tbuckley/cabot-search huggingface dataset:
Predicting acute care use following the initiation of systemic therapy for solid tumors.
Authors: Robert C Grant, Rahim Moineddin, Zhan Yao, Melanie Lynn Powis, Ruth Croxford, Eva Grunfeld, Vishal Kukreti, Monika K. Krzyzanowska
Journal: Journal of Clinical Oncology (2018)

6 Background: Emergency department (ED) visits and hospitalizations are undesirable and costly. We developed and validated the PROACCT (PRediction Of Acute Care use during Cancer Treatment) score to predict at least one acute care visit during the first 30 days (AC30) after initiating systemic therapy for cancer. Methods: Using administrative data, we identified patients in Ontario with the 18 most common solid tumors who started systemic treatment from July 1, 2014 to June 30, 2015. Southwestern and Northeastern Ontario formed the development and validation cohorts, respectively. We created a score to predict AC30 using multivariate logistic regression in the development cohort. Combinations of tumor sites and regimens were grouped into quintiles based on AC30. The score was assessed in the validation cohort. Results: AC30 occurred in 23% (4438/19359) of patients. Eleven factors predicted AC30 and formed the score: tumor site and regimen (2 nd quintile: 2; 3 rd -4 th : 3; 5 th : 4), recent ED visit (2), recent palliative radiation (1), rural residence (1) and Edmonton Symptom Assessment Scale anxiety (4+: 1), lack of appetite (4+: 1), pain (4+: 1), and wellbeing (4+: 1). Among the 204 tumor-regimen combinations, tumors with poor prognoses, such as pancreatic and lung, and platinum- and taxane-containing regimens, carried the highest risk for AC30. The score had moderate discrimination (c-statistic 0.65; P&lt; 0.001) and strong calibration (Table) in the validation cohort. Conclusions: PROACCT identifies factors that predict AC30 in patients starting systemic treatment for solid tumors and could be incorporated into electronic health records to select patients for preventative interventions. [Table: see text]
CT20p as a therapeutic for lung cancer with elevated chaperonin containing TCP1 (CCT) expression levels.
Authors: Priya Vishnubhotla, Ana C Carr, Amr Khaled, Rania Bassiouni, Annette R. Khaled
Journal: Journal of Clinical Oncology (2017)

e23163 Background: We previously reported, in breast cancer, the effectiveness of a novel therapeutic peptide called CT20p that displays cancer-selective cytotoxicity. CT20p targets for inhibition a macromolecular complex called Chaperonin-Containing TCP-1 (CCT) that is responsible for folding actin and tubulin and other proteins, like STAT3, into their active forms. CCT is composed of 8 subunits (CCT1-8) that are highly conserved among species. In breast cancer cases, we found that the genes for CCT were frequently amplified (CCT2), upregulating the chaperonin’s activity, which correlated with decreased patient survival. Methods: To determine whether CCT is active in other cancers and thereby a broad therapeutic target, we examined the protein levels of CCT2 in colon, liver, prostate and lung cancer by immunohistochemistry (IHC), using human tissue microarrays (TMAs). Genomic data from The Cancer Genome Atlas (TCGA) was used to support IHC findings. Immunoblot probing of three CCT subunits (CCT2, CCT4, CCT5) was performed to determine their relative expression level in five small cell lung cancer (SCLC) cell lines compared to normal lung cells and these cells tested for susceptibility to killing by CT20p. Results: Results of IHC staining for CCT2 were interpreted on a scale of 1 to 4 (with 4 being the strongest staining). We found that with the exception of colon cancer, all cancers expressed high levels of CCT2 with advancing stage. We identified a significant correlation with cancer progression in both small cell lung carcinoma (SCLC) and squamous cell lung carcinoma (SqCLC). While individual levels of the three probed CCT subunits varied amongst the SCLC cell lines, overall CCT expression was higher in the SCLC cells when compared to normal lung cells and correlated with susceptibility to killing by CT20p. Using the TCGA database, CCT gene alterations were detected in clinical lung cancer cases, with amplification of CCT4 gene in SqCLC cases linked to decreased survival. Conclusions: These results indicate that targeted inhibition of CCT through CT20p treatment is a promising treatment approach for those cancers like SCLC that currently lack effective therapeutics to sustain progression-free survival.
