tbuckley/cabot-search huggingface dataset:
Value of germline multi-gene panel next generation sequencing (NGS) in identification of hereditary cancer syndromes (HCS) in colorectal cancer population (CRC).
Authors: Jing Gu, Charite Ricker, Afsaneh Barzi
Journal: Journal of Clinical Oncology (2018)

1587 Background: Identification of HCS in probands (PB) provides a mechanism for cancer screening and prevention in 1st degree relatives (FDR). Lynch syndrome (LS) is the most common HCS in CRC. However, other HCS known to increase risk of breast and ovarian cancers (BC/OC) have been reported in CRC. We evaluated the value of NGS vs. tumor immunohistochemistry followed by MMR gene sequencing (T-MMR) in a CRC cohort with > 5% probability of HCS based on a predictive model. Methods: In a modeled cohort of CRC patients, those with over 5% probability of HCS by MMRpro are assessed using either T-MMR or NGS. FDR of PB with a HCS are offered target genetic testing for the known mutation. The output of this population is input in a Markov model, which simulates the life history of FDR to calculate their costs and quality adjusted life years (QALYs). This model incorporates the effects & costs of cancer screening strategies, preventive procedures, and treatments. The model has 3 states: cancer free, diagnosed with cancer, and deceased; subjects transition among these states based on their known cancer risk and US life tables. Our model takes a US societal perspective and a 3% annual discount rate for both costs and QALYs. Results: For a cohort of newly diagnosed CRC with US epidemiology, 27,775 individuals had a MMRPro score > 5%. T-MMR identified 2,584 (9.3%) PB with LS and subsequently 1,915 FDR with LS and 516 false negative relatives. With NGS, 8,076 (29.1%) PB with a HCS are identified, and 5,984 FDR tested positive for a HCS; including 3,814 with a mutation in a CRC associated gene and 2,170 with BC/OC associated gene mutation. The T-MMR arm failed to identify 2,929 PB and 4,393 FDR with a BC/OC associated gene mutation. Testing for T-MMR arm yields 645,874 QALYs while NGS arm yields 671,507 QALYs for CRC. Total costs are $1,215,670,597 for T-MMR tested group vs. $1,036,167,834 for NGS tested group, defining NGS as the dominant strategy for testing for HCS. One-way sensitivity analysis shows robust results. Conclusions: Compared to the T-MMR testing for LS, using a multi-gene NGS panel that included BC/OC cancer risk genes for HCS among CRC patients increases QALYs and saves costs.
Hospital utilization and disposition among patients with malignant bowel obstruction: A population-based comparison of surgical to medical management.
Authors: Sarah Bateni, Richard J. Bold, Susan L Stewart, Frederick J. Meyers, Robert J. Canter
Journal: Journal of Clinical Oncology (2018)

6571 Background: Malignant bowel obstruction (MBO) is often a terminal event in end-stage cancer patients. The decision to intervene surgically is complex, given the risk of harm in patients with a limited lifespan and the limited population-based research investigating clinically relevant outcomes with surgical versus medical MBO treatment. Therefore, we sought to compare hospital utilization and disposition among MBO patients treated with surgical versus medical management. Methods: We performed a retrospective analysis of hospitalized patients with MBO from 2006-2010 at all California licensed hospitals from the Office of Statewide Health Planning and Development dataset. Hospital-free days (HFD) at 30, 90, and 180 days were calculated accounting for all hospitalizations, emergency department visits, and skilled nursing facility lengths of stay. Adjusted-regression and competing risks models were used to compare HFDs, disposition, complications, in-hospital death, and survival for surgically versus medically treated MBO patients using inverse probability to treatment weighting with propensity scores. Results: We identified 4,576 MBO patients treated medically (74.8%) or surgically (25.2%). Surgical patients had higher rates of complications (44.0% vs. 21.3%) and in-hospital death (9.4% vs. 3.8%) with lower rates of disposition to home (75.4% vs. 88.6%) compared to medical patients (p < 0.0001 all). Surgical patients had fewer 30- and 90-day HFDs compared to medical patients (p < 0.05). However, at 180-days, there were no differences in HFDs between treatment groups. Additionally, there were no differences in overall survival for surgical and medical patients (median 6.5 vs. 6.4 months, p > 0.05). Conclusions: In this population-based analysis, medically managed MBO patients fared better with respect to less hospital utilization at 30 and 90 days, fewer in-hospital deaths, and more frequent returns to home. These data underscore the impact of surgical management on MBO patients at the end-of-life.
Next generation sequencing to identify actionable mutations in EGFR-wild type and KRAS mutant non-small cell lung cancer patients ed by the administration of adjuvant chemotherapy.
Authors: Dimitrios Mavroudis
Journal: Journal of Clinical Oncology (2016)

