tbuckley/cabot-search huggingface dataset:
Mutational status and thromboembolic risk in lung, gastrointestinal and breast cancer patients.
Authors: Marco Platania, Federico Nichetti, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2019)

e23147 Background: Cancer-Associated Thrombosis (CAT) is one of the most threatening complications of cancer. Recent evidences suggested a link between the molecular profile of solid tumors and the incidence of CAT. The aim of this study was to explore the relationship between the mutational status of breast, lung and gastrointestinal cancer patients and the risk of CAT. Methods: We retrospectively evaluated the molecular profile, analysed as per clinical practice, of all consecutive patients hospitalized at the National Cancer Institute’s Department in Milan from October 2017 to November 2018. Patients with previous thromboembolic events and patients under anticoagulant therapy at cancer diagnosis were excluded. Due to death as competing risk, the Fine and Gray proportional regression model was used to detect statistical association and estimate relative risk. Results: The resulting cohort consisted of 484 patients, of whom 47% had gastrointestinal cancers, 18% had lung cancer and 15% had breast cancer. Molecular investigations were available for 375 (77%) patients; in particular, a 50-gene Next Generation Sequencing (NGS) panel was performed on 148 (31%) patients. After a median follow up of 17 months, 118 patients (24%) exhibited clinical manifestations of thrombosis (i.e. deep vein thrombosis, pulmonary thromboembolism, splanchnic thrombosis, disseminated intravascular coagulation, arterial thrombosis) and 117 (24%) patients deceased without thrombotic events. A statistically significant association was observed between incidence of CAT and presence of TP53 (HR 0.50, p = 0.04), c-KIT (HR 4.30, p = 0.041), and SMAD4 (HR 3.19, p = 0.029) mutations. No significant association was detected for KRAS and MET gene mutations, even if HRs were &gt;2. Conclusions: In this study, the mutational status of TP53, SMAD4 and c-KIT genes was statistically associated to the risk of thrombosis. Due to methodological limits and low prevalence of mutations, large prospective studies are warranted, with the aim of better defining the role of oncogenes in CAT risk.
Abstract 15487: Building New Cellular Therapy for Heart Failure; Combined Strategy Using Adjuvant Drug and Somatic Stem Cells for Enhancement in Cytokine Paracrine Effects
Authors: Daisuke Mori, Shigeru Miyagawa, Satsuki Fukushima, Yoshiki Sawa
Journal: Circulation (2016)

Background: The efficacy of cell transplantation has been reported to be modest for heart failure and adjuvant drug combined with cell therapy may be one of options to improve the effectiveness in ...
Is it possible to effectively treat second-line gastric cancer, given the prognosis factors?
Authors: Georgy M. Manikhas, Rashida Orlova, Natalia P. Beliak, Svetlana I. Kutukova, Sanal Erdniev, Natalia V. Zhukova, Natalia V. Popova, Anastasia Ivanova, Nina Antimonik, Inna Avramenko, Ekaterina Zorina
Journal: Journal of Clinical Oncology (2019)

e15570 Background: Ramucirumab is the first anti-angiogenic targeted agent to demonstrate improved survival as monotherapy or in combination with CT among patients with disseminated stomach cancer. Methods: Under our supervision there were 24 patients: 12 men (50%) and 12 women (50%), from 29 to 72 years old, the median age was 52 years (95% CI 43.56-60.32). The median time to diagnosis of the 4th stage of the disease was 2 months (95% CI 0-11.44). All patients received 1 line of treatment; the median duration of 1-line therapy was 5 months (95% CI 4.00-6.83). Results: The duration of therapy with ramucirumab ranged from 2 to 16 months; median duration was 5.0 months (95% CI 3.00-7.44). The therapy with ramucirumab in 11 patients (45.83%) was followed by SD, in 3 patients (12.50%) - PR, in 4 patients (16.67%) - PD, and in 6 patients (25 , 00%) assessment of the effectiveness of therapy was not conducted due to the deterioration of the general condition during treatment. Thus, the ORR was 58.33%. The median overall survival was 18 months (95% CI 14–23). In order to identify adverse factors affecting overall survival, we constructed a Cox's regression model showing the dependence of overall survival on unfavourable prognosis factors. In general, the constructed model was reliable - p = 0.0013. The gender of the patients (p = 0.0642), the time before staging the 4th stage of the disease (p = 0.4312) and the duration of the 1st line therapy (p = 0.8675) did not have a significant effect on the survival of patients. Such factors as the patients' age (p = 0.0121), the localisation of the primary tumor (p = 0.0441), the differentiation of the tumor (p = 0.0095), the fact of removal of the primary tumor (p = 0.0133) had a significant impact, general status on the ECOG scale (p = 0.0250), the presence of anemia (p = 0.0192), damage to the peritoneum (p = 0.0022) and damage to metastases of more than 3 organs (p = 0.0062). Conclusions: An increase in OS in patients who received a combination of ramucirumab and paclitaxel can be considered clinically significant for this patient population and will allow considering this therapeutic regimen as a new standard of second line treatment of patients with poor prognosis of gastric cancer.
High <i>NPM1</i> mutant allele burden at diagnosis correlates with minimal residual disease at first remission in de novo acute myeloid leukemia
Authors: Sanjay S. Patel, Geraldine S. Pinkus, Lauren L. Ritterhouse, Jeremy P. Segal, Paola Dal Cin, Tamara Restrepo, Marian H. Harris, Richard M. Stone, Robert P. Hasserjian, Olga K. Weinberg
Journal: American Journal of Hematology (2019)

