tbuckley/cabot-search huggingface dataset:
Efficacy of receptor tyrosine kinase inhibitors (RTKIs) and immunotherapy (PD-1/PD-L1) for treatment of osseous vs. soft tissue metastases of renal cell carcinoma (RCC).
Authors: Katherine Yuxi Tai, Jad El Abiad, Carol Morris, Adam Levin, Mark Christopher Markowski
Journal: Journal of Clinical Oncology (2019)

e16094 Background: Checkpoint inhibitors and RTKIs have changed the standard of care in metastatic RCC. However, anecdotal evidence suggests these therapies may be less effective for treating bone metastases than soft tissue metastases. Our study aimed to evaluate this potential difference in treatment response between osseous and visceral metastases. Methods: Our institutional Cancer Registry database was queried for RCC patients treated at Johns Hopkins Hospital from 1997-2017 (n = 2212). 68 patients were identified with measurable bone and soft tissue metastatic disease who were treated with RTKIs and/or PD-1 inhibitors over the study period. The extent of metastasis was quantified at the time of therapy initiation, 3 mos., 6 mos., and 1 yr. Changes in disease status from baseline were categorized as partial response (PR), complete response (CR), stable (S), mixed (M) or progressive disease (PD) based upon RECISTv1.1 and MDA criteria for soft tissue and bone metastases, respectively. These categories were further organized into Controlled Disease (PR, CR, S) or Evidence of Progression (M, PD) in order to generate a generalized linear effects model with visceral response as the independent variable and bone response as the dependent. Results: Visceral response correlates with bone response at 3 (p = 0.005, n = 76) and 6 months (p = 0.017, n = 48). At 3 mos. 46 patients were treated with RTKI and 30 with PD-1. At 6 mos. 31 patients were treated with RTKI and 17 with PD-1. Of patients with controlled visceral disease, only 19% had progression in bone at 3 mos. (32% at 6 mos.). Of patients with progression in soft tissue, 42% had controlled bone disease at 3 mos. (41% at 6 mos.). Conclusions: This suggests that, contrary to anecdotal reports of a divergent response to biologic therapy, osseous metastases do not appear to respond worse than soft tissue metastases upon treatment with these agents. [Table: see text]
Arabidopsis S2Lb links AtCOMPASS-like and SDG2 activity in H3K4me3 independently from histone H2B monoubiquitination
Authors: Anne-Sophie Fiorucci, Clara Bourbousse, Lorenzo Concia, Martin Rougée, Anne-Flore Deton-Cabanillas, Gérald Zabulon, Elodie Layat, David Latrasse, Soon Kap Kim, Nicole Chaumont, Bérangère Lombard, David Stroebel, Sophie Lemoine, Ammara Mohammad, Corinne Blugeon, Damarys Loew, Christophe Bailly, Chris Bowler, Moussa Benhamed, Fredy Barneche
Journal: Genome biology (2019)

The functional determinants of H3K4me3, their potential dependency on histone H2B monoubiquitination, and their contribution to defining transcriptional regimes are poorly defined in plant systems. Unlike in Saccharomyces cerevisiae, where a single SET1 protein catalyzes H3K4me3 as part of COMPlex of proteins ASsociated with Set1 (COMPASS), in Arabidopsis thaliana, this activity involves multiple histone methyltransferases. Among these, the plant-specific SET DOMAIN GROUP 2 (SDG2) has a prominent role.We report that SDG2 co-regulates hundreds of genes with SWD2-like b (S2Lb), a plant ortholog of the Swd2 axillary subunit of yeast COMPASS. We show that S2Lb co-purifies with the AtCOMPASS core subunit WDR5, and both S2Lb and SDG2 directly influence H3K4me3 enrichment over highly transcribed genes. S2Lb knockout triggers pleiotropic developmental phenotypes at the vegetative and reproductive stages, including reduced fertility and seed dormancy. However, s2lb seedlings display little transcriptomic defects as compared to the large repertoire of genes targeted by S2Lb, SDG2, or H3K4me3, suggesting that H3K4me3 enrichment is important for optimal gene induction during cellular transitions rather than for determining on/off transcriptional status. Moreover, unlike in budding yeast, most of the S2Lb and H3K4me3 genomic distribution does not rely on a trans-histone crosstalk with histone H2B monoubiquitination.Collectively, this study unveils that the evolutionarily conserved COMPASS-like complex has been co-opted by the plant-specific SDG2 histone methyltransferase and mediates H3K4me3 deposition through an H2B monoubiquitination-independent pathway in Arabidopsis.