Patterns and determinants of pain and emotional distress in older adults with cancer: A population based study.
Authors: Amy J. Davidoff, Maureen Canavan, Shi-Yi Wang, Carolyn J Presley, Shelli Feder, Jennifer Kapo, Ella Sheinfeld, Erin Kent
Journal: Journal of Clinical Oncology (2018)

10105 Background: There is increasing concern about the adequacy of symptom management among older adults with cancer. We examined patterns and predictors of pain and emotional distress after a cancer diagnosis. Methods: Using the linked SEER-Medicare Health Outcomes Survey database, we selected participants from 2007-2012, within 5 years of cancer diagnosis. We used survey responses describing activity limits due to pain and emotional distress within the past 30 days to construct study outcomes. We undertook bivariate analyses and estimated multivariable logistic regression to determine the association of pain and emotional distress with cancer type, stage at diagnosis, years since diagnosis, demographics, socioeconomic status (educational attainment and area poverty rates) and chronic conditions. Results: Among 9481 respondents, prostate (31%) and breast (19%) cancers were most prevalent. Activity limits due to pain were reported by 22%, with highest rates among adults with lung cancer (37%), stage 4 diagnosis (34%), depression (53%) and heart failure (44%), minorities, and patients with lower socioeconomic status. The odds of reporting pain were increased for lung (ref = breast; adjusted odds ratio (aOR):1.5; 95% confidence interval (CI) 1.2-1.9); stage 2-4 (stage 4 aOR: 1.75; CI 1.36-2.25); and chronic conditions; and were decreased for prostate (aOR: .70; CI .54-.92) or colorectal cancers and higher socioeconomic status. Limitations due to emotional distress were reported by 14%, with the highest rates among patients with lung (27%), stage 4 (24%), prior depression (50%), Crohn's disease (33%), heart failure (30%), and lower socioeconomic status. The odds of emotional distress were higher with increasing age (80+ years, aOR: 2.1; CI 1.7-2.6), Hispanic ethnicity, prior depression (aOR: 7.9; CI 6.7-9.1), stroke, COPD, stage 3-4 diagnosis, and reduced for prostate cancer or lymphoma, initial surgery, and year 2 post diagnosis (ref=year 5). Conclusions: Despite an increased focus on symptom management, pain and emotional distress remain prevalent among older adults with cancer. Efforts to identify and target unmet supportive care needs are necessary to further improve quality of life.
A phase 1 clinical trial of a PSA/IL-2/GM-CSF containing prostate cancer vaccine in PSA defined biochemical recurrent prostate cancer patients.
Authors: Gregory A. Daniels, Michelle McKinney, Weg Ongkeko, Jessica Wang-Rodriguez, Kyoko Sakamoto, Robert Lange Elliott, Jonathan F. Head
Journal: Journal of Clinical Oncology (2016)

e14584 Background: Immunotherapy for cancer has had two main approaches that have led to clinical applications. The first is stimulating immune responses to tumor cells with cytokines or cellular immunotherapy and the second is blocking tumor immune evasion and the associated inhibition of T-cell activation with antibodies to the CTLA-4 receptor, PD-1 receptor or PD-L1. We have taken a different approach and have developed therapeutic cancer vaccines that are a combination of tumor antigens (proteins overexpressed by tumors) with biological adjuvants (the cytokines IL-2 and GM-CSF). Methods: This study is a Phase 1a/1b clinical trial of a PSA/IL-2/GM-CSF vaccine in recurrent prostate cancer in hormone-naïve and hormone-independent patients. Major inclusion criteria include adenocarcinoma of the prostate, rising serum PSA and no measurable disease. Phase 1a examines the rate of dose limiting adverse events (DLAEs) in an initial course of 6 vaccinations ("induction vaccination"). Twenty patients will receive intradermal injections of the PSA/IL-2/GM-CSF vaccine at weeks 0, 1, 2, 6, 10 and 14. Results: To date, twelve patients in the Phase 1a portion of the trial have received all 6 vaccines. Eight of the 11 patients who have received all 6 vaccines had increased immune responses to PSA in a lymphocyte blastogenesis assay by week 19. Six of 10 of the patients had an increase in the doubling time of their serum PSA, suggesting a slowing of the progression of the cancer. Median follow up after the first vaccine is 23 months (range: 4-32 months). Conclusions: None of the patients vaccinated in the Phase 1a portion have had a DLAE and enrollment continues in the Phase 1a. Clinical trial information: NCT02058680.