Abstract Acute myeloid leukemia (AML) with mutated NPM1 is a newly recognized separate entity in the revised 2016 WHO classification, and is associated with a favorable prognosis. While previous studies have evaluated NPM1 in a binary fashion, we recently demonstrated a significant independent negative prognostic effect of high NPM1 mutant allele burden (VAF) at diagnosis in a cohort of de novo AML patients. Although the importance of minimal residual disease (MRD) monitoring in NPM1 ‐mutated AML has been well characterized, the potential relationship between diagnostic allele burden and MRD is unknown. We retrospectively evaluated for MRD at first remission (CR1). We used either next‐generation sequencing (NGS) [n = 71], and/or immunohistochemistry (IHC) for mutant NPM1 (NPM1c) [n = 60], in a subset of patients from our recently examined cohort. We identified a statistically significant positive correlation between the VAF at diagnosis, and at CR1 (Spearman r = 0.4, P = .006), and enrichment for MRD in high diagnostic VAF patients ( P = .05), as previously defined. IHC‐positivity also correlated significantly with a higher median diagnostic NPM1 VAF (0.42 vs 0.39, P = .02), and with the VAF at CR1 (Spearman r = 0.7, P = .003). In multivariable analyses, both high diagnostic VAF ( P = .003) and MRD ( P = .02) were independent predictors of shorter event‐free survival (EFS). Our findings suggest a relationship between the NPM1 mutant allele burden at diagnosis, and the presence of MRD at first remission. Our findings support IHC as a potentially useful adjunctive tool for disease monitoring.
Abstract MP35: Relation of Left Ventricular Structure to Incident Heart Failure in African Americans: The Jackson Cohort of the Atherosclerosis Risk in Communities Study
Authors: Amir Azeem, Walter L Beard, Solomon Musani, Kenneth R Butler, Thomas H Mosley, Ervin R Fox
Journal: Circulation (2016)

Introduction: Studies in non-Hispanic whites suggest that early adaptive changes in cardiac structure due to hypertension may influence the development of heart failure (HF). The predictive value of left ventricular (LV) structure to incident acute decompensated HF (ADHF) has not been well-studied in African Americans (AA) despite the higher incidence of HF in this group. Hypothesis: We hypothesized that incidence of ADHF in AA varies according to cardiac structures and LV geometry type. Methods: The study sample included 1,737 participants who attended the third examination cycle of the Jackson cohort of ARIC between 1993 and1995 and underwent echocardiography, anthropometry and phlebotomy for glucose and lipids. Left atrial size, aortic root diameter (AOD), LV wall thicknesses and chamber dimensions, LV mass, LV mass index, LV hypertrophy (LVH) and LV geometric patterns [normal geometry, concentric hypertrophy, eccentric hypertrophy (EH), concentric remodeling] were determined by echocardiography. Cutoff for LVH was defined as above the 80th percentile of LV mass index. HF data was available up to December 31, 2011. In the primary analyses we adjusted for age, sex, smoking, diabetes, body mass index, systolic blood pressure, and use of hypertension medications in the multivariable model. Results: Over a follow-up period of approximately 18 years, 188 participants developed ADHF. Incident ADHF was significantly related to AOD [HR 1.42 (1.03, 1.97)], LV internal diameter in diastole (cm) [HR 1.60 (1.24, 2.05)], LV mass [HR 1.003 (1.002, 1.005)], LVM index [HR 1.01 (1.004, 1.02) and LVH [HR 1.62 (1.16, 2.27)]. In terms of LV geometry, EH was significantly related to incident ADHF in the multivariable model [HR 2.94 (1.70-5.10)]. Conclusion: In our large community-based sample of AAs, we observed that AOD, LV internal diameter in diastole, LV mass, LV mass index, LVH and EH geometry were significantly related to long-term incidence of ADHF independent of standard risk factors. These findings suggest echocardiography may be helpful in risk stratifying members of this high risk population for ADHF.
Light‐emitting diode–based photobiomodulation reduces features of allergic asthma in mice
Authors: Ji Hyeon Ryu, Yeonye Kim, Taehyung Kim, Young Mi Kim, Jaehoon Jung, Sang‐Yull Lee, Seung Eun Lee, Nam Gyun Kim, Yong‐Il Shin
Journal: Allergy (2019)