Relative contribution of clinical and molecular features to outcome within low and high risk T and N groups in stage III colon cancer (CC).
Authors: Frank A. Sinicrope, Lucas J. Huebner, Pierre Laurent-Puig, Thomas C. Smyrk, Josep Tabernero, Enrico Mini, Richard M. Goldberg, Gunnar Folprecht, Aziz Zaanan, Karine Le Malicot, Qian Shi, Steven R Alberts, Julien Taieb
Journal: Journal of Clinical Oncology (2019)

3520 Background: Duration of adjuvant FOLFOX or CAPOX for stage III CC is being guided by pt stratification into low (T1-3N1) and high (T4 or N2) risk groups based on the IDEA study. We determined the relative contributions of clinical and molecular features for prediction of time-to-recurrence (TTR) and survival after recurrence (SAR) within each risk group. Methods: Stage III CC (N=5,430) from 2 trials of adjuvant FOLFOX ± cetuximab with similar outcome by study arm [NCCTG N0147 (Alliance), PETACC-8] were used. Tumors were analyzed for mismatch repair (dMMR vs pMMR), mutations in KRAS (exon 2) and BRAFV600E. Median pt follow-up was 83.4 months. Relative contributions to predicting outcome were assessed using χ2 (Harrell’s rms) based on multivariable (MV) Cox models. Results: N (50.8%) and T (31.8%) stage were the top two contributors to prediction of TTR which supports risk grouping. High risk (n=2566) vs low risk (n=2774) pts had poorer TTR (HR 2.7, 95% CI, 2.4-3.0) and SAR [HR 1.6 (1.4-1.9)], both p&lt;.0001. TTR: KRAS contributed the most to predicting TTR among high (58.6%) and low (51.1%) risk pts (Table). Contribution of MMR (16%) to predicting TTR was limited to low risk pts. Contribution of BRAF V600E to TTR was nearly 3-fold increased in high vs low risk pts. SAR: BRAF V600E contributed the most to predicting SAR, especially in high vs low risk pts (2-fold increase). Tumor sidedness and performance status (PS) were key contributors to SAR, but not TTR. MV associations: TTR: low risk, KRAS [HR 1.7 (1.4-2.3], MMR [HR 0.55 (.35-.87), gender (M/F) [HR 1.3 (1.0-1.5)], all p&lt;.04]; high risk: BRAF [HR 1.3 (1.1-1.7)], sidedness (R vs L) [HR 1.14 (1.0-1.3)], KRAS [HR 1.4 (1.2-1.6)], all p&lt;.04]. SAR: BRAF, sidedness, PS (all p&lt;.05). Conclusions: KRAS mutation was the strongest predictor of shorter TTR in both risk groups whereas BRAF V600E was the primary driver of SAR, especially in high risk pts. Support: U10CA180821, U10CA180882, U24CA196171; BMS, Pfizer, Sanofi. NCT00079274.[Table: see text]
MED12 exerts an emerging role in actin-mediated cytokinesis via LIMK2/cofilin pathway in NSCLC
Authors: Meng Xu, Fang Wang, Guibo Li, Xiaokun Wang, Xiaona Fang, Haoxuan Jin, Zhen Chen, Jianye Zhang, Liwu Fu
Journal: Molecular Cancer (2019)

Mediator complex subunit 12 (MED12) is an essential hub for transcriptional regulation, in which mutations and overexpression were reported to be associated with several kinds of malignancies. Nevertheless, the role of MED12 in non-small cell lung cancer (NSCLC) remains to be elucidated. MED12 mutation was detected by Next-generation sequencing. The expression of MED12 in 179 human NSCLC tissue samples and 73 corresponding adjacent normal lung tissue samples was measured by immunohistochemistry (IHC). CRISPR-Cas9 was used to knock out MED12 in PC9 and SPC-A1 cells. MED12 rescued stable cell lines were generated by lentivirus infection. We traced cell division process by live cell imaging. The molecular mechanism of aborted cytokinesis resulted by MED12 knockout was investigated by RNA-seq. Effects of MED12 deletion on the proliferation of NSCLC cells were determined by MTT assay and Colony-formation assay in vitro and xenograft tumor model in nude mouse. Cell senescence was measured by SA-β-gal staining. In our study, no MED12 exon mutation was detected in NSCLC samples, whereas we found that MED12 was