tbuckley/cabot-search huggingface dataset:
Oncogenic ERG Represses PI3K Signaling through Downregulation of IRS2
Authors: Ninghui Mao, Dong Gao, Wenhuo Hu, Sunyana Gadal, Haley Hieronymus, Shangqian Wang, Young Sun Lee, Patrick Sullivan, Zeda Zhang, Danielle Choi, Neal Rosen, Charles L. Sawyers, Anuradha Gopalan, Yu Chen, Brett S. Carver
Journal: Cancer Research (2020)

Abstract Genomic rearrangements leading to the aberrant expression of ERG are the most common early events in prostate cancer and are significantly enriched for the concomitant loss of PTEN. Genetically engineered mouse models reveal that ERG overexpression alone is not sufficient to induce tumorigenesis, but combined loss of PTEN results in an aggressive invasive phenotype. Here, we show that oncogenic ERG repressed PI3K signaling through direct transcriptional suppression of IRS2, leading to reduced RTK levels and activity. In accordance with this finding, ERG-positive human prostate cancers had a repressed AKT gene signature and transcriptional downregulation of IRS2. Although overexpression of IRS2 activated PI3K signaling, promoting cell migration in a PI3K-dependent manner, this did not fully recapitulate the phenotype seen with loss of PTEN as PI3K signaling is not as robust as observed in the setting of loss of PTEN. Importantly, deletions of the PTEN locus, which promotes active PI3K signaling, were among the most significant copy-number alterations that co-occurred with ERG genomic rearrangements. This work provides insight on how initiating oncogenic events may directly influence the selection of secondary concomitant alterations to promote oncogenic signaling during tumor evolution. Significance: This work provides insight on how initiating oncogenic events may directly influence the selection of secondary concomitant alterations to promote tumorigenesis.
Serum IL-6: A biomarker in childhood asthma?
Authors: Daniel J. Jackson, Leonard B. Bacharier, Agustin Calatroni, Michelle A. Gill, Jack Hu, Andrew H. Liu, Lisa M. Wheatley, James E. Gern, Rebecca S. Gruchalla, Gurjit K. Khurana Hershey, Meyer Kattan, Carolyn M. Kercsmar, Haejin Kim, George T. O’Connor, Shilpa Patel, Jacqueline A. Pongracic, Robert A. Wood, William W. Busse
Journal: Journal of Allergy and Clinical Immunology (2020)
The role of type 1 interferons in Gram-negative bacteria-induced coagulation
Authors: Xinyu Yang, Xiaoye Cheng, Yiting Tang, Xianhui Qiu, Zhongtai Wang, Guang Fu, Jianfeng Wu, Haixia Kang, Jing Wang, Haichao Wang, Fangping Chen, Xianzhong Xiao, Timothy Billiar, Ben Lu
Journal: Blood (2020)
Apatinib combined with SOX neoadjuvant therapy for locally advanced gastric cancer: A multicenter, single-armed, prospective study.
Authors: Jian-Xian Lin, Changming Huang
Journal: Journal of Clinical Oncology (2020)

367 Background: Molecular targeted therapy has made great progress in the treatment of gastric cancer. In some previous studies, apatinib, an oral small molecular of VEGFR-2 TKI, had been confirmed can improve OS and PFS with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy. However, there is limited evidence about the safety and feasibility of apatinib combined with SOX regimen as neoadjuvant therapy for locally advanced gastric cancer (AGC). Methods: This is a multicenter, single-armed, prospective study. Patients with AGC (cT 2-4 N + M 0 ) without prior anti-cancer strategies were included. Patients were received 2 to 5 cycles (21 days a cycle) of neoadjuvant therapy using S-1 (po, 40-60 mg bid, day1-day14), oxaliplatin (iv, 130 mg/m 2 , day1), and apatinib (po, 500 mg qd). Apatinib was prohibited in the last cycle. The operation should be performed 2 to 4 weeks later of the neoadjuvant therapy. The primary endpoint was R0 resection rate. The secondary endpoint included safety, ORR, and DCR. Results: A total of 56 patients from 10 centers in China were recruited. There were 43 males and 13 females. The median age was 63.04 years (range 41-75 years). There were 43 patients with tumor response evaluation, 29 patients (67.4%) had partial response (PR), 12 patients (27.9%) had stable disease (SD), and 2 patient (4.6%) had progressive disease (PD). The ORR and DCR were 67.4% (29/43) and 95.3% (41/43), respectively. 36 patients received gastric surgery, the R0 resection rate was 97.2%, 3 patients had postoperative complication: one had intestinal obstruction and 2 had pneumonia (all Clavien-Dindo classification less than grade II). 46 patients were included for safety analysis. The incidence of adverse events (AEs) and grade 3/4 AEs were 84.8% (39/46) and 17.4% (8/46), respectively. The most common AEs were neutropenia (40%), low platelet count (40%), leucopenia (32.6%), vomit (13%). Conclusions: This prospective study shows that neoadjuvant therapy using apatinib plus SOX brings clinical benefit to AGC with a high disease control rate and tolerable adverse reactions. Clinical trial information: NCT 03192735.