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Prognostic and predictive value of an immune-related adverse event among stage III melanoma patients included in the EORTC 1325/KEYNOTE-054 pembrolizumab versus placebo trial.
Authors: Alexander M. M. Eggermont, Michal Kicinski, Christian U. Blank, Mario Mandalà, Georgina V. Long, Victoria Atkinson, Stéphane Dalle, Andrew Mark Haydon, Mikhail Lichinitser, Muhammad Khattak, Matteo S. Carlino, Shahneen Kaur Sandhu, Susana Puig, Paolo Antonio Ascierto, Clemens Krepler, Nageatte Ibrahim, Sandrine Marreaud, Alexander Christopher Jonathan Van Akkooi, Caroline Robert, Stefan Suciu
Journal: Journal of Clinical Oncology (2019)

2517 Background: Several studies suggested that patients (pts) with an immune-related adverse event (irAE) during immunotherapy have better outcomes than those without. It remains uncertain whether these observations can be explained by guarantee-time bias or the role of irAE as an indicator of drug activity. Here, we investigated the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 trial that compared pembrolizumab and placebo in high-risk stage III melanoma pts. Methods: Eligible pts included adults with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as stage IIIA (lymph node metastasis &gt; 1 mm), IIIB or IIIC (without in-transit metastasis) and with no active autoimmune disease that required systemic treatment in past 2 years. We used a Cox model adjusted for sex, age, and stage with a time-varying covariate taking a value zero before the irAE onset and a value one afterwards to estimate the association between the occurrence of irAEs and RFS. Results: Consistent with the main analysis in the ITT population (n = 1019, Eggermont et al, NEJM, 2018), RFS was longer in the pembrolizumab than in the placebo arm (HR = 0.56, 98.4% CI: 0.43-074) among pts who started the treatment (n = 1011). The incidence of irAE on study was 37.3% in the pembrolizumab (n = 509) and 9.0% in the placebo arm (n = 502) and, in each treatment group, it was similar in males and females. The occurrence of an irAE was significantly associated with a longer RFS in the pembrolizumab arm (HR = 0.61, 95% CI: 0.39-0.95, P = 0.03). This was true for both males and females. However, in the placebo arm, no association was observed (HR = 1.39, 95% CI: 0.83-2.32, P = 0.21). Compared to the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater (P = 0.028) after an onset of an irAE (HR = 0.37, 95% CI: 0.24-0.57) than without/before an irAE (HR = 0.61, 95% CI: 0.49-0.77). Conclusions: In the EORTC 1325/KEYNOTE-054 study conducted in high-risk stage III melanoma pts, the occurrence of an irAE was strongly associated with a longer RFS in those treated with pembrolizumab, but not with placebo. Clinical trial information: NCT02362594.
Adjuvant chemotherapy for pathological stage I non-small cell lung cancer with high-risk factors for recurrence: A multicenter study.
Authors: Yasuhiro Tsutani, Kentaro Imai, Hiroyuki Ito, Takahiro Mimae, Yoshihiro Miyata, Norihiko Ikeda, Haruhiko Nakayama, Morihito Okada
Journal: Journal of Clinical Oncology (2019)

