tbuckley/cabot-search huggingface dataset:
Morphologic and genomic characterization of circulating tumor cells in patients with metastatic colorectal cancer treated with combinational treatment of andecaliximab, bevacizumab and chemotherapy.
Authors: Stephanie Shishido, Peter Kuhn
Journal: Journal of Clinical Oncology (2019)

e14753 Background: The liquid biopsy is a noninvasive route to evaluate circulating tumor cells (CTCs) during the course of treatment to gain understanding of tumor biology, with potential prognostic utility. CTCs could serve as a predictive biomarker while aiding in the identification of resistance mechanisms to treatment through single cell genomic and proteomic analysis providing a longitudinal snapshots of tumor heterogeneity. Methods: Through the use of the high definition single cell assay (HD-SCA) workflow, we characterized the rare circulating cells to determine prognostic value of the liquid biopsy in monitoring the efficacy of andecaliximab in a combinational treatment as 1 st or 2 nd line therapy in patients with metastatic colorectal cancer (mCRC). 174 samples from 95 patients were analyzed to determine the significance of CTCs during treatment. Results: HD-CTCs were detected in 31% of samples, with 41 (43%) patients being CTC positive in at least 1 timepoint during the study. Patients receiving 1 st line therapy presented with a median of 0 (range 0-346.04) and a mean of 9.49 (±14.06) HD-CTC/mL at baseline (BL). At initiation of 2 nd line therapy, patients presented with a median of 0 HD-CTC/mL (range 0-277.37) and a mean of 10.94 (±15.32). There was no association between BL HD-CTC/mL and response, but for the 20 patients with &gt; 1 HD-CTC at BL, there was a trend toward response for higher HD-CTC/mL (non-response: mean 2.8, n = 12; response: mean 89.7, n = 8; p = .04). The 3 patients with &gt; 10 HD-CTC/mL at BL had undetectable HD-CTC on-treatment, which accompanied radiologic partial response; however, the 2 patients with complete radiological response had no HD-CTC detected at BL. In case studies, treatment pressure led to an observable change in HD-CTC morphology and genomic instability (single cell CNV analysis), suggesting these parameters may inform prognosis. Conclusions: Characterization of CTCs from patients with mCRC is feasible and may provide prognostic information to guide clinical decision making. Further evaluation of CTCs for pharmacodynamics and clinical monitoring in patients with mCRC is warranted.
A CRISPR monkey model unravels a unique function of PINK1 in primate brains
Authors: Weili Yang, Shihua Li, Xiao-Jiang Li
Journal: Molecular Neurodegeneration (2019)

Genetically modified rodent models have been valuable for investigating the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). Based on the fact that mutations in the PINK1 gene cause autosomal recessive juvenile parkinsonism, a number of mouse models with deletion of the PINK1 gene were generated. However, these PINK1 knockout mouse models fail to recapitulate the selective and overt neurodegeneration seen in PD patient brains. Recently, we generated a non-human primate model with PINK1 deletion using CRISPR/Cas9. This monkey model shows robust neurodegeneration in various brain regions, different from late-onset neurodegeneration in PD patients. Because of the limited pathological data available from humans carrying PINK1 mutations, the PINK1 mutant monkeys provide us with an important animal model to discuss the unique function of PINK1 that is essential for neuronal survival in primate brains. We also propose that the impairment of this unique function by PINK1 mutations in humans may account for the age-dependent and progressive neurodegeneration.
Retrospective determination of the correlation between the distance of tumor manifestation to peripancreatic arteries and overall survival in primary resected pancreatic ductal adenocarcinoma.
Authors: Uwe A Wittel, Michael Uhl, Frank Makowiec, Ulrich Theodor Hopt, Stefan Fichtner-Feigl, Jakob Neubauer
Journal: Journal of Clinical Oncology (2019)

