tbuckley/cabot-search huggingface dataset:
Illumina® - based multiplexed genotyping indicates a role for altered DNA repair and genomic maintenance in susceptibility to benzene toxicity
Authors: Qing Lan, Martyn T. Smith, Min Shen, Luoping Zhang, Guilan Li, Roel Vermeulen, Stephen M. Rappaport, Richard Hayes, Martha Linet, Blanche P. Alter, Songnian Yin, Meredith Yeager, Robert Welch, Stephen Chanock, Nathaniel Rothmann
Journal: Cancer Research (2006)

2032  Background: Benzene is a human hematotoxin and leukemogen, with a complex mechanism of action. High throughput genotyping of single nucleotide polymorphisms (SNPs) with an Oligo Pool (OPA) by Illumina® can analyze a large number of SNPs potentially related to benzene hematotoxicity. Methods: We studied 1,442 SNPs (51% intronic, 32% exonic, 12% in promoter regions, and 5% in serine, threonine, and proline (STP) regions) in 413 genes involved in metabolism, DNA repair, cell cycle control and other pathways in an OPA based on previously sequenced candidate genes in the SNP500Cancer project ( ). We examined the association of these SNPs with benzene hematotoxicity in 242 workers exposed to benzene and 122 unexposed controls in a cross-sectional study carried out in China. Linear regression was used to analyze the relationship between genetic polymorphisms and total White Blood Cell (WBC) count, adjusting for potential confounders and occupational exposure to benzene and toluene among exposed workers. Interaction was tested by adding a multiplicative term between the SNP (variant carriers vs. wild genotype carriers) and benzene exposure (yes/no) into a model with all subjects. The Benjamini-Hochberg False Discovery Rate (FDR) method was used to control for multiple comparisons. Results: One or more SNPs in 15 genes were associated with altered WBC counts among workers exposed to benzene (FDR adjusted p values
Changing the landscape of germline testing in patients with pancreatic adenocarcinoma.
Authors: Aly Athens, Lisa Amacker-North, Kelly Warsinske, Kunal C. Kadakia, Edward S. Kim, Mohamed E. Salem, Sara Elrefai
Journal: Journal of Clinical Oncology (2020)

676 Background: Results from the POLO trial demonstrated the benefits of PARP inhibition in patients (pts) with germline BRCA-mutated metastatic pancreatic cancer (PC). In 2018, ASCO and NCCN updated their guidelines to recommend that pts with a personal history of PC undergo germline testing. We examined referral patterns and frequency of germline pathogenic variants in pts with PC. Methods: A retrospective review was performed of PC pts seen at the Levine Cancer Institute (LCI) Center for Genetics between January 2010 and September 2019. Descriptive analyses were completed on demographics and appointment outcomes. Results: A total of 201 PC pts were referred; 20 canceled and 14 no-showed their appointment. The remaining 167 were seen and included in this analysis. Most pts (59%) were referred after July 2018. The median age was 65 years (range 32-90) and 19% were &lt; 50 years. The majority of pts were female (61%). Race was most often reported as white (72%) followed by black (20%). Reported family histories were as follows: 28 (17%) claimed at least one first-degree relative with PC; 54 (32%) claimed a first, second, or third-degree relative with PC; 24 (14%) had no known family history of PC; and 95 (57%) claimed a first-degree relative with another cancer (breast [37], prostate [25], colon [18], ovarian [9], uterine [6], and gastric [2]). Germline testing was pursued by 138 (83%) pts: 25 (18%) were found to have a pathogenic variant and 50 (36%) a variant of uncertain significance. Pathogenic variants were most commonly identified in ATM (24%), BRCA2 (20%), PALB2 (12%), and CDKN2A (8%). Variants were also observed in DIS3L2, HOXB13, MITF, MUTYH (heterozygote), NTHL1 (compound heterozygote), RAD50, PRSS1, and SDHA. Among pts that had a pathogenic variant, cascade testing was performed in 11 families (44%) for 29 individuals. Conclusions: Our data suggest that the referral of PC pts to genetics has increased following updated ASCO/NCCN guidelines. However, improved adherence to genetic counseling is needed. ATM and BRCA2 were the most common germline mutations observed. More effort to increase awareness of genetic testing and its potential implications for pts and their families is warranted and might reduce cancellations and missed visits.
Clinical characteristics and outcomes of patients with advanced hepatocellular carcinoma treated with immunotherapy: A “real world” retrospective study.
Authors: Adel Chergui, Eswar Gadde, Ana Acuna-Villaorduna, Rafi Kabarriti, Sanjay Goel, Andreas Kaubisch
Journal: Journal of Clinical Oncology (2020)

