tbuckley/cabot-search huggingface dataset:
Exploratory analysis of trifluridine/tipiracil in late-stage metastatic colorectal cancer (mCRC): Prognostic factors.
Authors: Meinolf Karthaus, B Hoell, G Zaun, M Guyot, Martin H. Schuler, Stefan Kasper
Journal: Journal of Clinical Oncology (2020)

24 Background: Trifluridine/Tipiracil (FTD/TPI) is effective in pts with refractory mCRC. Enrollment into in the RECOURSE trial was allowed only for pts with ECOG &lt; 1 pts, while real world pts may have a lower ECOG. In addition, predictive markers for the efficacy of FTD/TPI at late stage are open. This exploratory analysis assessed outcome of mCRC pts (including ECOG PS ≥ 2) upon FTD/TPI treatment by prognostic factors in the real world setting. Methods: This cohort included mCRC pts who were treated with FTD/TPI from 01/2016 until 08/2019 at two large volume CRC centers in Germany. Pts were classified with good prognosis characteristics (GPC) according to Tabernero et al. (abstract 677, ASCO-GI 2019) defined by 1 or 2 metastatic sites and time since diagnosis of first metastases ≥ 18 mo. Pts of this group without liver metastases had the best prognostic characteristics. Pts with poor prognostic characteristics (PPC) were characterized by ≥ 3 metastases sites and time since diagnosis of first metastases ≤ 18 mo. Results: A total of 44 mCRC pts were included in this analysis (mean age 62.5 yrs; 22 males and 22 females). Within the GPC population (n=28; median age 67 yrs; KRAS wt n= 21; KRAS mt n= 7; ECOG 0-1 n= 23; ECOG ≥ 2n=7) 6 pts were alive up to 08/2019 and 4 were lost to FU. Four pts of the GPC were without liver metastases. Within the PPC group (n=16; median age 59 yrs; KRAS wt n= 6; KRAS mt n= 10; ECOG 0-1 n= 15; ECOG ≥ 2 n=1) 2 pts were alive and 2 were lost to FU. The mPFS and mOS of the GPC group (n=18) were 2,15 mo (range 0,62-10,13) and 4,63 mo (range 0,95-14,39), respectively. The mPFS and mOS of the PPC group (n=12) were 1,31 mo (range 0,76-9,72) and 4,72 mo (range 0,76-16,61), respectively. Pts with an ECOG ≥ 2 had a mOS of 2,76 mo (range 0,95-6,92), and a mPFS 1,67 mo (range 0,53-1,77). Conclusions: GPC and PPC group pts treated with FTD/TPI differed with respect to mPFS, but these pts had a comparable mOS in the real world setting. PFS and OS were lower when compared to the Tabernero analysis of the RECOURSE trial, which may reflect the real world setting. Inclusion of pts with an ECOG of ≥ 2 was feasible but showed poor survival data in the third line. Nevertheless, all pts with mCRC benefited from FTD/TPI treatment.
Muscle Weakness in Myositis: MicroRNA‐Mediated Dystrophin Reduction in a Myositis Mouse Model and Human Muscle Biopsies
Authors: Travis B. Kinder, Christopher R. Heier, Christopher B. Tully, Jack H. Van der Muelen, Eric P. Hoffman, Kanneboyina Nagaraju, Alyson A. Fiorillo
Journal: Arthritis & Rheumatology (2020)

Objective Muscle inflammation is a feature in myositis and Duchenne muscular dystrophy ( DMD ). Autoimmune mechanisms are thought to contribute to muscle weakness in patients with myositis. However, a lack of correlation between the extent of inflammatory cell infiltration and muscle weakness indicates that nonimmune pathologic mechanisms may play a role. The present study focused on 2 micro RNA (mi RNA ) sets previously identified as being elevated in the muscle of patients with DMD —an “inflammatory” mi RNA set that is dampened with glucocorticoids, and a “dystrophin‐targeting” mi RNA set that inhibits dystrophin translation—to test the hypothesis that these mi RNA s are similarly dysregulated in the muscle of patients with myositis, and could contribute to muscle weakness and disease severity. Methods A major histocompatibility complex class I–transgenic mouse model of myositis was utilized to study gene and mi RNA expression and histologic features in the muscle tissue, with the findings validated in human muscle biopsy tissue from 6 patients with myositis. Mice were classified as having mild or severe myositis based on transgene expression, body weight, histologic disease severity, and muscle strength/weakness. Results In mice with severe myositis, muscle tissue showed mononuclear cell infiltration along with elevated expression of type I interferon and NF ‐κB–regulated genes, including Tlr7 (3.8‐fold increase, P &lt; 0.05). Furthermore, mice with severe myositis showed elevated expression of inflammatory mi RNA s (miR‐146a, miR‐142‐3p, miR‐142‐5p, miR‐455‐3p, and miR‐455‐5p; ~3–40‐fold increase, P &lt; 0.05) and dystrophin‐targeting mi RNA s (miR‐146a, miR‐146b, miR‐31, and miR‐223; ~3–38‐fold increase, P &lt; 0.05). Bioinformatics analyses of chromatin immunoprecipitation sequencing (ChIP‐seq) data identified at least one NF ‐κB consensus element within the promoter/enhancer regions of these mi RNA s. Western blotting and immunofluorescence analyses of the muscle tissue from mice with severe myositis demonstrated reduced levels of dystrophin. In addition, elevated levels of NF ‐κB–regulated genes, TLR 7 , and mi RNA s along with reduced dystrophin levels were observed in muscle biopsy tissue from patients with histologically severe myositis. Conclusion These data demonstrate that an acquired dystrophin deficiency may occur through NF ‐κB–regulated mi RNA s in myositis, thereby suggesting a unifying theme in which muscle injury, inflammation, and weakness are perpetuated both in myositis and in DMD .