e15745 Background: Current guidelines determine the resectability of PDAC by evaluating the contact of the tumor to peripancreatic vasculature. We wanted to evaluate the influence of this distance of the tumor to peripancreatic arteries on the overall survival of patients with primary resection of pancreatic ductal adenocarcinoma. Methods: Preoperative radiographs of 208 consecutive patients after distal pancreatectomy and/or pancreatoduodenectomy operated between 2007 and 2014 were included in the analysis. In reconstructions of CT and MRI data 90° planes to the centerline of the celiac trunc (CT), hepatic artery(HA) and superior mesenteric artery(SMA) were computed with Aquarius Intuition Viewer (V4.4.11, Terarecon). The closest distance between the tumor and the CT /HA and SMA was determined by an experienced pancreatic surgeon and radiologist independently and upon a deviation greater than 3 mm consent was reached by additional review in 33,2% (69/208) of the cases. Results: 176 CT and 32 MRI scans of 208 patients were evaluated. 2.4 % (5/208) of the radiographs were excluded due to insufficient quality. Average distance of the tumor to the CT/HA and SMA was 16.3 and 6.5 mm for PD and 12.7 and 11.0 mm for DP. Distance between the artery and the tumor did not influence the R0 resection rates (overall R0 &gt; 1mm resection margin 64%) and median overall survival was 24.0 months after R0 resection and 13.5 months after R1 resection (log-rank test P &lt; 0.05). Borderline resectable patients (n = 57) showed a median survival of 13.4 months, patients with their tumor 1-5mm distant to the closest artery (n = 65) and greater than 5 mm distance (n = 81) showed a median survival of 20.3 and 32.9 months respectively. Patients with 0-5 and greater than 5 mm distance between arteries and tumor showed a survival benefit from R0 resection (R0/R1 0-5mm 20.3/13.5 months; &gt; 5mm 37.3/12.8 months) while R0 resected borderline resectable patients showed a similar survival than R1 resected patients (R0 12.7months, R1 15.1 months). Conclusions: The negative resection margins in borderline resectable patients not increase the survival when compared to R1 resected patients. Patients with primary R0 resection and initially large distance of the tumor to peripancreatic vasculature show a prolonged survival.
Clinical predictors of radiographic progression of a hepatic lesion from Li-RADS 3 to Li-RADS 5 among a population of individuals at high risk of hepatocellular carcinoma.
Authors: Lindsay Marie Hannan, Patricia I Ojeda, Daniel S Hippe, Rebecca Mieloszyk, Guy E Johnson, James Oh Park, William Proctor Harris, Puneet Bhargava
Journal: Journal of Clinical Oncology (2019)

e15668 Background: We sought to identify clinical predictors of radiographic progression of a Li-RADS (LR) 3 lesion (i.e. indeterminate for hepatocellular carcinoma (HCC)) to a LR 5 lesion (i.e. definitely HCC) among patients (pts) at high risk of HCC. Methods: Radiology reports from the University of Washington with an LR assignment, 2013-2017, were reviewed (5037 reports, 1954 patients(pts)). Pts with an LR 3 lesion, a follow-up scan within 1 year of date of LR 3 lesion detection, and radiographic evidence of cirrhosis OR a diagnosis of chronic HBV were included in the analysis. Results: Of the 167 pts, 38 (23%) progressed to LR 5 status, 10 progressed to LR 4, and 12 were downgraded to LR 1-2. The remaining 64% were unchanged at LR 3. Radiographic data including year of LR 3 detection (2013-2014 47%) and LR 3 imaging modality (CT 50.3%, MR 49.7%) were obtained. Clinical data were abstracted from medical record review, including sex (65% male), age (80% &lt; 65), race (66% White), cirrhosis etiology (45% HCV, 27% EtOH, 22% NASH, 8% HBV), HCV genotype, HCV treatment status, AFP, and ALBI score (G2 54%, G3 16%, unk 15%). Variables of interest (age, sex, race, cirrhosis etiology, AFP, ALBI score, year of LR 3 detection, imaging modality) were included in proportional hazards modeling with the underlying time metric defined as time from LR 3 detection to date of LR 5 detection or date of last scan up to one year after LR 3 identification. Backwards elimination modeling was performed until remaining variables were associated with the outcome at a level of significance of p &lt; 0.05 (Table 1). Among those with chronic HCV, risk of progression to LR 5 did not differ by HCV genotype (1a, 1b, 2, 3, other, unknown) or sustained viral response status at the time of LR 3 detection. Table 1: Multivariate hazard ratios (HR) and 95% confidence interval (CI) estimates. Conclusions: Chronic HCV, older age at LR 3 detection, earlier year of LR 3 detection, and male sex appear independently associated with risk of progression to LR 5. The identification of clinical factors associated with LR 3 progression may allow for the development of risk modeling tools to assist clinicians in determining frequency of follow-up imaging and optimal timing of intervention.[Table: see text]
<i>RET</i> fusion in first/third-generation EGFR-TKIs resistance in advanced non-small cell lung cancer.
Authors: Yu Yao, Min Zhang, Xiuju Liu, Jun Zhao, Xiangyang Cheng, Aiping Zeng, Jinliang Kong, Hongliang Zhang, Rongrong Chen, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