e16644 Background: Advanced hepatocellular carcinoma (HCC) is an aggressive malignancy with dismal prognosis. Newer agents, including immunotherapy (IO), have been granted accelerated approval for patients previously treated or unable to tolerate sorafenib. However, information outside clinical trials is scarce. This study aims to describe clinical characteristics and outcomes of HCC patients treated with IO. Methods: HCC patients treated with IO were identified using the institutional software, Clinical Looking Glass. Data regarding demographics, clinical and treatment characteristics were collected by chart review. Neutrophil/lymphocyte ratio (NLR) and AFP were collected at IO treatment initiation and considered low if below 4 and 400, respectively. Progression-free survival (PFS) was defined as time from treatment initiation to progression of disease or death, and overall-survival (OS) as time from IO initiation to death from any cause. Disease characteristics were analyzed using descriptive statistics, PFS and OS were plotted using Kaplan-Meier curves. Results: 52 patients with a median age of 64.5 years and male predominance (38, 73.1%) were identified. There were 24 (54.5%) Hispanics, 9 (20.5%) Non-Hispanic Blacks, 7 (15.9%) Non-Hispanic White and 4 (9.1%) Asians. Cirrhosis present in 41 (83.7%), median MELD of 8 (IQ: 7-10). 37 (77.1%) patients had ECOG 0-1. Hepatitis B and C and B infection were encountered in 12 (24.5%) and 22 (44%) patients, respectively. Intravascular invasion present in 16 (34.8%) and extrahepatic metastases in 7 (14.9%). Local treatment was provided to 29 (59.2%) and radiation to 14 (28.6%). First line treatment (tx1) was Sorafenib in 29 (55.8%) and Nivolumab in 21 (40.4%). Nivolumab was second line treatment or beyond (tx2) in 31 (59.6%). Median PFS was 6.2 (3.1-10.6) months and it did not differ between tx1 and tx2 (8 vs 5.9 months, p = 0.90). Median OS was 13.2 months; there was a tendency towards higher survival rates in patients that were treated in tx2 (11.8 vs 14.3 months, 0 = 0.59) and in patients with low NLR (14.8 vs 9.2 months, p = 0.14). Median OS was higher in patients with low AFP at IO treatment initiation (15.7 vs. 9.2 months, p = 0.03). Conclusions: In this multiethnic cohort, the “real world” experience of the benefit of IO in HCC is encouraging, with a median OS exceeding one year. NLR showed potential as a possible biomarker. Expanded data may elucidate the differences if any, between use of IO as front vs. second line therapy, in PFS and OS.
Irreversible electroporation of the bile duct in swine: A pilot study.
Authors: Sang Hyun Kim, Jae Min Lee, Kang Won Lee, Sang Hoon Kim, Se Hyun Jang, Han Jo Jeon, Seong Ji Choi, Hyuk Soon Choi, Eun Sun Kim, Bora Keum, Yoon Tae Jeen, Hoon Jai Chun, Hong Sik Lee, Chang Duck Kim
Journal: Journal of Clinical Oncology (2020)