e20630 Background: Identification of actionable mutations in patients’ tumors is essential in guiding therapy. The aims of this study were: a) to validate mutation detection by next-generation sequencing (NGS) in a cohort of NSCLC patients and b) to identify molecular subgroups within EGFR wild-type and KRAS mutant NSCLCs. Methods: We used the Ion Torrent AmpliSeq Colon and Lung cancer panel to analyze formalin-fixed paraffin-embedded tumors from 76 NSCLC patients previously tested for EGFR mutations by Sanger Sequencing. The sensitivity of the method was assessed by using commercial reference FFPE standards with defined allelic frequencies. DNA was isolated from microdissected tumor tissue and sequencing was performed in the Ion PGM system. Results: Tumors were sequenced to a median coverage of 650X. The sensitivity of mutation detection was estimated at 4% and for mutation reporting we have used a baseline prevalence of ≥ 5%. Precision of the method was demonstrated by analyzing four tumor specimens two times in different library preparations and runs. A complete concordance was observed between the previously defined Sanger genotypes and the corresponding variants detected using NGS. A single mutation was detected in 30 of 76 (39.5%) specimens, two in an additional 30 (39.5%) whereas mutations in more than two genes were detected in 11 (14.5%). The most frequently mutated genes were TP53 (41/76; 54%) and KRAS (23/76; 30%). Among KRAS mutated tumors, 3 (13%) carried STK11, 2 (8.7%) kinase inactivating BRAF mutations and one (4.4%) the BRAF V600E. Between the EGFR/KRAS wild type tumors, 5 (13%) had a mutation in the PI3K pathway, 3 (7.3%) carried mutations in MET, 2 (4.9%) had the BRAF V600E and 6 (14.6%) carried STK11 loss of function mutations. Conclusions: NGS can be used for molecular diagnostics in NSCLC and may detect additional mutated pathways that can be targeted using novel therapies. Keywords: Next-generation sequencing, NSCLC, KRAS co-occuring mutations
TGF-β2 downregulates osteogenesis under inflammatory conditions in dental follicle stem cells
Authors: Soyoun Um, Joo-Hee Lee, Byoung-Moo Seo
Journal: International Journal of Oral Science (2018)

Bone formation is important for the reconstruction of bone-related structures in areas that have been damaged by inflammation. Inflammatory conditions such as those that occur in patients with rheumatoid arthritis, cystic fibrosis, and periodontitis have been shown to inhibit osteoblastic differentiation. This study focussed on dental follicle stem cells (DFSCs), which are found in developing tooth germ and participate in the reconstruction of alveolar bone and periodontal tissue in periodontal disease. After bacterial infection of inflamed dental tissue, the destruction of bone was observed. Currently, little is known about the relationship between the inflammatory environment and bone formation. Osteogenic differentiation of inflamed DFSCs resulted in decreased alkaline phosphatase (ALP) activity and alizarin red S staining compared to normal DFSCs. Additionally, in vivo transplantation of inflamed and normal DFSCs demonstrated severe impairment of osteogenesis by inflamed DFSCs. Protein profile analysis via liquid chromatography coupled with tandem mass spectrometry was performed to analyse the differences in protein expression in inflamed and normal tissue. Comparison of inflamed and normal DFSCs showed significant changes in the level of expression of transforming growth factor (TGF)-β2. Porphyromonas gingivalis (P.g.)-derived lipopolysaccharide (LPS) was used to create in vitro inflammatory conditions similar to periodontitis. The osteogenic differentiation of LPS-treated DFSCs was suppressed, and the cells displayed low levels of TGF-β1 and high levels of TGF-β2. DFSCs treated with TGF-β2 inhibitors showed significant increases in alizarin red S staining and ALP activity. TGF-β1 expression was also increased after inhibition of TGF-β2. By examining inflamed DFSCs and LPS-triggered DFSCs, these studies showed both clinically and experimentally that the increase in TGF-β2 levels that occurs under inflammatory conditions inhibits bone formation. During inflammation, increased transforming growth factor (TGF)-β2 inhibits bone formation in dental follicle stem cells (DFSCs). Hitherto, the relationship between inflammation and bone formation has been poorly understood. But a team headed by Byoung-Moo Seo of Seoul National University, Republic of Korea examined the different functions of two types of TGF-β (a protein that is a key regulator of bone formation): TGF-β1 and TGF-β2. By means of cell cultures and in vivo experiments in mice, the team conducted its investigation on DFSCs: stem cells (non-specialised cells) in the dental follicle, which surrounds a tooth before it erupts. The authors found that inflammation led to an increase in TGF-β2, and that increase inhibited bone formation. The results of the study have implications for the future therapeutic application of DFSCs in bone-loss diseases.
SEA-CD40, a non-fucosylated CD40 agonist: Interim results from a phase 1 study in advanced solid tumors.
Authors: Juneko E. Grilley-Olson, Brendan D. Curti, David C. Smith, Sanjay Goel, Thomas Gajewski, Svetomir Markovic, Olivier Rixe, David Lawrence Bajor, Martin Gutierrez, Timothy Kuzel, Amitkumar N. Mehta, Benny Amore, Abraham Guerrero, Zejing Wang, Andrew L. Coveler
Journal: Journal of Clinical Oncology (2018)