e20634 Background: EGFR-TKIs is the standard first/second-line treatment for EGFR-mutant advanced non-small-cell lung cancer (NSCLC). The mechanisms of EGFR-TKIs resistance are still under exploration. Acquired fusion have been reported contribute to EGFR-TKIs resistance. Here we focus on RET fusion in first/third-generation EGFR-TKIs resistant NSCLC. Methods: We retrospectively reviewed 3600 cases of EGFR-TKIs resistant NSCLC samples from 2016 to 2018 in our institute. Tumor biopsy, ctDNA or pleural effusion samples were analyzed using hybridization capture-based NGS ER-seq method, which enables simultaneously assess single-nucleotide variants (SNV), insertions/deletions (indel), rearrangements and somatic copy-number(CNV) variation at least 59 genes (range 59-1021 genes). Results: Seven cases with RET fusion were identified (7/3600, 0.2%), with co-occurring EGFR mutations. All were adenocarcinoma, median diagnosis age was 55 years old (range 38-84), four male and three female. Most common RET fusion subtype was CCDC6-RET (5/7, 71%), the other was NCOA4-RET (2/7, 29%). The primary EGFR mutation include four EX19del and three L858R. Six patients received prior first and third-generation EGFR-TKIs treatment. The seventh patient had received only gefitinib treatment, EGFR L858R + T790M + NCOA4-RET were discovered in his plasma when disease progression. Interestingly, one patient had EGFR EX19del + T790M + C797S (cis) + CCDC6-RET in plasma after osimertinib resistance. One patient who had EGFR L858R and NCOA4-RET chose lenvatinib, a RET inhibitor, and had a progression free survival of seven months. Conclusions: Broad NGS panel test suggests that RET fusion could be a rare mechanism of EGFR-TKIs resistance, include first and third-generation. There is no currently target treatment strategy available for these patients, and further investigations, like change target therapy drug or combined target therapy are needed.
MiR-1271-5p: An AR-modulatory microRNA with a distinct role in prostate cancer progression, through SND1 and MORF4L1 interaction.
Authors: Foteini Kalofonou, Damien Leach, Mark Hamilton, Sean Eric Mcguire, Claire Fletcher, Jonathan Waxman, Charlotte L Bevan
Journal: Journal of Clinical Oncology (2019)

e16562 Background: Current screening methodologies for prostate cancer (PCa) are relatively insensitive and there is a need for new treatments for castrate resistant disease. MicroRNAs (miRs) are considered to be master regulators of the genome. We have investigated the role of miRs in modulating androgen receptor function and their potential as treatments of PCa. We report that the AR-modulatory miR-1271-5p also targets SND1 and MORF4L1 and may have a role in PCa progression and screening. Methods: AGO2-PAR-CLIP analysis was performed to ascertain miR-1271-5p target genes in human PCa cell lines. MiR-1271-5p levels were manipulated in cell lines by transfection with miR mimic and or antisense inhibitor. SND1 and MORF4L1 were confirmed as targets by real-time qPCR and western blotting. The functional role of miR-1271-5p and its target genes was assessed by SRB growth assays . Immunohistochemical detection of SND1 and MORF4L1 expression was studied in a cohort of 63 PCa patients and compared with normal controls. Results: MORF4L1 mRNA levels were significantly reduced with the use of miR-1271-5p mimic in 22RV1 cells (p = 0.001), while SND1 mRNA levels were significantly decreased with the use of miR-1271-5p inhibitor in C42 cells (p = 0.0014). Targeting SND1 or MORF4L1, in combination with miR inhibition, significantly reduced C42 (p = 0.0003) and 22RV1 (p = 0.0014) cell growth. MORF4L1 expression was higher in patients with Gleason score (GS) 4+3 relative to those with GS 3+4 and in PCa tissue, as compared with normal prostatic tissue, but did not reach significance. SND1 immunostaining was significantly higher in patients with GS 4+3 or GS 3+4 PCa, compared with normal prostatic tissue (p = 0.0211, p = 0.0007 respectively). SND1 staining was significantly higher in patients with GS 4+3, compared to GS 3+4 (p = 0.0431) or GS 3+3 (p = 0.0251). Conclusions: MiR-1271-5p is an AR-modulatory microRNA, which shows great potential as a biomarker and therapeutic target in PCa. The interaction of miR-1271-5p with its target genes SND1 and MORF4L1 could provide the basis for therapeutic advance in screening and in the treatment of castrate resistant PCa.
A randomized phase III study of continuous maintenance bevacizumab with or without pemetrexed after induction therapy with carboplatin (Car), pemetrexed (Pem), and bevacizumab (Bev) for advanced non-squamous non-small cell lung cancer (nSQ-NSCLC) without sensitizing EGFR mutations: The COMPASS study (WJOG5610L).
Authors: Takashi Seto, Koichi Azuma, Takeharu Yamanaka, Shunichi Sugawara, Hiroshige Yoshioka, Akira Ono, Shinji Atagi, Yasuo Iwamoto, Hidetoshi Hayashi, Isamu Okamoto, Hideo Saka, Mitsuoka Shigeki, Daichi Fujimoto, Kazumi Nishino, Atsushi Horiike, Haruko Daga, Takashi Sone, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Yoichi Nakanishi
Journal: Journal of Clinical Oncology (2019)

