tbuckley/cabot-search huggingface dataset:
The Mutational Features of Aristolochic Acid–Induced Mouse and Human Liver Cancers
Authors: Zhao‐Ning Lu, Qing Luo, Li‐Nan Zhao, Yi Shi, Na Wang, Lan Wang, Ze‐Guang Han
Journal: Hepatology (2019)

Background and Aims Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure–induced liver cancer is absent. This study aims to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA‐mediated genomic alterations that could be implicated in human cancers with AA‐associated mutational signature. Approach and Results We subjected mice, including phosphatase and tensin homolog ( Pten )‐deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl 4 . Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose‐dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl 4 ‐treated or Pten ‐deficient mice. AAI led to DNA damage and AAI‐DNA adduct that could initiate liver cancers through characteristic adenine‐to‐thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA‐associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI‐DNA adduct in 25.8% (16/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA‐implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA‐affected human tumors. Conclusions This study provides evidence for AA‐induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA‐associated human cancers, especially liver cancers.
The Mechanism of Anti–PD-L1 Antibody Efficacy against PD-L1–Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector
Authors: Wenjuan Dong, Xiaojin Wu, Shoubao Ma, Yufeng Wang, Ansel P. Nalin, Zheng Zhu, Jianying Zhang, Don M. Benson, Kai He, Michael A. Caligiuri, Jianhua Yu
Journal: Cancer Discovery (2019)

Abstract Blockade of PD-L1 expression on tumor cells via anti–PD-L1 monoclonal antibody (mAb) has shown great promise for successful cancer treatment by overcoming T-cell exhaustion; however, the function of PD-L1 on natural killer (NK) cells and the effects of anti–PD-L1 mAb on PD-L1+ NK cells remain unknown. Moreover, patients with PD-L1− tumors can respond favorably to anti–PD-L1 mAb therapy for unclear reasons. Here, we show that some tumors can induce PD-L1 on NK cells via AKT signaling, resulting in enhanced NK-cell function and preventing cell exhaustion. Anti–PD-L1 mAb directly acts on PD-L1+ NK cells against PD-L1− tumors via a p38 pathway. Combination therapy with anti–PD-L1 mAb and NK cell–activating cytokines significantly improves the therapeutic efficacy of human NK cells against PD-L1− human leukemia when compared with monotherapy. Our discovery of a PD-1–independent mechanism of antitumor efficacy via the activation of PD-L1+ NK cells with anti–PD-L1 mAb offers new insights into NK-cell activation and provides a potential explanation as to why some patients lacking PD-L1 expression on tumor cells still respond to anti–PD-L1 mAb therapy. Significance: Targeting PD-L1 expressed on PD-L1+ tumors with anti–PD-L1 mAb successfully overcomes T-cell exhaustion to control cancer, yet patients with PD-L1− tumors can respond to anti–PD-L1 mAb. Here, we show that anti–PD-L1 mAb activates PD-L1+ NK cells to control growth of PD-L1− tumors in vivo, and does so independent of PD-1. This article is highlighted in the In This Issue feature, p. 1325
Impact of maximum standardized uptake value (SUVmax) evaluated by 18-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG PET/CT) on survival for patients with advanced renal cell carcinoma.
Authors: Noboru Nakaigawa, Masahiro Yao, Ukihide Tateishi, Ryogo Minamimoto, Hiroji Uemura, Tomio Inoue, Yoshinobu Kubota
Journal: Journal of Clinical Oncology (2012)