overexpressed in human NSCLC tissues, which positively correlated with the tumor volume and adversely affected patient survival. Furthermore, knockout MED12 in NSCLC cell lines resulted in cytokinesis failure, displayed a multinuclear phenotype, and disposed to senescence, and become non-viable. Lack of MED12 decreased the proliferative potential of NSCLC cells and limited the tumor growth in vivo. Mechanism investigations revealed that MED12 knockout activated LIMK2, caused aberrant actin cytoskeleton remodeling, and disrupted the abscission of intercellular bridge, which led to the cytokinesis failure. Reconstitution of exogenous MED12 restored actin dynamics, normal cytokinesis and cell proliferation capacity in MED12 knockout cells. These results revealed a novel role of MED12 as an important regulator for maintaining accurate cytokinesis and survival in NSCLC cells, which may offer a therapeutic strategy to control tumor growth for NSCLC patients especially those highly expressed MED12.
Sensitive detection of microsatellite instability in tumors and liquid biopsies using nuclease-based enrichment.
Authors: Ioannis Ladas, Harvey J. Mamon, Kimmie Ng, Fangyan Yu, Ka Wai Leong, Matthew H. Kulke, G. Mike Makgrigiorgos
Journal: Journal of Clinical Oncology (2019)

e15117 Background: The role of MSI in colorectal cancer (CRC) is well characterized, and tumors are classified as MSI-High or MSI-Stable by screening specific microsatellites. MSI-H reflects mismatch repair deficiency, is predictive for CRC therapy outcome in chemotherapy and immunotherapy and has a higher 5-year survival. While tumor testing is the gold standard, a convenient approach to screen for MSI before and during cancer treatment is screening circulating DNA (liquid biopsy) using a blood draw. However, using electrophoresis or next generation sequencing for MSI detection presents challenges at low levels of MSI due to polymerase slippage (‘stutter’) that generate high false positive rates at positions of homo-polymers. We present a new approach for enrichment of altered micro-satellites prior to DNA-amplification thereby reducing stutter from wild-type alleles and facilitating detection of MSI. The method employs a double-strand-DNA-specific nuclease and overlapping oligonucleotide-probes interrogating multiple micro-satellite targets (‘NaMe-PrO’, nuclease-assisted minor-allele enrichment with probe-overlap). Following DNA denaturation, the probes form double-stranded regions with their targets, thereby guiding nuclease digestion to selected sites. Microsatellite indels create ‘bulges’ that inhibit digestion, thus subsequent amplification yields DNA with microsatellite alterations enhanced at multiple targets. Methods: We first validated the method by evaluating 5 MSI targets simultaneously, NR27, NR21, NR24, BAT25 and BAT26 using DNA from tumor biopsies and circulating-DNA from colorectal cancer patients. The technique detected microsatellite alterations down to 0.01% altered allele frequency, thus improving detection sensitivity by &gt; 100-fold relative to current approaches. Next, a clinical study was performed. We screened microsatellites in circulating DNA from groups of early stage colon cancer patients with known MSI status in the tumor. Results: Combination of NAME-PRO with capillary electrophoresis demonstrated 100% sensitivity (10/10) and 90% specificity (9/10) in detecting MSI status in the blood, thereby opening the possibility of early cancer detection for MSI positive tumors, or for application in minimal residual disease detection. Conclusions: We anticipate application of this highly- multiplex-able method either with standard 5-plex reactions or with NGS-based detection of MSI on thousands of targets to enable sensitive detection in tumors and liquid biopsies.