Treatment of metastatic colorectal cancer (mCRC) according to age.
Authors: Laura Ortega, Gabriela Torres Pérez-Solero, Marta Arregui Valles, Manuel Alva Bianchi, Inmaculada Aparicio Salcedo, Gonzalo García González, Iria Gallego Gallego, Andres J. Muñoz Martín, Aitana Calvo Ferrándiz, Montserrat Blanco-Codesido, Miguel Martin, Pilar Garcia-Alfonso
Journal: Journal of Clinical Oncology (2020)

49 Background: Elderly patients with mCRC are underrepresented in clinical trials. For this reason, the optimal treatment in this population is uncertain. The aim of this study is to compare efficacy and safety outcomes in patients with mCRC treated in our institution according to age (&lt;65 vs ≥65 years). Methods: We conducted a retrospective analysis of 482 patients with mCRC attended in the Hospital Gregorio Marañón (Spain) between January 2010 and 2018. Results: Patients characteristics table. First-line: chemotherapy (CT) 98.7% vs 97.3% respectively (p=0.324), biologic agents (BA) 81.2% vs 79.0% (p=0.585). Significantly more &lt;65-year-old patients received FOLFOX (60.5% vs 44.4%) and more ≥65-year-old patients XELOX (9.2% vs 17.5%) or capecitabine (2.0% vs 7.5%). Second-line: CT 64.9% vs 63.5% (p=0.764), BA 60.4% vs 51.1% (p=0.055). Significantly more &lt;65-year-old patients received FOLFIRI (67.0% vs 54.5%) and more ≥65-year-old patients irinotecan (2.0% vs 8.6%). Third and subsequent lines: Significantly more young patients received a third-line (CT: 41.6% vs 31.0%; BA: 24% vs 21.6%), fourth-line (CT: 22.1% vs 11.9%; BA:16.2% vs 6.4%) and fifth-line of treatment (CT: 11.7% vs 5.8%; BA: 4.5% vs 3.6%). More young patients underwent metastasis resection (74.0% vs 58.1%, p=0.001). There were no differences in rate of post-operative complications (p=0.840). There were no differences in overall survival (36.05m vs 28.06, p=0.142), progression-free-survival (first-line: 12.73m vs 11.78m, p=0.139; second-line: 8.78m vs 62.71m, p=0.254) or adverse event rate (73.4% vs 73.6%, p=0.967). Conclusions: Intensive treatment could be an effectiveness and safe option in selected elderly patients. [Table: see text]
Trastuzumab associated with successive cytotoxic therapies beyond disease progression in metastatic breast cancer
Authors: J. Garcia-Saenz, M. Martin, C. Bueno, T. Sampedro, S. Lopez-Tarruella, J. Puente, L. Villalobos, L. Rodriguez, B. Garcia, A. Casado, E. Diaz-Rubio
Journal: Journal of Clinical Oncology (2006)

10617 Background: Whether trastuzumab should be continued after tumor progression remains unknown.We describe the activity of successive trastuzumab-containing regimens in patients with HER2-overexpressing metastatic breast cancer, as well as the response rate, time to progression and predictive factors for response. Methods: Descriptive retrospective study of trastuzumab activity in patients with HER2-overexpressing metastatic breast cancer treated at our hospital from 10/1999 to 07/2005. Results: 93 consecutive patients were evaluated obtaining an objective response rate (OR) for first-time administration of trastuzumab of 46.2%; stable disease (SD) 24.7%; clinical benefit (CB) 71%. Median time-to-progression (TTP) was 5 months (range: 1–39+). A total of 47 pts (50.5%) received a second trastuzumab-containing regimen with an OR of 29.8%; SD 21.3%; CB 51.1%; TTP 4 months (range: 1–31). A total of 21 pts (22.6%) received a third trastuzumab-containing regimen; OR 38.1%; SD 23.8%; CB 61.9%; TTP 4 months (range: 1–30+). A total of 10 pts (10.8%) received a fourth trastuzumab-containing regimen; OR 20%; SD 20%; CB 40%; TTP 4 months (range: 1–37). 