3093 Background: SEA-CD40 is a non-fucosylated, humanized IgG1 monoclonal antibody which binds CD40, an immune-activating TNF receptor. Binding to antigen presenting cells and crosslinking via FcγRIIIa stimulates inflammatory cytokine production and induction of immune co-stimulatory receptors, leading to T-cell activation and antitumor activity. On CD40-expressing malignant cells, SEA-CD40 can induce antibody-dependent cellular cytotoxicity through enhanced NK-cell binding. Methods: This is an ongoing phase 1 dose-escalation study in patients (pts) with relapsed/refractory metastatic solid tumors (NCT02376699). Antitumor activity is assessed q4 cycles (∼12 wks) by immune-related response criteria and RECIST. Results: 48 pts (median age 62 yrs [range, 28–81]; median of 4 prior systemic therapies [range, 1–11]) have received a median of 2 cycles (range, 1–16) of SEA-CD40 at doses 0.6–60 mcg/kg on Day 1 (n = 38), or 30 mcg/kg on Days 1 and 8 (n = 10) IV q3 wks. SEA-CD40 maximum concentrations increased dose-proportionally (10–60 mcg/kg; Day 1 dosing), with mean half-life estimates of 32–95 hrs and no accumulation upon repeat dosing. Dose-limiting toxicities occurred in 5 pts; all were infusion-related reactions (IRRs). Treatment-emergent AEs in ≥25% of pts were IRR (69%), chills (65%), fatigue (54%), nausea (52%), vomiting (35%), and dyspnea and headache (27% each). No treatment-related G5 AEs were reported. Chemokine/cytokine changes and associated immune-trafficking changes observed in the peripheral blood and tumor microenvironment support the proposed mechanisms of action. Best response in 34 efficacy-evaluable pts was 1 PR (basal cell carcinoma) and 10 SD, for a 32% disease control rate (DCR = CR+PR+SD) by RECIST. 5 pts had continued disease control as assessed at Cycle 8 (∼6 mos). Conclusions: SEA-CD40 monotherapy shows clinical (32% DCR) and biological activity in heavily pre-treated pts with advanced solid tumors. SEA-CD40 has a generally tolerable safety profile; strategies to manage IRRs are being evaluated as dose escalation continues at ≥45 mcg/kg. Combination therapy dose escalation (SEA-CD40 + pembrolizumab) in solid tumors is underway, as is monotherapy dose escalation in lymphomas. Clinical trial information: 02376699.
Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation
Authors: Lige Leng, Kai Zhuang, Zeyue Liu, Changquan Huang, Yuehong Gao, Guimiao Chen, Hui Lin, Yu Hu, Di Wu, Meng Shi, Wenting Xie, Hao Sun, Zhicheng Shao, Huifang Li, Kunkun Zhang, Wei Mo, Timothy Y. Huang, Maoqiang Xue, Zengqiang Yuan, Xia Zhang, Guojun Bu, Huaxi Xu, Qi Xu, Jie Zhang
Journal: Neuron (2018)
Circulating tumour DNA as an early marker of recurrence and treatment efficacy in ovarian carcinoma, the CIDOC study
Authors: R. Sabatier, C. Pomel, P.-E. Colombo, F. Narducci, S. Garnier, N. Carbuccia, A. Guille, D. Birnbaum, C. Zemmour, E. Lambaudie
Journal: Annals of Oncology (2018)