Survival impact of surgical management in reference centers for retroperitoneal sarcoma: A nationwide study of FSG-GETO and NETSARC.
Authors: Sylvie Bonvalot, Elodie Gaignard, Eberhard Stoeckle, Charles Honoré, Pierre Meeus, Nicolas Penel, Gwennael Ferron, Nelly Firmin, Florence Duffaud, Antonio Di Marco, Emmanuelle Bompas, Maria Rios, François Bertucci, Nicolas Isambert, Antoine Italiano, Isabelle Laure Ray-Coquard, Axel Le Cesne, Jean Michel Coindre, Francoise Ducimetiere, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2018)

11568 Background: Retroperitoneal sarcoma (RPS) are complex to treat. We previously reported that management and surgery in a reference center are independent prognostic factors for relapse free survival (RFS) in sarcoma. Here, we investigated the impact of the surgery in a reference center on RFS and overall survival (OS) in the nationwide NETSARC study. Methods: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers, funded by the French NCI. Since 2010, second pathological review are mandatory for sarcoma patients (pts) facilitating exhaustive collection. Pts characteristics and follow-up are collected in a database regularly monitored. From 2010 to 2016, RPS represented 10.0% (range 8.3-10.5%) of all sarcomas included in Netsarc. Results: 1286 RPS (M/F ratio: 1.09, median age 63, range 20-94) are reported in NETSARC from 01/2010 to 12/2016. WD/DDDLPS (63.7%), LMS (21,3%), UPS (6,3%) were the most frequent histotypes. 155 (12%) pts had metastasis (met) at diagnosis. 699 (54%) and 587 (46%) were presented to one of the 26 NETSARC multidisciplinary board before and after initiation of treatment. 477 (37%) and 809 (63%) were operated within vs outside a NETSARC reference center. The former group had larger tumor size, p < 0.0001, but no difference of age, grade, histotypes. More pts treated in NETSARC centers had documented imaging (92% vs 80%) and preoperative biopsy (81% vs 63%, p < 0.0001 both). Quality of final surgery was R2 or unknown, in 24% vs 69% in NETSARC vs non NETSARC centers (p < 0.0001). In univariate analysis on non met patients, surgery within a reference center was associated with a better OS (median not reached: 30-months OS 84% vs 63% respectively, logrank p < 0.001). Local RFS and RFS were significantly better for pts operated in reference centers (p < 0.0001). Surgery in reference center was an independent good prognostic factor for OS (HR: 0.23), LRFS (HR:0,56), RFS (HR:0,79) using Cox model (p < 0.001 all). Conclusions: In this nationwide unselected population of RPS over 7 years period, surgery in reference center is associated with a major reduction of the risk of relapse and death.
Incidence and impact of thromboembolic events in lung cancer patients treated with nivolumab.