8500 Background: The role of adjuvant chemotherapy for pathological stage I non-small cell lung cancer (NSCLC) is controversial. The purpose of this study was to investigate the effect of adjuvant chemotherapy for pathological stage I NSCLC with high-risk factors for recurrence. Methods: Prospectively collected data from 1,278 patients with pathological stage I (8th edition) NSCLC undergoing lobectomy were retrospectively analyzed. High-risk factors for recurrence were determined by multivariable Cox proportional hazards model for recurrence-free survival (RFS). RFS, overall survival (OS), and cancer-specific survival (CSS) were compared between patients who received adjuvant chemotherapy and those who did not. Results: In multivariable analysis, age (≥70 y; hazard ratio [HR], 2.14), invasive component size ( &gt; 2 cm; HR, 1.60), visceral pleural invasion (HR, 1.81), lymphatic permeation (HR, 1.67), and vascular invasion (HR, 2.78) were identified as independent factors for RFS. In patients with high-risk factors for recurrence such as invasive component size of &gt; 2 cm, visceral pleural invasion, lymphatic permeation, or vascular invasion (high-risk group; n = 641), RFS was significantly different between patients who received adjuvant chemotherapy (n = 222; 5-y RFS, 81.4%) and those who did not (n = 418; 5-y RFS, 73.8%; P = 0.023). OS and CSS were also significantly better in patients who received adjuvant chemotherapy (5-y OS, 92.7%; 5-y CSS, 95.0%) than in those who did not (5-y OS, 81.7%; P &lt; 0.0001; 5-y CSS, 89.5%; P = 0.012). In patients without any high-risk factors for recurrence (low-risk group; n = 637), RFS was not significantly different between patients who received adjuvant chemotherapy (n = 83; 5-y RFS, 98.1%) and those who did not (n = 554; 5-y RFS, 95.7%; P = 0.30). OS and CSS were also not significantly different between patients who received adjuvant chemotherapy (5-y OS, 98.0%; 5-y CSS, 100%) and those who did not (5-y OS, 95.6%; P = 0.35; 5-y CSS, 99.4%; P = 0.52). Conclusions: Adjuvant chemotherapy may improve survival in patients with pathological stage I NSCLC who have high-risk factors for recurrence such as invasive component size of &gt; 2 cm, visceral pleural invasion, lymphatic permeation, or vascular invasion.
Immunobiology, preliminary safety, and efficacy of CPI-006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced cancers.
Authors: Jason J. Luke, John D. Powderly, Jaime R. Merchan, Minal A. Barve, Andrew N. Hotson, Mehrdad Mobasher, Long Kwei, Gabriel Luciano, Joseph J. Buggy, Emily Piccione, Richard A. Miller
Journal: Journal of Clinical Oncology (2019)

2505 Background: CPI-006 inhibits CD73, a nucelotidase that converts AMP to adenosine and functions as a lymphocyte adhesion molecule. CPI-006 is a humanized IgG1 FcγR binding-deficient antibody that binds to CD73+ T and B lymphocytes leading to activation of B cells and expression of CD69. This study investigates the immunobiology, safety, and efficacy of CPI-006 monotherapy and in combination with CPI-444, an adenosine A2A receptor (A2AR) antagonist (NCT03454451). Methods: Patients with relapsed solid tumors were treated in a 3 + 3 escalation study with 1, 3, 6 or 12 mg/kg CPI-006 (Q3w IV infusion) monotherapy or in combination with CPI-444 (100 mg, PO, BID). Flow cytometry was performed on blood samples for lymphocyte subset analysis and receptor occupancy. Results: 17 patients were enrolled; 11 monotherapy and 6 combination. CPI-006 was associated with Grade 1 infusion reactions occuring within 30 minutes of the first infusion and were eliminated by premedication with non-steroidals. No DLTs with monotherapy or combination therapy were seen. Receptor occupancy on peripheral lymphocytes was maintained for the full dosing interval at 12 mg/kg. Pharmacodynamic effects suggesting immune modulation were observed within 1 hr of infusion at all dose levels and included a decrease in peripheral blood CD73 pos B cells (mean reduction 86%, p &lt; 0.05), increased CD73 neg CD4 T cells (mean increase 37%, p &lt; 0.01), and decreased CD8 T cells (mean reduction 20%, p &lt; 0.01) compared to baseline. Overall, CD4:CD8 ratios were increased. Tumor regression was observed in a prostate cancer patient after 5 cycles of monotherapy at 6 mg/kg; peripheral B cells partially returned by the second cycle and reached a new homeostatic level through subsequent cycles. No change in serum immunoglobulins were observed. Conclusions: CPI-006 induces a rapid lymphocyte redistribution, including a transient reduction of circulating CD73 pos B cells suggesting redistribution to lymphoid tissues, and an increased CD4:CD8 ratio, consistent with increased T H effector/memory cells in the blood. The treatment has been well-tolerated, and there is early evidence of anti-tumor activity of CPI-006 monotherapy. Clinical trial information: NCT03454451.
The efficacy and safety of extended use of endostatin plus platinum-based doublet chemotherapy in patients with advanced non-small cell lung cancer: An analysis of a 10-year retrospective study.
Authors: Jing Zhao, Jianhua Wang, Xueqi Zhao, Yi Cheng, Qingsong Xi, Qi Mei, Guangyuan Hu
Journal: Journal of Clinical Oncology (2019)