9003 Background: Two continuous maintenance therapies, “Pem after Pem+Platinum” and “Bev after Bev+Plt-doublet”, demonstrated the prolongation of survival for advanced nSQ-NSCLC. We conducted a randomized trial of Bev versus Bev+Pem as continuation maintenance therapy after Car+Pem+Bev induction therapy. Methods: Patients were eligible if they had previously untreated advanced nSQ-NSCLC whose EGFR status was either wild-type, unknown, or other than Del19 or L858R. They received the induction treatment with Car (AUC6), Pem (500 mg/m 2 ), and Bev (15mg/kg) every 3 weeks for 4 cycles. Those who showed no progression during the induction therapy were randomized to receive maintenance therapy using Bev or Bev+Pem in a 1:1 ratio. The primary endpoint was overall survival (OS) from randomization. The planned sample size was 620 to provide a power of 85% at one-sided significance level of 5%. Violations found at a study site led us to conduct source document verification for 95.4% of patients to assure data quality. (Trial Identifier, UMIN000004194). Results: Between September 2010 and September 2015, 907 patients had the induction therapy. Of those, 621 patients were randomized; five did not receive study treatment and 22 did not meet the eligibility criteria. Among 594 patients for evaluable (299 in the Bev+Pem arm and 295 in the Bev arm), median age was 65 years; Male, 72%; PS 0/1, 60/40%; Stage IV, 83%; EGFR status, wild-type/others, 91/7%. Median OS was 23.3 vs 19.6 months (mo) with a hazard ratio (HR) of 0.87 (95%CI, 0.72-1.04) and one-sided logrank P= 0.069; in patients with wild-type EGFR tumor, HR for OS was 0.82 (0.68-0.99). Median progression-free survival was 5.7 vs 4.0 mo with a HR of 0.67 (0.57-0.79). 87.4% of patients received subsequent therapy. No new safety signals were observed. Conclusions: The primary analysis was not met. However, the incorporation of Pem significantly prolonged OS in patients with wild-type EGFR. Clinical trial information: UMIN000004194.
5-year survival following radiotherapy in anal cancer audit in a single center.
Authors: Stacie Joanne Morgan, James Best, Selvaraj Giridharan
Journal: Journal of Clinical Oncology (2019)

e15070 Background: Anal cancer accounts for 1% of new cancer diagnoses. Incidence rates are increasing and predicted to rise. Randomised controlled trials have demonstrated superior outcomes with chemoradiation, the standard of care. The recommended dose for two phases is 50.4Gray in 28 fractions, with 5- fluorouracil (5-FU) and mitomycin C as per the UKCCCR ACT I trial. The addition of chemotherapy has been shown to improve outcomes, however is contraindicated in certain cases. Retrospective audit is important to ensure effectiveness of chemoradiation for anal cancer. Methods: Patients were identified retrospectively in a single centre, who had undergone radiotherapy for anal cancer between 2008 and 2013. The only histological subtype included was squamous cell carcinoma. Patients were included who received radiotherapy alone and concomitant chemotherapy. All TNM stages were included and patients treated with palliative intent at the outset were included. Available imaging was reviewed and staging updated in line with TNM 8 th edition. 5 year survival was primarily evaluated. The proportion of patients who had a defunctioning stoma and subsequent reversal was investigated. Results: 55 patients were included in the analysis. The overall 5 year survival was 75% and 5 year relapse free survival 87%. 45 patients received chemoradiotherapy and 38 (84%) of this group received mitomycin C and 5-FU regimen. 7 (13%) patients relapsed, 3 (43%) of which were local. All of these patients proceeded to an abdomino-perineal resection. The commonest fractionation schedule used was 50.4 Gray in 28 fractions. The median stage at presentation of this cohort was T2 N0 M0. The mean age at diagnosis 61.4 years. 1 patient died whilst receiving treatment. 13 (24%) patients had a defunctioning stoma prior to radiation treatment. 3 (23%) had a subsequent reversal of the stoma. Conclusions: Chemoradiotherapy is an effective treatment for squamous cell carcinomas of the anal canal, with good relapse free survival. When a defunctioning stoma is performed prior to chemoradiation there is a low rate of reversal.
Efficacy and toxicity of CDK 4/6 inhibitors in breast cancer: Systematic review and meta-analysis of the phase III clinical trials.
Authors: Faheem Farooq, Jules A. Cohen
Journal: Journal of Clinical Oncology (2019)