4626 Background: In this era of molecular targeting therapy when various systematic treatments can be selected, prognostic biomarkers are required for the purpose of risk-directed therapy selection. Numerous reports of various malignancies have revealed that 18-Fluoro-2-deoxy-D-glucose ( 18 F-FDG) accumulation, as evaluated by positron emission tomography, can be used to predict the prognosis of patients. The purpose of this study was to evaluate the impact of the maximum standardized uptake value (SUVmax) from 18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG PET/CT) on survival for patients with advanced renal cell carcinoma (RCC). Methods: A total of 67 patients with advanced or metastatic RCC were enrolled in this study. The FDG uptake of all RCC lesions diagnosed by conventional CT was evaluated by FDG PET/CT. The impact of SUVmax on patient survival was analyzed prospectively. Results: The mean duration of observation was 461 days (range, 7-1229 days). The SUVmax before treatment of 67 patients ranged between undetectable level and 16.6 (mean 7.6±3.6). The patients with RCC tumors showing high SUVmax before treatment demonstrated poor prognosis (p&lt;0.001 hazard ratio 1.289, 95% CI 1.161-1.430). The median survival time of 36 patients with RCC showing SUVmax less or 7.0 was 1229±991 days, that of 21 patients with RCC showing SUVmax between 7.0 and 12.0 was 446±202 days, and that of 10 patients RCC showing SUVmax higher than 12.0 was 95±43 days (≤7.0 vs. 7.0&lt; ≤12.0 p=0.0052, 7.0&lt; ≤12.0 vs. 12.0&lt;:p=0.0169, log-rank test). SUVmax demonstrated a tendency to predict the survival compared with the Memorial Sloan-Kettering Cancer Center classification (p =0.015 vs 0.315, multivariate Cox analyses). Conclusions: The survival of patients with advanced RCC can be predicted by evaluating their SUVmax using FDG PET/CT. FDG PET/CT has potency as an “imaging biomarker” to provide helpful information for the clinical decision-making.
Abstract 13879: Drug-Coated Balloon Angioplasty for Recurrent Multimetal-Layered In-Stent Restenosis Impact of Previous Stent Fracture
Authors: Katsuya Miura, Kazushige Kadota, Seiji Habara, Akimune Kuwayama, Masanobu Ohya, Takenobu Shimada, Hidewo Amano, Shunsuke Kubo, Yusuke Hyodo, Suguru Otsuru, Takeshi Tada, Hiroyuki Tanaka, Yasushi Fuku, Tsuyoshi Goto
Journal: Circulation (2016)

Objective: We aimed to investigate the clinical outcomes of patients with recurrent drug eluting stent (DES) in-stent restenosis (ISR) (multimetal-layered ISR) treated with Drug-coated balloon (DCB). Backgrounds: Little is known about the efficacy of DCB treatment for multimetal-layered ISR. Methods: The study population comprised 123 patients (145 lesions) who underwent DCB angioplasty for multimetal-layered ISR lesions. Two serial angiographic follow-up were routinely planned for the patients (at 6 and 18 months after procedure). Results: Early follow-up angiography was performed for 132 lesions (91.0%). Recurrent restenosis occurred 36 lesions (27.3%) and target lesion revascularization (TLR) was performed for 26 lesions (19.7%). Late follow-up angiography was performed for 94 lesions (88.7%) of the remaining 106 lesions (excluding TLR lesions). Late recurrent restenosis occurred 25 lesions (26.6%) and TLR was performed for 16 lesions (17.0%). Proportion of right coronary artery (RCA) and incidence of previous stent fracture were significantly higher in patients with recurrent restenosis (43.3% vs. 66.7%, p = 0.008, and 6.0% vs. 30.0%, p = 0.001). Multivariate analysis revealed RCA ostial lesion (odds ratio [OR]: 4.28; 95% confidence interval [CI]: 1.06 to 22.0; p = 0.04) and previous deployed stent fracture (OR: 6.14; 95% CI: 2.04 to 23.1; p = 0.001) was an independent risk factor of recurrent restenosis. Cumulative event rates of TLR and MACE (All-cause mortality, myocardial infarction, and TLR) were significantly higher in previous stent fracture group (60.6% vs 27.0%, log rank p = 0.007 and 65.0% vs. 35.3%, log rank p = 0.007). Conclusion: Our study suggests that previous stent fracture was a risk factor of recurrent restenosis after DCB angioplasty for multimetal-layered ISR. Further study was necessary to identify the optimal treatment for multimetal-layered ISR with stent fracture.
Assessment of Deep Natural Language Processing in Ascertaining Oncologic Outcomes From Radiology Reports
Authors: Kenneth L. Kehl, Haitham Elmarakeby, Mizuki Nishino, Eliezer M. Van Allen, Eva M. Lepisto, Michael J. Hassett, Bruce E. Johnson, Deborah Schrag
Journal: JAMA Oncology (2019)