5 pts (5.4%) received a fifth trastuzumab-containing regimen; OR 0%; SD 60%. Age &lt; 45 years is a significant prognostic factor (p: 0.005, 95% CI, OR 5.6 (1.5–20.6)). A better response rate in the successive trastuzumab-containing regimens was observed, when there was a response in the first regimen: p = 0.04; 95% CI; OR 3.84 (1.07–14.65). With a follow-up of 16,5 months 45 pts (48,4%) are alive. Conclusions: Trastuzumab-containing therapies beyond disease progression in metastatic breast cancer show activity. There were more responses in younger pts. Those pts who had a previous response to trastuzumab therapy were more likely to respond to successive trastuzumab-containing regimens. Additional controlled studies are needed to test this approach. No significant financial relationships to disclose.
Assessing real-world biomarker testing rates in metastatic colon cancer.
Authors: Shazia Nakhoda, Mengying Deng, Pritish Iyer, Elizabeth A. Handorf, Rishi Jain, Neal J. Meropol, Efrat Dotan
Journal: Journal of Clinical Oncology (2020)

209 Background: Despite national guideline recommendations for universal biomarker testing (KRAS, NRAS, BRAF, and mismatch repair/microsatellite instability [MMR/MSI]) in all patients with metastatic colorectal cancer (mCRC), little is known regarding adherence to these recommendations in the community. Methods: We evaluated 20,333 patients aged &gt;18 years with mCRC diagnosed between 1/1/2013-12/27/18 from the nationwide de-identified Flatiron Health electronic health record-derived database. Changes in rates of biomarker testing based upon chart abstraction according to date of mCRC diagnosis were assessed in patients with ≥ 6 months of follow-up using Cochran-Armitage trend tests. We also assessed whether testing differed by patient characteristics using chi-square tests. Results: Biomarker testing rates increased between 2013 and 2018 (15.3 to 65.7% for NRAS, 23.9 to 56.6% for BRAF, and 34 to 76.6% for MMR, all p &lt; 0.0001). There was no change in rate of KRAS testing (63.8 to 68.3% p= 0.1695) over this period of time. Univariate analysis showed that patients with, worse performance status, and Medicare/Medicaid insurance were less likely to be tested (for all variables, p &lt;0.0001). There were no meaningful differences in testing rates by tumor sidedness, race, gender, or initial stage. Conclusions: In mCRC, adoption of guideline-driven recommendations for NRAS, BRAF and MMR/MSI testing increased significantly between 2013-2018. Adoption of BRAF and NRAS testing has neared the rate of KRAS testing. Interpretation of overall testing rates must recognize potential for missing biomarker test information for care not captured within the Flatiron network. Further study is required to characterize the magnitude of and reasons for absent biomarker testing among patients with metastatic colorectal cancer.
An open-label phase II study of lenvatinib plus pembrolizumab in patients with advanced gastric cancer (EPOC1706).