541 Background: Irreversible electroporation (IRE) is a relatively new ablative method. However, the application of IRE ablation has not been attempted for the treatment of biliary disease. Minimally invasive approach using endoscopic retrograde cholangio-pancreatography (ERCP) can be a novel therapeutic modality for IRE ablation. In this study, we investigated the feasibility and effect of endoscopic IRE for biliary tract in animal model. Methods: A new catheter electrode was developed for endoscopic IRE ablation of biliary tract. The electrode for IRE ablation has two band-shaped electrodes on catheter tip. We performed ERCP and endoscopic IRE ablations on normal common bile duct in 6 Yorkshire pigs. Experimental parameters of IRE were 500V/cm, 1000V/cm and 2000V/cm (under 50 pulses, 100 µs length). Animals were sacrificed after 24 hours and ablated bile duct were collected. H &amp; E stain, immunohistochemistry and western blot were performed. Results: Well-demarcated focal color changes were observed on the mucosa of the common bile duct under all experimental parameters. After IRE ablation, bile duct epithelium was disappeared around ablated area and it showed fibrotic change in H&amp;E stain. Depth of change after IRE was different between each experimental parameters. Apoptotic change of bile duct was localized around mucosa in 500V. Diffuse transmural fibrosis of bile duct was shown after IRE ablation with 2000V. TUNEL immunohistochemistry showed the cell death of bile duct mucosa and submucosa along the electrode. Within 24 hours, no complication was observed in pigs after endoscopic IRE ablation. Conclusions: Endoscopic IRE ablation using ERCP was successfully performed on common bile duct by using catheter-shaped electrode. It can be a potential therapeutic option as minimally invasive ablation for treatment of biliary tumors.
Basal cell carcinoma: an emerging epidemic in women in Iceland*
Authors: J.A. Adalsteinsson, D. Ratner, E. Olafsdóttir, J. Grant‐Kels, J. Ungar, J.I. Silverberg, A.K. Kristjansson, J.G. Jonasson, L. Tryggvadottir
Journal: British Journal of Dermatology (2020)

An epidemic of basal cell carcinoma (BCC) has led to a significant healthcare burden in white populations. To provide an update on incidence rates and tumour burden in an unselected, geographically isolated population that is exposed to a low level of ultraviolet radiation. This was a whole‐population study using a cancer registry containing records of all cases of BCC in 1981–2017. We assessed BCC incidence according to age, residence and multiplicity and assessed trends using join‐point analysis. Age‐standardized and age‐specific incidence rates were calculated along with cumulative and lifetime risks. During the study period, the age‐standardized incidence rates increased from 25·7 to 59·9 for men, and from 22·2 to 83·1 for women (per 100 000). Compared with the single‐tumour burden, the total tumour burden in the population was 1·72 times higher when accounting for multiplicity. At the beginning of the study period, the world‐standardized rates in men and women were similar, but by the end of the study period the rates were 39% higher in women (83·1 per 100 000, 95% confidence interval 77·9–88·3) than in men (59·9 per 100 000, 95% confidence interval 55·6–64·2). This increase was most prominent in women on sites that are normally not exposed to ultraviolet radiation in Iceland: the trunk and legs. This is the only reported population in which the incidence of BCC is significantly higher in women than in men. The period of notable increase in BCC lesions correlates with the period of an increase in tanning beds and travel popularity. The high multiplicity rates suggest that the total tumour burden worldwide might be higher than previously thought. What is already known about this topic? Basal cell carcinoma (BCC) is becoming an increasing healthcare burden worldwide, especially in white populations. Recent population studies have reported a rapid increase in incidence among younger individuals, especially women. What does this study add? Iceland is the only reported population in which the incidence of BCC is significantly higher in women than in men, and there does not seem to be a clear relationship between latitude and BCC incidence in Europe. Men might be comparatively protected in the northern low‐ultraviolet environment, with tanning beds and travel abroad likely playing important roles in the observed incidence increase, especially in women. The high multiplicity rates suggest that the total tumour burden worldwide might be higher than previously thought. Linked Comment: Pandeya. Br J Dermatol 2020; 183:799–800.
Rate of conversion from unresectable to resectable metastatic colorectal cancer (mCRC) in real-world patients (RWP) treated with FOLFIXIRI ± bevacizumab: A population-based retrospective cohort study.
Authors: Tayyaba Bhatti, Michael Moser, Jon Tan, Adnan Zaidi, Duc Le, Haji I. Chalchal, John Shaw, Selliah Kanthan, mussawar iqbal, Yigang Luo, Kamal Haider, Tehmina Asif, Dueck Dorie-Anna, Dilip Gill, Nathan Ginther, Shahid Ahmed
Journal: Journal of Clinical Oncology (2020)