Authors: Aparna Madhukeshwar Hegde, Chipman Robert Geoffrey Stroud, Cynthia R. Cherry, Meera Yogarajah, Sulochana Devi Cherukuri, Paul R. Walker
Journal: Journal of Clinical Oncology (2017)

e20624 Background: Lung cancer has one of the highest incidences of thromboembolic events (TEE) ranging from 8.4 to13.2%. Cisplatin-based chemotherapy in lung cancer is a well-established risk factor for TEE (11.8%). The incidence of TEE in lung cancer patients (pts) treated with nivolumab (nivo) is unclear. The objective of this study was to evaluate the incidence of TEE, risk factors and its impact on overall survival in lung cancer pts treated with nivo. Methods: This was a retrospective cohort study that included all lung cancer pts treated with nivo from April 2015 to October 2016 at our institution. Medical records were reviewed for incidence, timing, CTCAE grade, type and site of TEE, risk factors and patient demographics. Cox proportional hazard model was used to identify independent predictive factors for TEE. Risk factors with p &lt;0.15 in univariate analysis were included in multivariate model using a stepwise approach. Kaplan-Meier method was used to estimate overall survival (OS). Results: The cumulative incidence (CI) of TEE over a median follow up of 10.8 months after starting nivo was 18.4% (14/76 pts). Of the 14 pts who had TEE, 8 had deep vein thrombosis (DVT), 7 had pulmonary embolism (PE), 1 had concurrent DVT/PE and 2 had arterial thrombosis (AT). 28.6% (4/14) of pts experienced recurrent TEE resulting in 18 total episodes. Median time to TEE after starting nivo was 2.9 months (95% CI 1.9 - 8.4). Gender was the only covariate included in multivariate analysis that showed a significant association with TEE (Female vs Male HR 3.1, 95% CI 1.02 – 9.5, p= 0.045). At a median follow up of 31.8 months since diagnosis of lung cancer, pts who had TEE before receiving nivo had worse OS. TEE occurring after nivo had no impact on OS. Conclusions: The CI of TEE is significantly high at 18.4% in lung cancer pts treated with nivo. However, it had no impact on OS. Further studies are needed to determine the role of prophylactic anticoagulation in this high-risk population. [Table: see text]
The mutational landscape of circulating cell free DNA in patients with esophageal squamous cell carcinoma response and non-response to neoadjuvant chemotherapy.
Authors: Ruixiang Zhang, Ying Hu, Tao Zhou, Wenbo Han, Yanhui Chen, Xianben Liu, Shilei Liu, Yin Li, Henghui Zhang
Journal: Journal of Clinical Oncology (2018)

e16082 Background: This study was designed to explore the plasma cell free DNA (cfDNA) mutation profile in the patients with esophageal squamous cell carcinoma (ESCC) response and non-response to neoadjuvant chemotherapy. Methods: A total of 43 patients with ESCC were recruited for the study from the affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital) between April 2015 and July 2016. All subjects were received neoadjuvant chemotherapy and their blood samples were collected at baseline. The plasma cfDNA and leukocytes DNA were sequenced by cancer gene targeted NGS panel. Results: At baseline, the driver gene molecular mutation burden (MMB) of plasma cfDNA of ESCC patients in non-response group (n = 16 cases) was significantly higher than patients in response group (n = 27 cases)(P< 0.01). Moreover, principal component analysis showed the copy number variation (CNV) in plasma cfDNA was significantly different between ESCC patients that response and non-response to neoadjuvant chemotherapy. Compared with patients in response group, higher frequency CNV loss in GNAS, CDKN2A, UGT1A1, KIT, CDH1, and NTRK3 genes and CNV gain in PRKAR1A, KDR, BCR, ETV1, PIK3CB, ROS1, STK11, and PIK2R2 genes were detected in plasma cfDNA of patients in non-response group. CNV of plasma cfDNA had an area of 0.93 under the receiver operation characteristic curve for predicting the ESCC patient response to neoadjuvant chemotherapy. Conclusions: The molecular mutation burden and copy number variants of plasma cfDNA may be potential biomarkers for predicting the therapeutic response to neoadjuvant chemotherapy in esophageal squamous cell carcinoma patients.