The alarming rise in gastric and colorectal cancers in young adult patients: Analysis of large databases.
Authors: Amir Ali Khan, Philip HG Ituarte, Isaac Benjamin Paz, Ajay Goel, Lily L. Lai, Yuman Fong, Yanghee Woo
Journal: Journal of Clinical Oncology (2020)

805 Background: The alarming rise in the incidence of gastric (GC) and colorectal (CRC) adenocarcinomas in young adults (YA) over the past three decades is not well understood. How YA populations differ from older patients with the same gastrointestinal malignancies warrants further investigation. Methods: We retrospectively analyzed the California Cancer Registry and the Office of Statewide Health Planning and Development data for all GC and CRC cases from 2000 to 2012. Pearson’s Chi-square analysis was used to analyze differences in demographic, clinical and histopathologic features and log-rank test to compare survival between young (≤ 40 years old) and older adults (40-90 years old) with GC or CRC. Results: Of the GC (n = 19,368) and CRC (n = 117,415) patients included in the study, YA accounted for 4.5% (n = 883) of GC and 3.2% (n = 3723) of CRC. Hispanic ethnicity was more common in YA for both cancers compared to older patients (50.9% vs 26.8% GC, 29.6% vs. 15.7% CRC, p &lt; 0.0001). YA were more likely to have poorly differentiated (74.6% vs. 59.8% GC, 22.5% vs 17.5% CRC, p &lt; 0.0001), higher grade (77.0% vs 61.6% GC, 23.9% vs 18.6 CRC, p &lt; 0.0001), and signet ring features (44.6% vs 21.0% GC, 3.2% vs 1.1% CRC, p &lt; 0.0001) compared to older patients. Synchronous peritoneal metastases were more common in YA compared to older patients (32.1% vs. 14.1% GC, 8.8% vs 5.4% CRC, p &lt; 0.0001). YA with GC or CRC had a greater 5-year survival compared with older patients with the same stage of malignancy. Subgroup analysis of Stage I GC demonstrated lower survival in YA compared with adults aged 41-49 and 50-64 years (65.1% vs. 70.7% and 69.1%, 95% CI 49.7-76.9%, 62.5-77.3%, 65.2-72.7% respectively). Conclusions: GC and CRC in young adults have distinctly worse clinical and histopathologic features compared to older patients with the same malignancy. Ethnic disparity exists in the YA patients. This study contributes to improving the understanding of younger versus older GI cancer patients.