Authors: Akihito Kawazoe, Shota Fukuoka, Yoshiaki Nakamura, Yasutoshi Kuboki, Yuichi Mikamoto, Hikari Shima, Noriko Fujishiro, Tsukiko Higuchi, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Kohei Shitara
Journal: Journal of Clinical Oncology (2020)

374 Background: Pembrolizumab, anti–PD-1 antibody, provides response rates of around 15% in patients (pts) with PD-L1-positive advanced gastric cancer (AGC). Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased the tumor-associated macrophages and increased infiltration of CD8-positive T cells and enhanced anti-tumor activity of PD-1 inhibitors in vivo model. This phase 2 study has been conducted to evaluate efficacy and safety of the combination of lenvatinib plus pembrolizumab in pts with AGC. Methods: Eligible pts were with AGC having measurable lesions according to RECIST ver. 1.1. Pts could be enrolled regardless of PD-L1 status. Pts received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Primary endpoint was objective response rate (ORR). Planned sample size was 29 pts based on Simon’s optimal two-stage design with one-sided ɑ = 5% and power = 80%. The threshold and expected ORRs were 10% and 30%. PD-L1 combined positive score (CPS) was assessed using the anti–PD-L1 22C3 antibody. Results: From October 2018 to March 2019, 29 pts (27 MSS and 2 MSI-H) were enrolled and assessed for anti-tumor response. Fourteen pts received the study treatment as first-line and 15 pts as second-line. ORR was 69% (95% CI 49 to 85). The disease control rate was 100%. ORR in MSS pts was 70%. ORR was numerically higher in pts with CPS≥1 (n=19, ORR 84%) than that of pts with CPS&lt;1 (n = 10, ORR 40%). Median progression-free survival was 6.9 months (95% CI, 4.4-9.4 months) with 14 pts with ongoing treatment at the data cut off in August 2019. Grade ≥ 3 treatment related adverse events occurred in 13 pts (45%) including hypertension (34%), proteinuria (17%), and platelet count decreased (7%). Conclusions: Lenvatinib with pembrolizumab showed a promising antitumor activity with acceptable safety profiles for pts with AGC, which warrants further investigations in a larger cohort. Clinical trial information: NCT03609359 .
SOlar: A translational phase II study of single-agent olaparib in the treatment of advanced esophagogastric cancer.
Authors: Elizabeth Cartwright, Caroline Yean Kit Fong, Michael Hubank, Claire Saffery, Eleftheria Kalaitzaki, Kate Young, Tracy Coyne, Annette Musallam, Nicos Fotiadis, Andrew Wotherspoon, Ruwaida Begum, Imene Zerizer, Sheela Rao, David J. Watkins, Marco Gerlinger, Irene Yu-Shing Chong, Christopher J. Lord, Ian Chau, David Cunningham, Naureen Starling
Journal: Journal of Clinical Oncology (2020)

TPS471 Background: Oesophagogastric (OG) cancers represent a significant health burden and leading cause of cancer related death. Prognosis in advanced disease is poor and novel therapies are needed to improve outcomes. Molecular features of advanced OG cancer suggest that assessment of DDR (DNA damage repair) targeted agents is warranted. Specifically, ATM and ARID1A defects and mutational scars indicative of homologous recombination defects are present in a subset of OG cancers and are associated with polyadenosine 5’diphosphoribose polymerase inhibitor (PARPi) sensitivity. Methods: SOlar is a multi-centre, open-label, single arm, phase II study of olaparib, a PARPi, in patients with advanced oesophageal, gastro-oesophageal junction and gastric adenocarcinoma. The trial will use a single-arm Simon two-stage design to evaluate the anti-tumour activity of olaparib in advanced OG cancers. The primary endpoint is disease control rate (DCR) at 8 weeks by RECIST v1.1. To rule out a DCR of ≤15% while aiming for DCR ≥30% (alpha = 0.09, power = 89%), 54 patients must be recruited it total. An interim analysis will take place when 27 patients have been accrued, dosed and followed until the 8-week disease evaluation. If 4 or fewer patients have disease control (DC) the study will be terminated. If 5 or more patients have DC, an additional 27 patients will be enrolled to a total of 54 patients. If ≥12/54 have DC in the final analysis then it will be concluded that the treatment has shown anti-tumour activity compatible with 30% and an investigation of potential biomarkers of response will be carried out. Secondary endpoints are ORR, DoR, OS, PFS, time to radiological progression and safety. This highly translational study incorporating serial tumour biopsies will investigate candidate predictive biomarkers of PARPi sensitivity with the aim of identifying responder/non-responder subpopulations. Further exploratory objectives will investigate the predictive role of early FDG-PET/CT in assessing tumour response and the creation of an organoid biobank. The trial opened to recruitment in July 2019 and will recruit up to 54 patients over 3 years. Clinical trial information: NCT03829345.