Phase 1b/2 study of pexidartinib (PEX) in combination with radiation therapy (XRT) and temozolomide (TMZ) in newly diagnosed glioblastoma.
Authors: Howard Colman, Jeffrey J. Raizer, Tobias Walbert, Scott Randall Plotkin, Marc C. Chamberlain, Eric T. Wong, Vinay K. Puduvalli, David A. Reardon, Fabio Massaiti Iwamoto, Maciej M. Mrugala, Brett Johnson, Karthik Sonty, David Alan Karlin, Michael Pelayo, Marguerite Hutchinson, Henry Hsu
Journal: Journal of Clinical Oncology (2018)

2015 Background: PEX is an oral small molecule inhibitor of KIT and CSF1 receptor expressed on microglia, blood vessels, and glioblastoma (GBM) tumor cells. PEX achieved good tissue exposure in a prior recurrent GBM study, and preclinical studies indicate PEX may sensitize GBM to standard of care (SOC) therapy through effects on both tumor and microenvironment. Methods: Phase Ib determined the recommended Phase II dose (RP2D) with SOC XRT/TMZ. Phase II primary endpoint was progression free survival (PFS); secondary endpoints included overall survival (OS) and safety. Patient entry criteria were designed to replicate the RTOG 0525 control arm, which was used as a historical control. Results: The identified RP2D was PEX 400mg BID 5 days/week during and 7 days/week after SOC XRT/TMZ. Of the total RP2D population, 42 were evaluable for comparison and demonstrated similar characteristics to the RTOG 0525 control arm. As of November 2017, mPFS from registration is 6.7 months in PEX patients (95% CI 4.2, 10.2) vs. 7.5 months in historical controls. Estimated mOS for PEX is 15.4 months (95% CI 12.3, 20.7) vs. 18.9 months in controls. PEX was well tolerated, with most common drug-related toxicities including neutropenia and increased ALT/AST. MGMT unmethylated patients comprised 60% of the patients, with estimated mOS of 13.8 months (95% CI 12.3, 20.7) vs. 68% and estimated mOS of 16.6 months in historical controls. MGMT methylated patients comprised 40%, and mOS not yet reached vs. 32% and estimated mOS of 23.5 months in historical controls. Tumors with high expression of monocyte/macrophage marker CD163 and macrophage stimulating factor CSF1 trended to worse overall survival. mOS was 13.8 months for tumors with high expression of CD163 vs. 19.2 in tumors with low expression (p = .323). mOS was 12.3 months in tumors with high CSF1 expression vs. 19.2 in tumors with low (p = .328). Conclusions: PEX can be safely combined with SOC XRT/TMZ in newly diagnosed GBM. Results suggest minimal PEX activity when added to XRT/TMZ in an unselected GBM population for improving PFS and OS compared to robust, well-matched historical controls. Further investigation in relevant biomarker subgroups is ongoing. Clinical trial information: NCT01790503.
