee, Jong Seung Lee, Jisoo Shin, Baofang Cui, Kisuk Yang, Yi Sun Choi, Nakwon Choi, Soo Hyun Lee, Jae-Hyun Lee, Yong-Sun Bahn, Seung-Woo Cho
Journal: Nature Biomedical Engineering (2021)