Aberrant Salience? Brain Hyperactivation in Response to Pain Onset and Offset in Fibromyalgia
Authors: Catherine S. Hubbard, Asimina Lazaridou, Christine M. Cahalan, Jieun Kim, Robert R. Edwards, Vitaly Napadow, Marco L. Loggia
Journal: Arthritis & Rheumatology (2020)

While much brain research on fibromyalgia (FM) focuses on the study of hyperresponsiveness to painful stimuli, some studies suggest that the increased pain-related brain activity often reported in FM studies may be partially explained by stronger responses to salient aspects of the stimulation rather than, or in addition to, the stimulation's painfulness. Therefore, this study was undertaken to test our hypothesis that FM patients would demonstrate elevated brain responses to both pain onset and offset-2 salient sensory events of opposing valences.Thirty-eight FM patients (mean ± SD age 46.1 ± 13.4 years; 33 women) and 15 healthy controls (mean ± SD age 45.5 ± 12.4; 10 women) received a moderately painful pressure stimulus to the leg during blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Stimulus onset and offset transients were analyzed using a general linear model as stick functions.During pain onset, higher BOLD signal response was observed in FM patients compared to healthy controls in dorsolateral and ventrolateral prefrontal cortices (DLPFC and VLPFC, respectively), orbitofrontal cortex (OFC), frontal pole, and precentral gyrus (PrCG). During pain offset, higher and more widespread BOLD signal response was demonstrated in FM patients compared to controls in frontal regions significantly hyperactivated in response to onset. In FM patients, some of these responses were positively correlated with pain unpleasantness ratings (VLPFC, onset; r = 0.35, P = 0.03), pain catastrophizing scores (DLPFC, offset; r = 0.33, P = 0.04), or negatively correlated with stimulus intensity (OFC, offset; r = -0.35, P = 0.03) (PrCG, offset; r = -0.39, P = 0.02).Our results suggest that the increased sensitivity exhibited by FM patients in response to the onset and offset of painful stimuli may reflect a more generalized hypersensitivity to salient sensory events, and that brain hyperactivation may be a mechanism potentially involved in the generalized hypervigilance to salient stimuli in FM.
Comparison of doublet chemotherapy with monotherapy for vulnerable advanced colorectal cancer patients.
Authors: Mitsuhiro Furuta, Kentaro Yamazaki, Takeshi Kawakami, Hiromichi Shirasu, Takahiro Tsushima, Nozomu Machida, Satoshi Hamauchi, Tomoya Yokota, Akiko Todaka, Akira Fukutomi, Yusuke Onozawa, Hirofumi Yasui
Journal: Journal of Clinical Oncology (2020)

143 Background: The efficacy of doublet chemotherapy (fluoropyrimidine + oxaliplatin/irinotecan) for vulnerable colorectal cancer patients is controversial. Some prospective trials have not shown the benefit of doublet chemotherapy for vulnerable patients compared to fluoropyrimidine monotherapy. On the other hand, one trial did show an advantage for doublet chemotherapy in PFS. Moreover, although these trials are designed for vulnerable patients, inclusion was limited by trial criteria, and patient conditions might have been better than those of vulnerable patients in clinical practice. Therefore, the advantage of doublet chemotherapy over monotherapy for vulnerable patients in clinical practice remains unclear. Chemotherapy toxicity and frailty are increased in high modified Glasgow score (mGPS = 2) patients. Therefore, we examined the efficacy of doublet chemotherapy for vulnerable patients, using mGPS. Methods: We retrospectively examined vulnerable advanced colorectal cancer patients who received monotherapy (n = 52) or doublet chemotherapy (n = 195) as 1st line treatment between 2005 and 2016. We defined vulnerable as fulfilling one of the following conditions; age ≥75, ECOG PS = 2, or mGPS = 2. Results: Patient characteristics in the monotherapy group vs the doublet group were as follows; median age (range), 80 (63-88) vs 66 (29-87); gender male/female, 28/24 vs 111/84; ECOG PS 0/1/2, 15/25/12 vs 76/79/40; mGPS = 2, 13 (25%) vs 134 (68%); median metastatic sites (range), 1 (1-3) vs 2 (1-5); presence of ascites, 9 (17%) vs 59 (30%), primary tumor location left, 35 (67%) vs 125 (64%); KRAS mutation 18 (35%) vs 52 (27%); bevacizumab/anti-EGFR antibody, 30/0 vs 79/19. The median PFS was 6.9 months in the monotherapy group and 7.7 months in the doublet group (HR = 1.129, p = 0.480). The median OS was 13.3 months in the monotherapy group and 14.8 months in the doublet group (HR = 0.999, p = 0.994). Multivariate analysis did not show the benefit of doublet chemotherapy in PFS (HR = 0.908, p = 0.615) or OS (HR = 0.764, p = 0.176). Conclusions: This study suggests that doublet chemotherapy may not be beneficial for vulnerable advanced colorectal cancer patients in clinical practice.