21 Background: Recent evidence from randomized trials suggests that FOLFOXIRI (5FU, oxaliplatin, and irinotecan) ± bevacizumab is associated with higher response rates with a potential for conversion of unresectable to resectable disease in mCRC. Yet limited evidence is available about efficacy and safety of this regimen in RWP with mCRC. The current study aims to evaluate conversion rate and safety of FOLFOXIRI ± bevacizumab in RWP with unresectable mCRC. Methods: Each year about 175 patients are diagnosed with mCRC in Saskatchewan. Patients who were diagnosed with unresectable mCRC between Jan 2015 to Dec 2018 and received FOLFOXIRI ±bevacizumab were assessed. Kaplan Meier survival methods and log rank test were performed. Logistic regression analysis was performed to assess factors correlate with conversion. Results: 28 eligible patients with median age of 51 yrs (IQR:39-60) and M:F of 11:16 were identified. 42% patients had a comorbid illness, and 43% had WHO performance status of 0. 39% had rectal cancer, 46% had extrahepatic disease and 46% had bilobar liver metastases. 58% patients had a positive response to therapy, 60% had grade 3/4 toxicity &amp; 32% required hospital admission. No treatment-related mortality was noted. 54% patients underwent metastasectomy (liver 73%, peritoneum and or ovaries 20%, lung 6%). 68% had primary tumor resection, 29% received rectal radiation, 21% had ablation and 18% had second surgery for recurrence. At 4 years 50% patients are alive. Median progression free survival of patients who underwent surgery is 18 (95%CI:11.3-24.7) vs. 11 months (4-18.1) without surgery (P = 0.28). Median overall survival of patients with surgery is 33 (17.5-48.5) vs. 16 months (8.3-23.7) without surgery (P = 0.03). Positive response to treatment is correlated with conversion (odd ratio 21.7, p = 0.002). Conclusions: In the real world setting younger patients with good performance status received FOLFIRINOX ± bevacizumab. Despite high rates of toxicity, more than half of patients were able to undergo surgery. A positive response to treatment significantly correlates with metastasectomy.
Effect of proton pump inhibitors on the occurrence and development of gastric cancer and the polarization of macrophages in the microenvironment to M2-type.
Authors: Xiao-Qing Lu, Shengxiao Zhang, Huan-Hu Zhang
Journal: Journal of Clinical Oncology (2020)