e14591 Background: Selective CDK4/6 inhibitors such as palbociclib, abemaciclib, and ribociclib have demonstrated efficacy in advanced HR+/HER2- breast cancer. Drug-related toxicity has been manageable, but variable amongst the drugs. This meta-analysis was conducted to guide CDK inhibitor choice based on efficacy and toxicity. Methods: A systematic literature review of Pubmed, Cochrane Library, and EMBASE was performed in December 2018. Efficacy was evaluated via reported progression free survival (PFS) and pooled hazard ratios (HR). Overall response rate (ORR), treatment discontinuation, and treatment-related adverse events (AEs) were measured via pooled odds ratios (OR). Meta-analyses were performed using random effects modeling and 95% confidence intervals (CI). Results: A pooled analysis of 7 phase III clinical trials (n = 4415) demonstrated a HR of 0.55 (CI: 0.51-0.60) for PFS and an OR of 1.93 (CI: 1.54-2.42) for ORR. First-line treatment trials (n = 3020) pairing CDK 4/6 inhibitors with NSAI/tamoxifen had a HR of 0.56 (CI: 0.51-0.60) for prolonged PFS and an OR of 1.64 (CI: 1.39-1.95) for ORR. Second-line treatment trials (n = 1916) pairing CDK 4/6 inhibitors with fulvestrant had an HR of 0.54 (CI: 0.48-0.61) for prolonged PFS and an OR of 2.48 (CI: 1.57-3.90) for ORR. Palbociclib and ribociclib had similar rates of grade 3/4 AEs, neutropenia, and treatment discontinuation. Abemaciclib had lower rates of grade 3/4 AEs overall, but significantly increased rates of diarrhea and treatment discontinuation due to AEs. Conclusions: Each drug demonstrated a significant improvement in PFS. However, there is no statistical difference in efficacy among the three CDK inhibitors. Treatment decisions can be guided by the tolerability of AEs amongst the medications. Further patient follow-up will illuminate whether there is an OS advantage in this novel drug class. [Table: see text]
A phase I study investigating the absorption, metabolism, and excretion of <sup>[14C]</sup> anlotinib in patients with advanced refractory solid tumors.
Authors: Yiqian Liu, Tongpeng Xu, Lianke Liu, Yongqian Shu
Journal: Journal of Clinical Oncology (2019)

e14701 Background: Anlotinib is a novel oral multi-targeted receptor tyrosine kinase inhibitor, which selectively inhibits VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret, and has shown antitumor activity in patients with advanced refractory solid tumors. The human plasma pharmacokinetics of anlotinib have been described previously, but detailed analyses of the absorption, metabolism and excretion pathways of anlotinib have not yet been published. Methods: Six male patients were divided into two groups, one group included two patients was performed by 13.51mg Anlotinib hydrochloride and 0.64 mg/80 μCi [14C] anlotinib hydrochloride and the rest four patients in another group received 13.19mg anlotinib hydrochloride and 0.96mg/120 μCi [14C] anlotinib hydrochloride, followed by collection of blood, urine, and fecal samples. The primary outcomes of study were absorption, metabolism, and excretion of [14C] anlotinib and the second outcomes were efficacy and safety. Results: In plasma, the average time of total plasma radioactivity peak (Tmax) was 4.42h and the average peak concentration (Cmax) was 18.80 ng Eq./g. The average value of AUC last was 4071 h∙ng Eq./g, AUC 0-∞ was 13555 h∙ng Eq./g, and MRT 0-t was 145h. The average recovery rate of total radioactivity in urine and feces was 62.03%. Prototype drugs and metabolites were mainly excreted through feces, accounting for 48.52% of the administered dose, otherwise rine excretion accounted for 13.51%. The liver and kidney were the main drug excretion organs. Five patients developed adverse reactions, and one person developed SAE. Three of study population were assessed as stable disease (SD), two with partial response (PR), and one had progressive disease (PD). Conclusions: Anlotinib showed a favourable pharmacokinetic profile with high absolute bioavailability and an extensive hepatic metabolism. The adverse events and efficacy were as expected. Clinical trial information: CTR20160329.