Determining when endoscopic ultrasound (EUS) changes management for patients with pancreatic cystic neoplasms.
Authors: Hasrit Sidhu, Khaola Maher, Dave Farnell, Leo Chen, Ian Gan, Maja Segedi
Journal: Journal of Clinical Oncology (2020)

641 Background: Pancreatic cystic neoplasms (PCNs) are being incidentally detected at an increased rate due to the widespread use of CT and MRI. CT and MRI cannot always differentiate between malignant and benign PCNs. EUS is an emerging tool that provides higher quality descriptions of pancreatic cysts and can be used to differentiate between benign and malignant features. Considering that EUS is a resource dependent tool, we hope to identify the PCN cases in which EUS changes management. Methods: We conducted a retrospective case-control chart review evaluating patients, who were diagnosed with pancreatic cysts and underwent EUS for analysis between January 1, 2010 and December 31, 2017. We determined whether EUS correctly identified high-risk features (HRFs) relative to CT/MRI and whether EUS upstaged or downstaged the CT/MRI diagnosis to change overall patient management. Results: EUS was found to have a high specificity (&gt; 95%) for all high-risk features identified in the AGA and FG guidelines and a low sensitivity ( &lt; 70%) for all high risk features except cyst size &gt; 3cm (82.35%) and mural nodule &lt; 5mm (100%). EUS was found to change management in 29.4% of cases (18.2% upstaged, 11.2% downstaged). EUS screening led to a total of three adenocarcinoma diagnoses, in which two were reported to be invasive. Conclusions: The high specificity of EUS supports its use in the differentiation of high risk PCNs identified on cross-sectional imaging. Its low sensitivity indicates that the reliance on operator experience may be a substantial limitation resulting in inconclusive diagnoses. In conclusion, considering that EUS is successful in changing patient management of PCNs, it should be readily referred when any HRF is identified on cross-sectional imaging.
DPYD gene polymorphisms in patients with gastrointestinal tumors receiving chemotherapy with 5-fluorouracil.
Authors: Oleg Ivanovich Kit, Liubov Yu Vladimirova, Natalya N. Timoshkina, Anna E. Storozhakova, Natalia A. Petrusenko, Dmitry Yu. Gvaldin, Sergey N. Kabanov, Ludmila A. Ryadinskaya, Natalia M. Tikhanovskaya, Irina L. Popova, Natalia A. Abramova, Natalia Yu. Samaneva, Maria A. Teplyakova, Aza A. Lyanova, Kristina A. Novoselova, Elena Aleksandrovna Kalabanova, Yana V. Svetitskaya, Vladimir Trifanov, Evgeniy N. Kolesnikov
Journal: Journal of Clinical Oncology (2020)

90 Background: Complete or partial deficiency of the DPD enzyme due to genetic polymorphisms of the DPYD gene causes acute toxicity of fluoropyrimidines, which are widely used in combination chemotherapy regimens for various malignant neoplasms. The purpose of the study: to identify polymorphisms of the DPYD gene significant for 5-fluorouracil-induced toxicity. Methods: Venous blood samples from Caucasian patients were used to identify alleles of *2А rs3918290, 5* rs1801159, *13 rs55886062 and rs67376798 DPYD by RT-PCR and direct sequencing. Inclusion criteria were: verified diagnosis of gastrointestinal tumors, age&gt;18 years old, fluoropyrimidine-containing regimes of treatment. Results: 104 pts were included, 54% were female. Mean age-61 years. Colorectal cancer was found in 80.7% pts, non-colorectal in 19.3% pts. Hematological and non-hematological toxicity Gd.3-4 was found in 24% pts. Allele * 5rs18011595, which causes enzyme deficiency was found in 28% of patients, (frequency was 0.281) which is significantly higher than the population frequency of the allele charactering for Caucasoid population (p &lt;0.05). Meanwhile genotyping did not reveal the *2A, *13 alleles and rs67376798 alleles in the DPYD gene. Conclusions: *5rs1801159 allele was found as the main DPYD polymorphism associated with fluoropyrimidine toxicity in Caucasian pts with gastrointestinal tumors.