437 Background: Long-term use of Proton pump inhibitors was associated with an increased gastric cancer(GC) risk in subjects even after HP eradication therapy. In contrast some basic research showed that PPI inhibited the growth of GC. In the tumor-microenvironment (TME), macrophages that are recruited around the tumor are activated to form the tumor-associated macrophages (TAMs), which are the most abundant mononuclear cells in the tumor infiltrating leukocytes. Many studies have shown that TAMs are associated with poor prognosis of tumors. Methods: Immunohistochemistry was used to detect the phenotype of macrophages in patients with gastric cancer treated with PPI or without PPI. Transcriptomics sequencing analyzed the signal pathways that were highly expressed in PPI-treated gastric cancer for further exploring the mechanism of PPI's main role in gastric cancer cells. In vitro, explore the effects of PPI on gastric cancer cells and the next step on macrophages. The effects of PPI on the growth of gastric cancer and the degree of infiltration and phenotype transformation of macrophages were verified by in vivo experiments. Results: In the gastric cancer tissues treated with PPI, the macrophage phenotype is mostly M2 type, thereby exerting a cancer promoting effects. Transcriptome results showed high expression of genes associated with endoplasmic reticulum stress in gastric cancer tissues after PPI treatment, compared with patients who were not treated with PPI. Among them, GRP78 is a classic marker of endoplasmic reticulum stress. It was not only highly expressed in gastric cancer treated by PPI, but also acted on macrophages through exosomes secreted by gastric cancer cells, and caused macrophage to polarize to M2. Conclusions: PPI caused GC cells to overexpress GRP78 which was secrete into the microenvironment through exosomes, thereby transforming macrophages into M2 type under the action of GRP78. Finally M2 type macrophages promoted the progression of gastric cancer.
Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice
Authors: Simone Ragusa, Borja Prat-Luri, Alejandra González-Loyola, Sina Nassiri, Mario Leonardo Squadrito, Alan Guichard, Sabrina Cavin, Nikolce Gjorevski, David Barras, Giancarlo Marra, Matthias P. Lutolf, Jean Perentes, Emily Corse, Roberta Bianchi, Laureline Wetterwald, Jaeryung Kim, Guillermo Oliver, Mauro Delorenzi, Michele De Palma, Tatiana V. Petrova
Journal: Journal of Clinical Investigation (2020)

Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1) was reduced in desmoplastic APC-mutant human CRCs. In genetic Apc-mutant mouse models, loss of Prox1 promoted the growth of desmoplastic, angiogenic, and immunologically silent tumors through derepression of Mmp14. Although chemotherapy inhibited Prox1-proficient tumors, it promoted further stromal activation, angiogenesis, and invasion in Prox1-deficient tumors. Blockade of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2) combined with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming of Prox1-deficient tumors, destroyed tumor fibrosis, and unleashed T cell–mediated killing of cancer cells. These results pinpoint the mechanistic basis of chemotherapy-induced hyperprogression and illustrate a therapeutic strategy for chemoresistant and desmoplastic CRCs.
PCSK9のモノクローナル抗体であるエボロクマブ(AMG145)の心血管高リスクの高コレステロール血症でスタチン治療を受けている日本人患者における効果 第2相湯川研究からの最初の結果
Authors: Hirayama Atsushi, Honarpour Narimon, Yoshida Masayuki, Yamashita Shizuya, Huang Fannie, M Wasserman Scott, Teramoto Tamio
Journal: Circulation (2014)
Abstract 13937: Proton Therapy Preserves Acute Left Ventricular Ejection Fraction Relative to Conventional X-Ray-Based Therapy in Breast Cancer
Authors: Shruti Siva Kumar, Julie Bradley, Brandon Terracino, Alex Waler, Eric Zeng, Christopher Klassen, Michael Rutenberg, Xiaoying Liang, Natalie Lockney, Raymond Mailhot, Nancy Mendenhall, Walter O’Dell
Journal: Circulation (2019)

Introduction: Radiotherapy (RT) yields a survival benefit in breast cancer treatment but can also result in radiation exposure to the heart. RT using protons (PT) can reduce the mean heart dose (MH...
Efficacy and safety of lenvatinib (LEN) in Korean patients (pts) with advanced hepatocellular carcinoma (aHCC): Multicenter retrospective analysis.
Authors: Jaekyung Cheon, Changhoon Yoo, Yeonghak Bang, Hong Jae Chon, Baek-Yeol Ryoo
Journal: Journal of Clinical Oncology (2020)