FRI0226 Efect of low doses of prednisolone on bone mineral density (bmd) in sjogren’s syndrome
Authors: NS Shornikova, VI Vasiliev, AV Smirnov
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Lately the effect of corticosteroids on BMD during different diseases including autoimmunic ones was widely discussed. <h3>Objectives</h3> To determine the effect of long-term (&gt;5 years) taking of Prednisolone in daily dosage of 2–2.5 mg on BMD in pts with Sjogren's syndrome (SS). <h3>Methods</h3> 112 female pts aged 33–73 with reliable SS diagnosis were examined. 56 (50%) out of them were treated for more then 5 years by low doses of hormones. As it was evident that menopausal beginning influenced BMD, all examined persons were divided into 4 groups: pts with retained menstrual cycle who did not receive hormones (1st group – 32pts with median age 40.7(7.8 years) and those who for a long time took low doses (&lt;5 mg/day) of Prednisolone (2nd group – 24 pts with median age 41.5(4.7 years); women of postmenopausal period who were never treated by hormones (3d group – 24 pts aged 57.5(6.7 year, postmenopausal period 7.3(0.8 years) and those who for a long time took low doses of Prednisolone (4th group – 32 pts aged 52.3(5.6 years; postmenopausal period 8.1(0.7 years). All groups of pts were comparable by weight and height coefficient. Assessment of BMD in lumbar area of the spine (L1-L4) and left femoral neck was carried out by double X-ray absorptiometry on densitometer QDR-1000 («Hologic», USA). Statistical analysis was done by Student's t-criterion and (2 criterion). <h3>Results</h3> BMD in L1-L4 was correspondingly to 1–4 groups: 1.030(0.128 g/cm<sup>2</sup>, 0.983(0.100 g/cm<sup>2</sup>, 0.858(0.123 g/cm<sup>2</sup> and 0.837(0.124 g/cm<sup>2</sup>, there were no reliable difference in comparison of 1st and 2nd, 3d and 4th groups. BMD in femoral neck was as follows according to groups: 0.891(0.115 g/cm<sup>2</sup>, 0.815(0.104 g/cm<sup>2</sup>, 0.740(0.116 g/cm<sup>2</sup> and 0.763(0.090 g/cm<sup>2</sup>. During analysis it turned out that BMD in femoral neck in the 2nd group was reliably lower than in the 1st group (t = 2.59, p &lt; 0.01), during comparison of the 3d and 4th group there were no differences. In the 1st and 2nd groups there was no osteoporosis (T &lt;2.5 SD), osteopenia (T &lt;1.0 SD) in L1-L4 and in neck developed correspondingly in 25% and 18.75% of cases in the1st group and in 33.3% and 41.7% in the 2nd group. In the 3d and 4th groups osteoporosis and osteopenia developed mainly with equal frequency in corresponding areas. <h3>Conclusion</h3> In women with retained menstrual cycle the long-term taking of low doses of Prednisolone results in BMD decrease in femoral neck, frequency of osteopenia grows but osteoporosis in this case does not develop. In postmenopausal period taking of low doses of hormones has no substantial effect on the frequency of osteoporosis and osteopenia development.
Prediction of hepatic metastasis and relapse: Concordance analysis among noninvasive liver fibrosis scores from colorectal cancers.
Authors: Sanjun Cai, Xiang Hu, Weixing Dai, Yaqi Li, Xiaoji Ma, Junjie Peng
Journal: Journal of Clinical Oncology (2020)

202 Background: Liver fibrosis, resulted from several liver diseases, are increasing up to 25% in population globally. It remains undetermined how much of an impact liver fibrosis have on the development of hepatic metastasis and relapse in colorectal cancer (CRC). Hence the aim of this study was to clarify the role of liver fibrosis on hepatic metastasis and relapse in CRC undergoing curative therapy. Methods: We enrolled consecutive 1652 patients with radical surgery as the discovery cohort, and the validation set enrolled 432 CRC patients with hepatic metastasis treatment. To determine the degree of liver fibrosis, the NFS, FIB4 and APRI were applied. The influence of liver fibrosis on hepatic metastasis and relapse was assessed by survival analyses. Nomograms with fibrosis score incorporated was established to identify the incremental value for individualized relapse estimation, which was then assessed with respect to calibration, discrimination, and clinical usefulness. Results: The high liver fibrosis score patients had significantly worse outcomes than low score in 5-year hepatic metastasis (22.6 vs . 8.7%) in discovery cohort, and RFS (58.2 vs. 44.1%) in validation cohort. Multivariate analysis revealed liver fibrosis score as an independent prognostic factor. The distribution analysis also demonstrated higher liver fibrosis score a powerful prognostic factor for hepatic metastasis and relapse. Incorporating the liver fibrosis score into the nomogram resulted in better performance evaluated by C-index and AUC than TNM staging system and clinicopathologic nomograms. Importantly, in validation cohort, the discriminatory capacity of the fibrosis score incorporated was superior to that of the CRS score in predicting RFS, as demonstrated by the C-index and AUC. The concordance study showed well agreement among NFS, FIB4 and APRI in predicting DFS and RFS. Among these three noninvasive liver fibrosis scores, NFS score performed the best in predicting hepatic specific DFS and RFS. Conclusions: The liver fibrosis was a powerful predictor of hepatic specific DFS and RFS in CRC. Fibrosis niche may be a favorable microenvironment for metastatic formation in the liver.