Enhanced efficacy of anti-VEGFR2/taxane therapy after progression on immune checkpoint inhibition (ICI) in patients (pts) with metastatic gastroesophageal adenocarcinoma (mGEA).
Authors: Lionel Aurelien Kankeu Fonkoua, Sakti Chakrabarti, Mohamad Bassam Sonbol, Pashtoon Murtaza Kasi, Jason Scott Starr, Alex John Liu, Melanie C. Bois, Henry C. Pitot, Chandrikha Chandrasekharan, Helen J. Ross, Tsung-Teh Wu, Rondell P. Graham, Svetomir Markovic, Haidong Dong, Harry H. Yoon
Journal: Journal of Clinical Oncology (2020)

4541 Background: Anti-VEGFR2 therapy (ramucirumab/paclitaxel [RAM/TAX]) and ICI are approved as 2 nd - and 3 rd -line therapy (Tx), respectively, for pts with mGEA. We unexpectedly saw durable responses in 2 pts on RAM/TAX after progression on an ICI trial (KN-059; PMID 29674442). We performed a pilot to examine the clinical activity of ICI followed by RAM/TAX. Then we retrospectively compared the outcomes of pts who received this serial Tx to pts who received RAM/TAX without prior ICI. Methods: All pts with mGEA at Mayo Clinic who received RAM/TAX (2014-19) were included (N = 87). Outcomes were best objective response rate (ORR: complete [CR] or partial response) per RECIST1.1, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Chi square and multivariate (MV) logistic and Cox regression were used. Results: 15 consecutive pts with measurable mGEA received ICI immediately followed by RAM/TAX after irRECIST progression. Most pts (95%) did not respond to ICI. Yet on RAM/TAX, 100% (15/15) had tumor reduction (range -8% to -100%) with an ORR of 73% (11/15), including 3 CRs. In these pts (who received ICI followed by RAMTAX), PFS on RAMTAX was longer than on last chemotherapy before ICI (12.3 vs 3.0 m, P &lt; .001). Outcomes on RAM/TAX in these pts were significantly better than in pts who received RAM/TAX alone (see Table). Associations were strengthened after adjusting for total lines of Tx, line of Tx of RAM/TAX, age, and ECOG PS. Exploratory analysis of paired tumor biopsies collected pre-ICI and on RAM/TAX in a small subset revealed that the frequency of intratumoral immunosuppressive FOXP3 + Tregs decreased on RAM/TAX, whereas the frequency of antitumor CD8 + T cells was preserved. Conclusions: RAM/TAX immediately preceded by ICI was associated with significantly higher OS, ORR, and DOR than RAM/TAX alone, suggesting ICI may enhance efficacy of subsequent anti-VEGFR/taxane therapy. This novel sequence of therapy will be tested prospectively in a new randomized phase 2 trial (NCT04069273). [Table: see text]
Preoperative serum artemin (ARTN) as a predictive biomarker of recurrence following curative resection for hepatocellular carcinoma (HCC).
Authors: Sophie Feng, Hao-Wen Sim, Roxana Bucur, Reenika Aggarwal, Phillipe Abreu, Monali Ray, Michael Herman, Dangxiao Cheng, Zhuo Chen, Wenjiang Zhang, Paul David Greig, Alice Chia-chi Wei, Carol-Anne Moulton, Ian M. McGilvray, Sean P. Cleary, Steven Gallinger, Gonzalo Sapisochin, Jennifer J. Knox, Geoffrey Liu, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2020)

571 Background: Tumor-induced generation of splenic erythroblast- like cells (Ter-cells) has been shown to promote tumor progression. These Ter-cells produce the glial-line derived neurotropic factor, ARTN. We investigated the association of pre-operative serum ARTN and the risk of recurrence in HCC patients (pts) undergoing curative resection. Methods: Blood samples were collected prior to surgery as part of an institutional molecular epidemiologic study. Serum ARTN concentration was measured using an enzyme-linked immunosorbent assay (ELISA). Demographics, pathological variables known to be associated with outcomes and clinical outcomes were collected. Uni- and multi-variate analysis were conducted. The optimal cutpoint method was used to define high and low ARTN concentrations. Cox models (hazard ratios, HR) were used