A rapid learning health care system for oncology will require scalable methods for extracting clinical end points from electronic health records (EHRs). Outside of clinical trials, end points such as cancer progression and response are not routinely encoded into structured data.To determine whether deep natural language processing can extract relevant cancer outcomes from radiologic reports, a ubiquitous but unstructured EHR data source.A retrospective cohort study evaluated 1112 patients who underwent tumor genotyping for a diagnosis of lung cancer and participated in the Dana-Farber Cancer Institute PROFILE study from June 26, 2013, to July 2, 2018.Patients were divided into curation and reserve sets. Human abstractors applied a structured framework to radiologic reports for the curation set to ascertain the presence of cancer and changes in cancer status over time (ie, worsening/progressing vs improving/responding). Deep learning models were then trained to capture these outcomes from report text and subsequently evaluated in a 10% held-out test subset of curation patients. Cox proportional hazards regression models compared human and machine curations of disease-free survival, progression-free survival, and time to improvement/response in the curation set, and measured associations between report classification and overall survival in the curation and reserve sets.The primary outcome was area under the receiver operating characteristic curve (AUC) for deep learning models; secondary outcomes were time to improvement/response, disease-free survival, progression-free survival, and overall survival.A total of 2406 patients were included (mean [SD] age, 66.5 [10.8] years; 1428 female [59.7%]; 2170 [90.2%] white). Radiologic reports (n = 14 230) were manually reviewed for 1112 patients in the curation set. In the test subset (n = 109), deep learning models identified the presence of cancer, improvement/response, and worsening/progression with accurate discrimination (AUC >0.90). Machine and human curation yielded similar measurements of disease-free survival (hazard ratio [HR] for machine vs human curation, 1.18; 95% CI, 0.71-1.95); progression-free survival (HR, 1.11; 95% CI, 0.71-1.71); and time to improvement/response (HR, 1.03; 95% CI, 0.65-1.64). Among 15 000 additional reports for 1294 reserve set patients, algorithm-detected cancer worsening/progression was associated with decreased overall survival (HR for mortality, 4.04; 95% CI, 2.78-5.85), and improvement/response was associated with increased overall survival (HR, 0.41; 95% CI, 0.22-0.77).Deep natural language processing appears to speed curation of relevant cancer outcomes and facilitate rapid learning from EHR data.
Application of the H<sub>2</sub>FPEF score to a global clinical trial of patients with heart failure with preserved ejection fraction: the TOPCAT trial
Authors: Peder L. Myhre, Muthiah Vaduganathan, Brian L. Claggett, Carolyn S.P. Lam, Akshay S. Desai, Inder S. Anand, Nancy K. Sweitzer, James C. Fang, Eileen O'Meara, Sanjiv J. Shah, Amil M. Shah, Eldrin F. Lewis, Jean Rouleau, Bertram Pitt, Scott D. Solomon
Journal: European Journal of Heart Failure (2019)
Role of chronic macrophage activation in patients with primary breast cancer.
Authors: Mya Sanda Thein, Alka Jain, Maria Clara Ingaramo, Antia Kohli, Neal Fedarko
Journal: Journal of Clinical Oncology (2012)

e13042 Background: Breast cancer progression has been associated with altered immune function and macrophage activation. Neopterin (Neo), a GTP metabolite, is secreted by interferon-γ activated macrophages. Chitotriosidase (ChT), a member of the glycosyl hydrolase family, is secreted by chronically activated macrophages. Osteopontin (OPN), a phosphorylated glycoprotein, produced by tumor and immune cells, is a modulator of macrophage activity and infiltration. OPN and neopterin have been studied separately as markers of solid malignancy including breast cancer. Methods: The purpose of our study was to test for correlations between breast cancer presence and stage with macrophage produced markers of acute (Neo), and chronic (ChT) macrophage activation as well as tumor/immune cell produced marker of macrophage infiltration (OPN). The study included 66 patients with primary breast cancer (Group I: 14 with metastatic disease) and 111 participants in a control group (Group II). Serum levels of OPN and Neo were measured by ELISA, while ChT levels in serum were measured by enzyme activity assays. Comparisons between groups were analyzed by Mann Whitney U test. Results: ChT and OPN levels were significantly higher in Group I compared to Group II (Table I). ChT was elevated at early stage disease while OPN increased with more advanced disease. Although Neo was not increased in patients with breast cancer, a subgroup analysis within group I demonstrated that it was higher in patients with metastatic disease (6.8 vs 9.3 p &lt;0.01). Conclusions: High levels of ChT in breast cancer patients may indicate that chronic macrophage activation plays a significant role in early breast cancer progression. OPN and Neo, elevated in late stage and metastatic disease, respectively may be useful biomarkers of tumor aggressiveness and/or metastatic progression. Further studies should be done to validate these biomarkers and understand the role of acute and chronic macrophage activation in cancer progression. [Table: see text]
Pseudoplatelets and apoptosis in Burkitt lymphoma
Authors: Barbara J. Bain
Journal: American Journal of Hematology (2019)