Prospective evaluation of metabolic intratumoral heterogeneity using <sup>18</sup>F-FDG-PET-CT in patients with advanced gastric cancer receiving palliative chemotherapy.
Authors: Shin Hye Yoo, Seo Young Kang, Gi Jeong Cheon, Do-Youn Oh, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2019)

4059 Background: Metabolic intratumoral heterogeneity (ITH) gives important information on treatment response and prognosis. However, temporal changes in metabolic ITH and their associations with treatment outcome have not been reported yet in gastric cancer (GC). We aimed to evaluate the early changes in metabolic ITH and their predictive roles in advanced GC patients receiving palliative chemotherapy. Methods: Unresectable locally advanced or metastatic GC patients were prospectively enrolled before the first-line palliative chemotherapy and underwent 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET-CT) at baseline (T1) and at the first response evaluation follow-up (T2). SUVs (Standardized uptake values), volumetric parameters, and textural features including entropy Histo and contrast GLCM were extracted from the primary gastric tumor at T1, T2, and ΔT (T2-T1) was evaluated. Associations of these parameters with treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed. Results: 87 patients were analyzed. Of 86 evaluable patients, 44 obtained partial response, 33 stable disease, and 8 progressed. The objective response rate was 51.8% (95% confidence interval [CI], 40.7% to 62.7%). The median PFS and OS were 7.3 months (95% CI, 5.4 to 8.2 months) and 11.5 months (95% CI, 10.1 to 14.3 months), respectively. From T1 to T2, metabolic ITH was significantly reduced ( P &lt; 0.01), and the degree of decrease was greater in responders than in non-responders ( P &lt; 0.01). By multiple Cox regression analyses adjusted for clinical variables, low entropy Histo at T2 ( P= 0.001), larger decreases in coefficient of variance ( P= 0.003) and contrast GLCM ( P= 0.017) were associated with better PFS. Low SUV peak at T2 ( P= 0.001), larger decreases in coefficient of variance ( P= 0.032) and being a responder were associated with better OS. Conclusions: Early reduction in metabolic ITH is useful to predict response to palliative chemotherapy, PFS and OS in advanced GC patients.
Efficacy and safety of sintilimab in combination with XELOX in first-line gastric or gastroesophageal junction carcinoma (GC/GEJC).
Authors: Nong Xu, Lin Shen, Haiping Jiang, Yulong Zheng, Jiong Qian, Chenyu Mao, Hui Zhou, Shuyan Wang
Journal: Journal of Clinical Oncology (2019)

4042 Background: Immune checkpoint inhibitors have shown clinical benefit in advanced GC/GEJC. This phase 1b study evaluates the efficacy and safety of sintilimab, an anti-programmed cell death-1 antibody (PD-1 Ab) in combination with XELOX for GC/GEJC in first-line setting. Methods: This phase 1b study enrolled treatment-naïve unresectable locally advanced or metastatic GC/GEJC patients without HER2 amplification in cohort F. Patients received sintilimab 200mg IV q3w until disease progression, unacceptable toxicity or death, in combination with XELOX regimen (oxaliplatin 130mg/m 2 IV D1 and capecitabine 1000mg/m 2 PO BID D1-14) for up to 6 cycles. The primary objective was to evaluate the efficacy of the combination per RECIST v1.1 and safety and tolerability. Results: Totally 20 patients were enrolled in cohort F. As data cutoff (15 Jan 2019), median follow up was 5.8 months (range, 2.4 to 12.5). The median dose of sintilimab was 6.5 (range, 4 to 12). The objective response rate (ORR) was 85.0% (95%CI, 62.1 to 96.8) and disease control rate (DCR) was 100.0% (95%CI, 83.2 to 100.0). Among 17 patient with BOR of PR, two patients achieved a complete response (CR) of the target lesion. The median duration of response (DOR) and median progression free survival (PFS) had not been met. Three patients underwent resection of primary tumor after achieving a BOR of partial response (N=2) and stable disease (N=1). The incidence of treatment emergent adverse events (TEAEs) was 85.0%. Treatment-related AEs (TRAEs) occurred in 14 (70.0%) patients. The incidence of TRAE ≥ Grade 3 was 15%. AEs of immune-related etiology, occurred in 6 patients (30.0%). There were no AEs that resulted in death. As data cutoff, 12 patients were still in treatment and 8 had discontinued treatment and were under survival follow up. The biomarker analysis including PD-L1 expression in tumor specimen was ongoing. Conclusions: Sintilimab in combination with XELOX in first-line GC/GEJC shows promising anti-tumor efficacy and a tolerable safety profile. The further randomized, phase 3 study of Sintilimab in combination with XELOX in this setting is ongoing (NCT03745170). Clinical trial information: NCT02937116.