e20523 Background: Endostatin is a potent inhibitor of angiogenesis developed and approved in China. We aimed to evaluated the efficacy and safety of extended use of endostatin with platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC) in this study. Methods: We performed a retrospective analysis of chemotherapy-naïve patient with stage IIIB-IV or recurrent NSCLC who had been treated with first-line chemotherapy plus endostatin between January 2008 and June 2018. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The Cox proportional hazards regression model was used to assess the prognostic importance of risk factors (age, gender, smoking status, ECOG performance status, stage, histology, EGFR gene status and endostatin cycles). Results: A total of 105 patients were eligible for analysis. The median (range) cycles of chemotherapy with endostatin were 4 (2-19). The objective response rate and disease control rate were 45.1% and 87.3%, respectively. Under multivariate analysis, non-smoking status and extended use of endostatin (≥4 cycles) were significantly correlated with better PFS, and squamous cell cancer and extended use of endostatin (≥4 cycles) were significantly correlated with better OS. The median (95% CI) PFS and OS for patients with extended use of endostatin (≥4 cycles) or not were 8.2 (5.6-12.7) vs. 5.3 (2.8-7.3) months, HR = 0.63, p= 0.014, and 21.2 (6.8-37.7) vs. 11.9 (4.1-23.9) months, HR = 0.77, p= 0.028, respectively. Patients with squamous cell cancers significantly benefited from the extended use of endostatin (≥4 cycles) (n = 55, p= 0.043) but not adenocarcinoma (n = 46, p= 0.089). Hematologic and gastrointestinal toxicities occurred more frequently in patients who received extended use of endostatin (≥4 cycles), but no statistically significant difference was detected in those who did not. Conclusions: In patients with advanced/recurrent NSCLC, extended use of endostatin (≥4 cycles) could provide additional survival benefits and satisfactory toxicity profiles, especially for those with squamous cell cancer, which merits further evaluation in a larger prospective study.
Cell cycle progression score differentiates indolent from aggressive prostate cancer in men diagnosed by TURP.
Authors: Jack M. Cuzick, Steven Stone, Saradha Rajamani, Henrik Møller, Daniel M. Berney, Todd Cohen, Peter T. Scardino
Journal: Journal of Clinical Oncology (2019)

e16560 Background: Improved selection of men with localized prostate cancer for conservative management remains a clinical need. We previously showed that the Cell Cycle Progression (CCP) score provides a significant amount of independent prognostic information in men with prostate cancer who opt for conservative management. Here, we extend those results by evaluating the performance of the CCP score in a newly analyzed cohort of conservatively managed men and in a large pooled cohort of men who deferred initial curative therapy. Methods: The CCP score (based on 31 CCP genes and 15 housekeepers) was derived from FFPE tumor sections as previously described. For this study, the CCP score was evaluated in several independent cohorts: 1) a newly studied retrospective cohort from the U.K. diagnosed by a transurethral resection of the prostate (TURP1B, N = 192); 2) a previously studied cohort from the U.K. diagnosed by TURP (TURP1A, N = 200); and 3) two previously studied cohorts from the U.K. diagnosed by needle biopsy (TAPG1, N = 180 and TAPG2, N = 585). The combined cohort included 1,157 conservatively managed men with complete clinical data. Median follow-up for all cohorts was 9.8 years. Hazard ratios (HR) are for a one-unit change in score, and the endpoint for this study was disease specific mortality (DSM). Results: The CCP score was a highly significant predictor of DSM in TURP1B. The univariate HR was 2.96 (95% CI 2.32, 4.04, p = 3.6x10 -9 ), and the multivariate HR after adjusting for CAPRA was 2.27 (95% CI 1.59, 3.23, p = 1.3x10 -5 ). These results are very similar to the HRs obtained in TURP1A cohort, and the test for HR heterogeneity was not significant after adjusting for CAPRA (p = 0.30). In the pooled analyses, the interaction between CCP and cohort was not significant after adjusting for clinical variables. Interestingly, sample type (TURP vs. Needle biopsy) was prognostic even after adjusting for clinical variables. Summaries of the pooled analyses are given in Table. Conclusions: The CCP score adds a significant amount of independent prognostic information for outcome in conservatively managed men. As such, it can be used to help select appropriate patients for deferred treatment regimens like AS or watchful waiting. [Table: see text]