Background: Ovarian carcinomas (OvC) are the fifth cause of death by cancer in women and display a very poor prognosis (5-y survival of 30%). Genomic alterations involved in OvC can be identified only by invasive tumour sampling using surgical procedures or guided-biopsies, and are thus not easily monitored during treatment and follow-up. In the last years, circulating tumour DNA (ctDNA) has been explored in many fields for several tumour localizations. Concerning OvC, ctDNA detection is feasible and its correlation with response to treatment has been mentioned for relapsing disease. However, the capacity of ctDNA to be an early marker of relapse has not been described. Trial design: This prospective, national, multicentre, observational study (NCT03302884) is exploring the capacity of ctDNA to be an early marker of OvC recurrence after front-line treatments, i.e. to show significant modifications before clinical, radiological (RECIST v1.1) or biological (CA-125) diagnosis of relapse. CtDNA events are defined as the re-appearance of mutations non-detectable after treatment or an increase of mutant allele fraction (at least one log above the nadir). Tumour and germline DNA are collected to identify somatic mutations by panel-based NGS (Illumina NextSeq500). Patients are then classified according to their mutational profile with a specific DR subset of cases with DNA repair genes alterations. After cell-free DNA isolation, somatic mutations identified by tumour NGS are analysed using droplet digital PCR (BioRad QX200) to reach the highest level of sensitivity. Considering that the rate of ctDNA increase before diagnosis of relapse is significantly higher than the null value 0.70 (H0), assuming a true accuracy rate equal to 0.78 (H1), using a unilateral right-sided Z-score test, α = 5%, and β = 20%, the required sample size is 202, including 80 in the DR group. To fit the inclusion criteria, patients must be diagnosed with an ovarian, tubar or primitive peritoneal carcinoma without previous treatment and requiring (neo)adjuvant chemotherapy. The planned enrolment period is 2 years. Twenty patients have been included until June 2018 in the first opened centre. Clinical trial identification: NCT03302884. Legal entity responsible for the study: Institut Paoli Calmettes. Funding: AstraZeneca. Disclosure: All authors have declared no conflicts of interest.
Preliminary correlative analysis of PD-L1 expression from the SUNRISE study.
Authors: Nikoletta Lea Kallinteris, Rachel E. Sanborn, Leora Horn, David E. Gerber, Ronald B. Natale, Min Tang, Sean Downing, Amanda Clement, Tobias Guennel, Joseph Shan, Cliff Hoyt
Journal: Journal of Clinical Oncology (2017)

11603 Background: SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer, demonstrated similar overall survival (OS) in both treatment arms. Biomarkers including pre-treatment PD-L1 expression are being retrospectively assessed in on-going exploratory analyses. Methods: Archival tissue obtained at the time of diagnosis was requested but not required in the SUNRISE trial. FFPE slides were stained with a panel of lymphoid cell markers: CD3+, CD8+, FoxP3+, PD-L1+, CD163+, CK+ and DAPI using a 6-plex quantitative immunohistochemistry (IHC) assay (OPAL, PerkinElmer, Hopkinton, MA, USA). Baseline PD-L1 expression was retrospectively scored on tumor cells (TC) as a percentage of PD-L1 expressing tumor cells: TC3≥50%, TC2≥5% and &lt; 50%, TC1≥1% and &lt; 5%, and TC0 &lt; 1%. Cox regression models for PD-L1 IHC subgroup populations were used for correlation with OS. Results: In the subset of patients with available diagnostic biopsies (110 out of 597 randomized patients), the prevalence of PD-L1 expression was 5% for TC3, 18% for TC2/3, 35% for TC1/2/3, 65% for TC0. Median OS (mOS) of the D+B arm is 11.5 months (TC0, &lt; 1%) and 6.0 months (TC1/2/3, ≥1%) with HR 0.38 (95% CI, 0.19-0.76); p-value = 0.004. mOS of the D+P arm is 11.1 months (TC0, &lt; 1%) and 10.4 months (TC1/2/3, ≥1%) with HR 0.93 (95% CI, 0.47-1.87); p value = 0.844. Conclusions: Baseline PD-L1 expression in a subset of SUNRISE patients demonstrated that PD-L1 expression (TC0) was associated with a significantly prolonged OS compared to positive PD-L1 expression (TC1/2/3) in patients receiving D+B. No difference in OS was observed in the D+P group by PD-L1 expression. These observations are consistent with the hypothesis that bavituximab may demonstrate more effect in PD-L1 negative or low expressing “immune cold” tumors. Clinical trial information: NCT01999673.
Metformin use in diabetic patients with multiple myeloma (MM): A SEER-Medicare study.
Authors: Shivaprasad Manjappa, Mark A Fiala, Ravi Vij, Keith Stockerl-Goldstein, Mark A. Schroeder, Tanya Marya Wildes
Journal: Journal of Clinical Oncology (2017)