490 Background: LEN has demonstrated the efficacy and safety in pts with aHCC as first-line treatment in the pivotal REFLECT trial. Further evaluation in real-world setting is necessary to measure the clinical outcomes of LEN in daily practice. Methods: This is a multicenter retrospective analysis from 3 Korean referral cancer institutions. Between September 2018 and August 2019, a total of 74 pts received LEN for the management of BCLC B or C aHCC, and 66 pts who had at least one follow-up visit after the start of LEN were included in this analysis. Results: Median age was 58 years (range, 19-81), and 46 pts (69.7%) were male. Baseline characteristics were as follows; Child-Pugh class A/B/C in 46 (69.7%)/14 (21.2%)/6 (9.1%), BCLC B/C/D in 1 (1.5%)/63 (95.5%)/2 (3.0%), prior systemic therapy in 25 (37.9%) including 14 (21.2%) with prior immune checkpoint inhibitors (ICIs). LEN was used as first/second/third to fourth lines of therapy in 41 (62.1%)/13 (19.7%)/12 (18.2%) pts, and 27 (40.9%) had extensive disease extent excluded in the REFLECT trial. With a median follow-up duration of 4.8 months (95% CI, 3.4–6.1), the median PFS and OS were 4.6 (95% CI, 3.2-6.0) and 7.5 months (mo) (95% CI, 3.7–11.2), respectively, in overall pts: first-line setting, 4.2 (95% CI, 3.2-5.2) and 6.5 mo (95% CI, 5.0-8.1), respectively; ≥ second-line setting, 6.1 mo (95% CI, 3.6–8.5) and not reached, respectively. In pts with prior ICIs, median PFS was 6.1 mo (95% CI, 1.8-8.4) and median OS was not reached. According to the RECIST v 1.1, response rates and disease control rate were 12.1% and 71.2%, respectively, in overall pts. The most common grade 3-4 toxicities were hyperbilirubinemia (n=9, 13.6%), AST elevation (n=5, 7.6%), diarrhea (n=4, 6.1%) and fatigue (n=4, 6.1%). Conclusions: LEN was effective and well tolerated in pts with aHCC in Korean real-life setting.
Distinct clinical characteristics of young-onset pancreatic cancer patients.
Authors: Suleyman Yasin Goksu, Syed Mohammad Ali Kazmi, Nina Niu Sanford, Todd Anthony Aguilera, David Hsieh, Aravind Sanjeevaiah, Udit Verma, Radhika Kainthla, Leticia Khosama, Mary Claire Maxwell, Benjamin David Fangman, Jonathan Scott Bleeker, Muhammad Shaalan Beg, Muslim Atiq
Journal: Journal of Clinical Oncology (2020)

674 Background: Young-onset pancreatic adenocarcinoma (YOPC) is uncommon but there are limited studies for these patients. We used a population based registry to compare the characteristics and outcomes of young-onset vs. older patients with pancreatic adenocarcinoma. Methods: We selected the patients with pancreatic adenocarcinoma from the SEER registry diagnosed between 2004 and 2015. Cases with age of diagnosis less than 50 were termed young-onset pancreatic cancer. Stage 4 patients were excluded. We compared baseline characteristics of YOPC vs. older using Chi-square. Kaplan Meier and Cox regression were used for survival analysis of these patients. Results: Of 28,904 patients, 1,415 (4.9%) had YOPC while 27,489 (95.1%) were older. YOPC were more likely to have stage 3 compared to older patients with PC (31.6% vs. 25.3%). YOPC had a higher rate of surgery than older patients (40% vs. 29.1%, p &lt; 0.001), were more likely to be male, black and of Hispanic ethnicity. The primary tumor location was not different between the two groups. Overall survival (OS) was higher in YOPC versus older patients (12 vs. 9 months, p &lt; 0.001). The analysis of multivariable Cox regression confirmed that there is a significant association between survival and YOPC group after adjusting for stage, grade, gender, ethnicity, surgery and race (HR 1.23, 95% CI: 1.13-1.33, p &lt; 0.001). Conclusions: Patients with non-metastatic YOPC represent a group of patients with distinct clinical characteristics. YOPC have a higher rate of surgery and better overall survival compared to older patients. [Table: see text]