Pseudoplatelets are particles of similar size to platelets that are counted as platelets by automated instruments. They are a known feature of acute myeloid and acute lymphoblastic leukemia, being reported in 30% and 18% of cases, respectively, in a large series of patients.1 They have also been reported in occasional cases of hairy cell leukemia2 and lymphocytic lymphoma.3 Pseudoplatelets can also be a prominent feature of the leukemic phase of Burkitt lymphoma. The images shown are from a 57-year-old HIV-positive African man. His blood count showed: white cell count 55 × 109/L, hemoglobin concentration 96 g/L, and “platelet count” 39 × 109/L. A blood film showed that the true platelet count was much lower, the factitious elevation being due to the presence of pseudoplatelets. These were easily recognizable as fragments of the cytoplasm of lymphoma cells since they were basophilic and often contained vacuoles. The top image shows two Burkitt lymphoma cells and three pseudoplatelets, one with a prominent vacuole. In the presence of pseudoplatelets, impedance and light scattering counts are erroneous but a correct count can be obtained on instruments that can perform an immunological count. Alternatively, the ratio of platelets to pseudoplatelets can be determined from the blood film, and the count can then be corrected. Recognizing this phenomenon is important since dangerous thrombocytopenia may otherwise be missed. Another common feature of Burkitt lymphoma is a high rate of apoptosis, which may be reflected in the blood film. The lower image shows two intact lymphoma cells, two apoptotic cells, a pseudoplatelet and a smear cell. It may be postulated that the presence of numerous pseudoplatelets is linked to the presence of fragile apoptotic cells. The author declares no conflict of interest.
A phase II study of sorafenib in combination with cisplatin and 5-fluorouracil in the treatment of recurrent or metastatic nasopharyngeal carcinoma.
Authors: Cong Xue, Qitao Yu, Jian-ji Pan, Yuanlu Sun, Li Zhang
Journal: Journal of Clinical Oncology (2012)

5538 Background: Nasopharyngeal carcinoma (NPC) is a disease with distinctive epidemiology and clinical behavior compared with Head and neck cancer (HNC) and more common in South-East Asia. Sorafenib monotherapy has been shown modest anticancer activity in HNC and NPC (C Elser et al; JCO 2007). This study was to evaluate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) for patients with recurrent or metastatic NPC. Methods: A phase II, single arm clinical trial was conducted in three centers in China. Chemotherapy-naive histologically confirmed NPC patients with recurrent or metastatic disease were enrolled. Patients received oral sorafenib 400mg bid continuously until disease progression or unacceptable toxicity, cisplatin 80mg/m 2 intravenously (iv) on day 1-5, and 5-FU 400mg/m 2 iv infusion for 96 hours on day 1. Treatment was repeated every 21 days for a maximum of 6 cycles. Results: 54 patients were enrolled. Most patients were with bone metastases (70.0%), followed by liver (56%) and lung metastases (56%). The median chemotherapy administrated was 4.0 cycles (range, 2 - 6 cycles). The disease control rate (DCR) reached 90.7%, including one complete response (CR), 41 partial responses (PR) and 7 stable diseases (SD). Median PFS was 7.2 months (95% CI 6.8-8.4 months) and median OS was 11.8 months (95% CI 10.6-18.7 months). Tumor cavitation after treatment was observed in 32.1% of patients with lung metastases. Decreased percentage of contrast update in responder patients (PR and CR) with liver metastases was also observed by Contrast-Enhanced Doppler ultrasound. The major toxicities include hand foot syndrome (HFS), myelo-suppression and gastrointestinal reaction.Dose reduction of sorafenib was required in 22 patients (40.7%) and dose interruption in 14 patients (25.9%) because of toxicity. Conclusions: Sorafenib combined with cisplatin and 5-FU has an encouraging efficacy profile with tolerable toxicity. Further randomized studies are needed to confirm the clinical benefit of sorafenib combined with chemotherapy in recurrent or metastatic NPC.
The role of prognostic factors in metastatic renal cell carcinoma (mRCC) treated with targeted therapies (TT): Data from an Italian retrospective multicentric study.
Authors: Carmen Barile, Anna Paola Fraccon, Fable Zustovich, Fernando Gaion, Luigi Salvagno, Francesco Massari, Ignazio Martellucci, Caterina Modenesi, Mauro Giusto, Romana Segati, Alessandra Bearz, Chiara Ogliosi, Sveva Macrini, Marco Maruzzo, Francesca Larussa, Linda Nicolardi, Giorgio Bonciarelli, Daniela Menon, Alessandro Inno, Felice Pasini
Journal: Journal of Clinical Oncology (2013)