Percutaneous pericardiocentesis versus pericardial window: A retrospective subset analysis in a cancer population.
Authors: Benjamin C Hofeld, Michael Widlansky, Michael Gitter
Journal: Journal of Clinical Oncology (2019)

e23093 Background: Malignant pericardial effusions (PEs) must often, and for a multitude of reasons, be managed invasively. Options for intervention include percutaneous or surgical drainage. There is a paucity of data directly comparing efficacy of these interventions. This study compares efficacy of surgical pericardial window (PW) percutaneous pericardiocentesis (PP) in cancer subjects with PEs, with respect to mortality, readmission, and repeat procedure. Methods: We performed a 5 year, retrospective, single center study at a major academic center. 79 patients were selected using ICD codes for PP (n = 19) and PW (n = 59) and grouped by first procedure performed. Log Rank Regression of Kaplan-Meier Curves was performed for major adverse events, as defined by repeat procedure, readmission, or mortality during the surveillance period. Results: Log Rank Tests of readmission and mortality were not statistically significant (P = 0.54, 0.656 respectively). Single Variate Log Rank Test of repeat procedure favored PW (P = 0.008, event rates: PP 21.1% vs PW 3.4%. Multivariate Log Rank Test of and all 3 events was not statistically significant (P = 0.168). Fig 1: Kaplan-Meier Analysis of PP (0) vs PW (1) by any event (repeat procedure, readmission, or mortality). Event Rate = 89.5% PC, 89.5% PW. Conclusions: PW patients had a lower incidence of repeat procedures. There were no differences in readmission, mortality, or a composite of all 3 events. Future aims will identify risk factors associated with repeat procedures in PCs and PWs.
Receptor status conversion between primary and recurrent/metastatic breast cancer: A single institutional study.