e18127 Background: Metformin, an oral hypoglycemic agent, has been linked to favorable outcomes among patients (pts) with cancer (Coyle et al. Ann Oncol 2016). Wu et al. demonstrated better overall survival (OS) with metformin use in pts with mm and Diabetes Mellitus (DM) (Br J Cancer 2014). They also found that patient with steroid-induced DM [SID] had worse outcomes than pts with pre-existing DM [PDM]. However, Keller et al. did not find these associations in a study of VA mm pts (Blood 2015 126:4502). We evaluated the impact of DM and metformin use on outcomes of pts with mm in the SEER-Medicare database. Methods: We used SEER-Medicare claims from 2007-2013 for pts with newly diagnosed MM. DM was identified using ICD-9 codes, antidiabetic medications by Medicare part D prescription claims. Multivariate analysis was performed by Cox proportional hazard modelling to evaluate (1) Association of DM type (PDM or SID) with mm outcomes and (2) Impact of metformin on outcomes of pts with mm and DM. Covariates included age, gender, transplant, CKD (chronic kidney disease), CCI (Charlson Comorbidity Index), and use of other antidiabetic medications. Potential smoldering mm cases in the dataset were controlled for using a pre-established algorithm (Fakhri, et al,Blood 2016 128:2348) Results: Out of 4708 mm pts, 45% had DM. Among the pts with DM, 28% were on metformin. Out of the 2112 pts with DM, 20% had SID. Median follow up was 26 months. We found no association between PDM (aHR 1.04, 95% CI 0.96-1.12) or SID (aHR 1.03, 0.91-1.17) with OS when compared to non-diabetic pts. Metformin use, female gender, transplant and CCI &lt; 5 were significantly associated with improved OS. Metformin use was associated with an 18% decrease in mortality (aHR 0.82, 0.72-0.93, p = 0.002); controlling for CKD did not impact the association (aHR 0.83 (0.73- 0.94, p = 0.005). Other antidiabetic medications including insulin were not associated with OS. Conclusions: DM (PDM or SID) and insulin use were not associated with poorer outcomes. Metformin use was associated with improved OS among pts with mm and DM in the SEER-Medicare database. The impact of metformin on outcomes in mm pts should be further investigated in prospective clinical trials.
miR-4317, a promising player tuning the anti-tumor armamentarium against breast cancer
Authors: R.A. Youness, R.A. Assal, A. Abdelmotaal, M.Z. Gad
Journal: Annals of Oncology (2018)

Background: Despite the clinical success of immune checkpoint inhibitors in Breast Cancer (BC), yet, the incidence of poor clinical responses in some patients had recently appeared in the clinics suggesting the emergence of drug resistance. Recent research has shifted towards innate immunity highlighting the promise of natural killer cells (NKs) as a more directed immunotherapeutic tool. Yet, cancer cells can still evade immune recognition by NK cells by shedding NKG2D ligands. MICA and ULBP2 are among the most de-regulated NKG2D ligands in BC patients. Tumor microenvironment is also capable of dampening NKs cytotoxicity. Therefore, researchers hypothesize that a potential anti-cancer agent should disturb such triad: halt the oncogenic activity of BC cells, improve its immunogenic profile and alleviates the immune-suppressive microenvironment. miRNAs are suggested as multifunctional players tuning the expression of several targets simultaneously. Finding a novel miRNA that could efficiently halt such triad of oncogenicity was our main goal. miR-4317 is a novel miRNA that has seldomly been analyzed in oncology. Thus, our aim was to investigate the impact of miR-4317 on BC oncogenic and immunogenic profiles. Methods: MDA-MB-231 and MCF7 cells were transfected using lipofection method. Functional analysis was performed using trypan blue, scratch, colony forming and invasion assays. Total RNA was extracted and quantified by qRT-PCR. Peripheral blood was collected from 50 healthy controls and NK cells were isolated using untouched negative selection method. Cytolytic activity of NK cells was assessed using LDH Assay. Results: Ectopic expression of miR-4317 in BC cells resulted in a marked repression of cellular viability, migration, invasion and clonogenicity of BC cells. miR-4317 resulted in a significant increase in the MICA and ULBP2 immune ligands on BC cell lines and alleviating the immune suppressive microenvironment. On the functional level, miR-4317 induced NK cells cytotoxicty upon co-culturing with BC cells. Conclusions: miR-4317 potentiates NK cells mediated killing through improving immunogenic recognition ability of BC cells, re-modeling tumor microenvironment and hijacking BC hallmarks. Legal entity responsible for the study: German University in Cairo. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.