e15512 Background: Several prognostic factors in mRCC have been largely described in the literature. This study was aimed to verify whether some of these factors maintain their prognostic role in a cohort of pts treated in the community setting outside clinical trials. Methods: 902 pts with mRCC treated with TT from 2007 to December 2012 in 28 Italian centres were included in the analysis. Various potential prognostic factors were correlated with overall survival (OS). Results: Median age was 60 (range 25-89), 75% of pts were males; median OS (mOS) was 24 mo. Histology was clear cell (CC), CC with sarcomatoid component, papillary, NOS, not available in 82%, 6%, 4%, 4% and 4 %, respectively. mOS in the CC subgroup was 28 vs 12.5 mo of the non CC subset (p&lt;0.001). Nephrectomy was performed in 88% of the cases. mOS of these pts was 28 mo vs 6.5 in those without surgery (p&lt;0.001). The number of metastatic sites was &gt;2 in 43% of the pts. mOS of this group was 18 mo vs 31 mo of pts with ≤2 metastatic sites (p=0.0001). MSKCC risk was good in 32%, intermediate in 53% and poor in 15% of the pts. According to MSKCC risk score, mOS was 6.4, 24 and 49 mo in poor, intermediate and good subsets, respectively (p&lt;0.001). The small subset of pts (2%) with both thrombophilia and neutrophilia had a dismal mOS of 3 mo. PS (ECOG) was 0-1 in 90% of the pts; mOS of pts with PS ≥2 was 6 mo (p=0.0001). The findings of multivariate analysis are showed in the Table. Conclusions: The results of our survey confirm that clear cell histology, prior nephrectomy, number of metastatic sites, PS, MSKCC risk, platelets, and neutrophils count maintain their prognostic value also in mRCC pts treated with TT in the everyday clinical practice. [Table: see text]
Digital Rectal Examination Remains a Key Prognostic Tool for Prostate Cancer: A National Cancer Database Review
Authors: Jenna F. Borkenhagen, Daniel Eastwood, Deepak Kilari, William A. See, Jonathan D. Van Wickle, Colleen A. Lawton, William A. Hall
Journal: Journal of the National Comprehensive Cancer Network (2019)

Prostate cancer clinical stage T2 (cT2) subclassifications, as determined by digital rectal examination (DRE), are a historic method of staging prostate cancer. However, given the potential discomfort associated with prostate examination and the wide availability of other prognostic tests, the necessity of DRE is uncertain. This study sought to determine the prognostic value of the prostate cancer cT2 subclassifications in a contemporary cohort of patients.The National Cancer Database was used to identify a cohort of men with high-risk clinical T2N0M0 prostate cancer treated with external-beam radiotherapy and androgen deprivation therapies ± surgery from 2004 to 2010. We assessed overall survival from a landmark time of 10 months using Kaplan-Meier and log-rank test analysis. A multivariate proportional hazards model was used to estimate the simultaneous effects of multiple factors, including cT2 subclassification and other well-established prognostic indicators of overall survival in prostate cancer.A total of 5,291 men were included in the final analysis, with a median follow-up of 5.4 years. The cT2a, cT2b, and cT2c subclassifications demonstrated increasing hazard ratios of 1.00 (reference), 1.25 (95% CI, 1.07-1.45; P=.0046), and 1.43 (95% CI, 1.25-1.63; P<.0001), respectively, reflecting a higher probability of death with each incremental increase in cT2 subclassification. This finding was independent of other known prognostic variables on multivariate analysis.Results show that cT2 subclassifications had independent prognostic value in a large and contemporary cohort of men. cT2 classification remains an important, low-cost prognostic tool for men with prostatic adenocarcinoma. The clinical relevance of this test should be appreciated and accounted for by providers treating prostate adenocarcinoma.