Authors: Poornima Ramadas, Jennifer Leibovitch, Karan Ramakrishna, Prathik Krishnan, Dongliang Wang, Sam Benjamin
Journal: Journal of Clinical Oncology (2019)

e14735 Background: Hormone receptor and HER2 status have both predictive and prognostic implications in breast cancer (BC). Studies report differences of 3% to 54% for Estrogen receptor (ER), 5% to 78% for Progesterone receptor (PR), and 0% to 34% for HER2 between primary (P) and recurrent/metastatic breast cancer (RMBC). To evaluate this difference, we conducted an observational single institution study in adult patients (pts) ≥ 18 years with RMBC. Methods: After IRB approval, we conducted a retrospective chart review of pts diagnosed with RMBC between January 1 st , 2010 and October 31 st , 2018, with history of PBC. We recorded age at PBC diagnosis, stage, tumor type, receptor status, initial treatment, age at RMBC diagnosis, if biopsy performed, receptor status and survival. We studied the differences in ER, PR and HER2 receptors between P and RMBC. Descriptive statistics was used for analysis. Results: We found a total of 179 pts in the time interval. Median age was 54 ± 13.2 years at PBC diagnosis, 98.9% females, 1.1% males. 187 events were recorded. At PBC diagnosis, 27.4% had Stage I, 37.4% had Stage II and 31.8% had Stage III disease. Tumor type was ductal in 83.8% and lobular in 12.2%. 78.8% was ER+, 68.7% was PR+ and 14% was HER2+. 70.9% received chemotherapy, 12.8% received HER2 therapy and 67% received hormonal therapy. Age at RMBC was median of 61 ± 13.1 years. Biopsy was done in 93.3%. Time between PBC and RMBC ranged from 7 and 324 months. 31.3% had local recurrence and 68.7% had distant disease. In RMBC, 59.2% was ER+, 41.9% was PR + and 13.4% was HER2 +. 58.7% are alive and 38% deceased. With RMBC, 19.2% who were ER+ became ER-, 4.9% who were ER- became ER+, 37.5% who were PR+ became PR-, 8.6% who were PR- became PR+, 23.1% who were HER2+ became HER2-, 4.5% who were HER2 - became HER2+. In pts who became ER-/PR-, 88.5% received hormonal therapy and 61.5% received chemotherapy at the time of PBC. In pts who became HER2-, 83.3% received HER2 therapy at the time of PBC. Conclusions: In our study, we found a difference of 24.1% in ER, 46.1% in PR and 27.6% in HER2 between PBC and RMBC. It is recommended that patients with RMBC should have a biopsy to evaluate the receptor status as it would impact treatment and survival.
Detection of bone metastases through diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) compared with PET/CT <sup>18</sup>F-NaF.
Authors: Hector Manuel Barragan-Campos, Anne Laurence Le Faou, Martín Burgos-Jaramillo, Fernando Lopez-Soto, Javier Altamirano Ley, Roberto De la Peña-Lopez
Journal: Journal of Clinical Oncology (2019)

e23086 Background: To evaluate a diagnostic test which can allow the comparison between Diffusion-weighted imaging with background suppression (DWIBS) the novel diagnostic modality versus PET/CT 18 F-NaF, the gold standard for the diagnosis of bone metastases (BM). Methods: University bioethics committee authorized the protocol. Patients with solid cancer and suspicion of BM (by clinical findings, imaging, and tumor biomarkers), who met inclusion criteria were included and provided their signed informed consent. The DWIBS in a MR 3.0 T was performed first and then the PET/CT 18 F-NaF. Each study was interpreted blinded. Statistics to evaluate a diagnostic test were performed. Results: From April 2014 to April 2016, 91 patients (100%) were interviewed, 88 (93.4%) met the inclusion criteria. Nine patients (8%) were excluded: death 3, respiratory failure 2, refused participating 2, pacemaker 1, claustrophobia 1. Seventy-nine patients (86.8%) were included, of which 81.0% (64/79) were women. Primary cancer was: a) breast 73.4 b) prostate 15.2%; c) Non-Hodgkin lymphoma 2.5%; d) cervical 2.5%; e) thyroid 2.5%; f) lung 1.3%; g) colon 1.3%; and h) testicular 1.3%. Diagnostic performance of DWIBS compared to PET/CT 18 F-NaF, sensitivity 88.1% (Confidence Interval [CI95%, 73.3-96.0), specificity of 48.7% (CI 95%, 31.9-65.6), PPV of 66.0% (CI 95%, 58.2-73.1), NPV of 78.3% (CI 95%, 59.7-89.7), PLR 1.7 (CI 95%, 1.2-2-4), NLR 0.2 (CI 95%, 0.1-0.6) and prevalence of 53.1% (CI 95%, 41.6-54.5). Results were stratified in quartiles (excellent, good, fair, and poor). Conclusions: DWIBS has excelent sensibility, fair specificity, good PPV, and excellent NPV. These data suggest DWIBS could be used as a proxy of PET/CT 18 F-NaF.