to compare progression-free (PFS, primary endpoint), and overall survival (OS) of pts with high vs low serum ARTN. Results: Pre-operative blood samples were available for 58 pts. Median age was 63 years (range: 25-85 years); 74% were male and 50% were Asian. Etiology of liver disease was hepatitis B (43%) and hepatitis C (22%); 43% of tumors were ≤5cm, and vascular invasion was seen in 62%. A baseline alpha-fetoprotein (AFP) of &gt; 100 mcg/L was observed in 36% pts. Median follow-up was 18.9 months. Median ARTN concentration was 0.322 ng/mL. The optimal ARTN concentration cut-off was 0.206 ng/mL. Median PFS for pts with high ( &gt; 0.206 ng/mL) vs low (≤0.206 ng/mL) ARTN was 15.7 vs 55 months (p = 0.04) respectively. Three year PFS was 34% vs 55%, and three year OS 54% vs 91% for high vs low groups. Univariate analysis found that high ARTN concentration (HR 2.44, p = 0.05) and multifocal tumors were associated with a worse PFS. In a multivariate analysis adjusted for AFP &gt; 100mcg/L, vascular invasion, hepatitis status and multifocal tumors, high ARTN remained a negative prognostic factor for PFS, aHR 3.32 (95% CI: 1.22-9.05, p = 0.02). Conclusions: A high pre-surgery serum ARTN is associated with earlier recurrence in HCC pts undergoing curative resection. ARTN should be further studied in HCC to determine its value as a prognostic marker.
Blood neuroendocrine gene transcripts (NETest) as a diagnostic of pancreatic neuroendocrine tumors and to identify the efficacy of surgical resection.
Authors: Stefano Partelli, Francesca Muffatti, Valentina Andreasi, Massimo Falconi, Irvin Mark Modlin
Journal: Journal of Clinical Oncology (2020)

631 Background: Surgery is the only treatment for cure of pancreatic neuroendocrine tumours (PNET). There are no effective biomarkers to assess completeness of resection and predict recurrence. The aims of this study were 1) evaluate if blood measurement of neuroendocrine gene transcripts (NETest) were diagnostic of PNET and 2) assess if blood levels correlated with the resection type (R0/ R1/R2). We compared transcript analysis with Chromogranin A (CgA), the current standard of care. Methods: A prospective, longitudinal, single center study (ClinicalTrials.gov ID: NCT03012789) of 30 PNETs. Blood for NETest and CgA were collected preop and on postop day 30 (POD30). Transcript measurement: real-time quantitative reverse transcription PCR and multianalyte algorithmic analysis (NETest) (normal 0-20, &gt; 20 stable and &gt; 40 progressive disease; CgA: (ELISA) (normal &lt; 109mg/ml). Analysis: Student’s t test, Mann-Whitney U test and Fisher’s exact test. Data: mean±SEM. Results: Surgical resections ( n= 30) were: 26 R0, 2 R1, 2 R2. In vitro diagnostic: Preop NETest positive in all 30 (NETest: 38±4) (1005) whereas CgA levels positive (220±66ng/ml) in 9 (30%, p&lt; 0.0001). Surgery R0: ( n= 26): NETest significantly decreased from pre-op of 45±3 to 21±4 ( p&lt; 0.001) at POD30. Post operatively 13 (50%) exhibited an elevated score. One patient (Ki67 18%; extensive nodal involvement) had a score of 80, consistent with residual progressive disease. The remaining 12 had NETest levels of 27 at POD 30. CgA was elevated in 8 (31%) with no decrease at POD30 (154±44ng/ml vs. 109±22ng/ml). R1/R2 ( n= 4): NETest scores unchanged (42±17 vs 46±16) at POD30. CgA levels unchanged (378±332 vs. 753±634ng/ml). Conclusions: The NETest is an accurate in vitro diagnostic biomarker for PNET (100%). After R0 resection NETest decrease indicates the blood test is concordant with tumor removal. Elevated post-resection scores are consistent with residual disease and with reported recurrence rates after pancreatic surgery. CgA exhibited no clinical utility. At 1 month post-surgery, the NETest provides an early indication of high risk recurrence patients who can be stratified for further therapy. Clinical trial information: NCT03012789.