Abstract 12987: Annulus Deformity Index Obtained by Using Four-dimension Multidetector Computed Tomography in Patients With Severe Aortic Stenosis is Useful for Predicting Over Moderate Paravalvular Regurgitation Immediately After Transcatheter Aortic Valve Replacement
Authors: Harutoshi Tamura, Nobuo Iguchi, Yuko Utanohara, Keitaro Mahara, Itaru Takamisawa, Atsushi Seki, Makoto Suzuki, Tetsuya Tobaru, Morimasa Takayama, Jun Umemura, Tetsuya Sumiyoshi, Hitonobu Tomoike
Journal: Circulation (2015)

Background: Correct assessment of annulus diameter before transcatheter aortic valve replacement (TAVR) using multidetector computed tomography (MDCT) is important to minimize complications such as annulus rupture and paravalvular aortic regurgitation (PVR). The form of the annulus was previously reported to be oval, while the form of the SAPIEN XT valve was circular. However, the association between the ellipsoid degree of annulus and PVR remains unclear. A new technique of measuring variability in a region of interest through a cardiac cycle using voxel tracking for image data obtained by four-dimensional MDCT (4D-MDCT) was recently reported. This technology allows evaluation of changes of the annulus through the cardiac cycle, and detection of the cardiac phase of maximum and minimum annulus area correctly compared with conventional methods. In the present study, we examined whether evaluating the annulus ellipsoid degree obtained by 4D-MDCT is useful for predicting the occurrence of PVR immediately after TAVR. Methods: We performed 4D-MDCT in 72 patients with severe aortic valve stenosis before TAVR (mean age, 82 years; mean AVA, 0.61 cm 2 ). All patients were implanted SAPIEN XT. The 4D-MDCT image data were analyzed offline on a workstation using a voxel-tracking method (Ziosoft Inc.). We defined the deformity index calculated as the ratio of short axis diameter to large axis diameter of the annulus. Results: Mean R-R% of the maximum and minimum annulus area were 14.5% and 46.4%, respectively. Patients with PVR (n=20) had a significantly lower deformity index at maximum, minimum, and R-R 30% annulus area phase compared with no PVR patients. Receiver operating characteristic curve analysis showed that the deformity index at phase of maximum annulus area was an excellent marker for predicting PVR when compared to other cardiac phases (Figure). Conclusion: Low deformity index obtained using 4D-MDCT may be a useful marker for predicting PVR immediately after TAVR.
Initial tumor flare or mixed tumor response following single PD-1 vs. dual PD-1/CTLA-4 blockade in non-small cell lung cancer (NSCLC).
Authors: Monica Sheila Chatwal, Ben C. Creelan, Jhanelle Elaine Gray, Tawee Tanvetyanon
Journal: Journal of Clinical Oncology (2018)

e21037 Background: Initial increase in tumor size following immunotherapy can pose a therapeutic dilemma. This may signal treatment failure or may just represent immune reaction. Slight increase among limited lesions may manifest as mixed response. More pronounced increase is known as tumor flare or pseudo-progression. We sought to understand factors associated with flare or mixed response among patients who ultimately responded to immunotherapy. Methods: We pooled data across 8 prospective clinical trials of PD-1/PD-L1 inhibitor with or without CTLA-4 inhibitor at our institution. Patients were included if they were clinical benefit population – achieving partial or complete response (PR/CR) or stable disease ≥12 weeks as best response. Flare was defined as any increase in sum of RECIST target lesions. All initial CT scan occurred at 6 weeks and treatment beyond progression was allowed. Results: Of 247 patients treated, 79 met the criteria for clinical benefit population: 32 (41%) received dual inhibitors; 47 (59%) received single inhibitor. Median age was 67 years; 71% had adenocarcinoma. At 6-week assessment, tumor flare or mixed response occurred in 21 patients (27%). Those with tumor flare (N = 11) had mean increase of 13.3% (SD 3.6) in sum of target lesions; only 2 patients had ≥20% increase. Flare or mixed responses were significantly more prevalent with single inhibitor than dual inhibitors: 17/47 (36%) vs. 4/32 (13%), p= 0.022. Multivariable logistic regression incorporating age, gender, line of therapy, histology, size or number of target lesions showed that the receipt of dual inhibitors was the only factor predicting the absence of flare or mixed response: relative risk 0.39 (95% CI: 0.16-0.99). Patients who experienced flare or mixed response were less likely to achieve CR/PR and had worse median overall survival: 21.8 months vs. not reached, p= 0.013. Conclusions: Among clinical benefit NSCLC population, initial flare or mixed tumor response occurs much less frequently following dual inhibitors than single inhibitor. This finding suggests that when the phenomenon is entertained following treatment with dual inhibitors, it is more likely indicative of treatment failure.