tbuckley/cabot-search huggingface dataset:
Germline and somatic homologous recombination gene mutations in high-grade serous ovarian cancer and clinical outcome.
Authors: Victoria Mandilaras, Stephanie Lheureux, Neda Stjepanovic, Julia Burnier, Michelle K. Wilson, Lisa Wang, Blaise Clarke, Patricia Ann Shaw, Hal K. Berman, Raymond Kim, Susan Randall Armel, Jeanna McCuaig, Alexandra Volenik, Lailah Ahmed, Maksym Misyura, Philippe L. Bedard, Lillian L. Siu, Suzanne Kamel-Reid, Tracy Stockley, Amit M. Oza
Journal: Journal of Clinical Oncology (2016)

5579 Background: Mutations in homologous recombination (HR) genes other than BRCA1/2 genes have been reported to cause a BRCA-like phenotype in up to 50% of HGSOC. PARP inhibitors (PARPi) are effective in patients (pts) with germline or somatic BRCA1/2 mutations (gBRCAm and sBRCAm) and perhaps in pts with other HR deficiency or loss of heterozygosity. It has been reported that platinum free interval (PFI) in pts with gBRCAm predicts for response to PARPi. We aim to investigate if pts with non-gBRCAm HR gene mutational variants (HRV) have a longer PFI than those with no HRV. Methods: Matched blood and archival tumor samples (FFPE) from HGSOC pts unselected for family history or age at diagnosis, enrolled in an institutional molecular screening program (NCT01505400), were selected for additional targeted sequencing with a lab-developed Hereditary Cancer Panel using Illumina MiSeq/NextSeq for 52 cancer predisposition genes, including 11 HR genes (BRCA1/2, RAD51, FANCA, FANCC, FANCD2, FANCF, FANCG, PALB2, ATM and NBN). All pts provided consent for research on banked samples. Medical records were reviewed for outcomes and the first platinum-free interval (PFI) was recorded. Student t-test was used to determine if PFI differed based on presence of a mutation in a HR gene (including BRCA). The analysis was repeated excluding pts with known gBRCAm to investigate whether non-gBRCAm HRV impacted PFI. Results: Of 41 pts enrolled, 38 had stage II-VI disease evaluable for PFI. The median age was 54 years. The distribution of HR gene mutations is outlined in the table below. There was a significant difference in PFI between pts with HR gene mutations and pts with no HR mutation (25.8 vs. 10.2 months, p = 0.01). When, gBRCAm pts were excluded, PFI remained longer in the 10 pts with HR mutations than in those without but was not significant (27.3 vs. 10.2 months, p = 0.09). Conclusions: In this initial cohort, pts with HR gene mutations have a longer PFI in HGSOC. The role of HRV should be further investigated as being a potential target for HR deficiency-targeted treatments such as PARPi. Type of HR mutation N = 38 (%) BRCA: 19 (50) -pathogenic gBRCAm 14 -gBRCA variant of unknown significance 2 -sBRCAm alone 3 HRV 5 (13) No HR mutation 14 (37)
Mammography interpretation delays in a main public healthcare unit in Nuevo Leon, Mexico.
Authors: Elizabeth Sanchez-Guillen, Manuel Ramirez-Sanchez, Edna Anakarenn Lopez-Martinez, Jose Felipe Muñoz-Lozano, Fernanda Mesa-Chavez, Cynthia Mayte Villarreal-Garza
Journal: Journal of Clinical Oncology (2018)

e18677 Background: In Mexico, inadequate infrastructure and use of analogue mammography equipment over digital for breast cancer (BC) screening and diagnosis contribute to prolonged total time intervals, with the greatest delays occurring between initial medical consultation and diagnosis (4 months). However, it is currently unknown where the longest delays occur within the BC diagnosis trajectory. The aim of this study was to measure the time intervals of mammography interpretation in a public healthcare facility. Methods: We performed a retrospective assessment of all mammographies that were received and interpreted in a main referral public hospital in Nuevo Leon in a 6-month period. Studies were taken at five primary and secondary healthcare facilities in the region and sent for interpretation. We measured the time intervals between date of study, arrival, interpretation, and return of results to the respective healthcare unit. Results: A total of 3,220 mammographies were logged during the study time. Median time from date of study to return of results was 39 days. Only 10% of study request forms included clinical information. Data regarding the time to delivery of results to patient was not available. Noteworthy, 76% were interpreted and returned in > 1 month (not taking into account time to results delivery to the patient), which already surpasses 21 workdays, the official country guideline for total mammography results delivery. Conclusions: In low-middle income countries such as Mexico, with human, infrastructure and financial limitations, diagnostic over screening mammography should be implemented as a more cost-effective strategy to enhance early diagnosis and downstaging. Prioritization of symptomatic patients and those with abnormal breast findings can improve referral and admission to tertiary-care services to facilitate prompt BC care. Additionally, centralization of high-quality standard equipment and trained radiologists in referral breast units can shorten time delays related to geographical barriers. Date of mammography to hospital arrival Hospital arrival to interpretation Interpretation to return of results Total days Average 10 14 18 42 Median 9 11 16 39 SD 4.7 10.7 11.8 17 Range 1-25 1-49 1-48 13-92
Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors
Authors: Jacquelyn Nestor, Yoshiyuki Arinuma, Tomás S. Huerta, Czeslawa Kowal, Elham Nasiri, Nina Kello, Yuichiro Fujieda, Alison Bialas, Tim Hammond, Uma Sriram, Beth Stevens, Patricio T. Huerta, Bruce T. Volpe, Betty Diamond
Journal: The Journal of Experimental Medicine (2018)

Cognitive impairment occurs in 40–90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment. The latter pathology becomes evident only after DNRAbs are no longer detectable in the brain. Here we investigate the mechanism of long-term neuronal dysfunction mediated by transient exposure to antibody. We show that activated microglia and C1q are critical mediators of neuronal damage. We further show that centrally acting inhibitors of angiotensin-converting enzyme (ACE) can prevent microglial activation and preserve neuronal function and cognitive performance. Thus, ACE inhibition represents a strong candidate for clinical trials aimed at mitigating cognitive dysfunction.
FLYWCH1: A novel transcription factor with tumor suppressor activity
Authors: S. Almozyan
Journal: Annals of Oncology (2018)

Background: Wnt/bβ-catenin-signaling pathway is the principal force of intestinal hemostasis and morphogenesis. Aberrant activity of this pathway is highly implicated in cancer development, particularly in colorectal cancer (CRC). Although Wnt/β-catenin pathway is a well-studied pathway, the precise molecular mechanisms involved in the nuclear interactions of β-catenin with DNA-binding transcription factors (other than TCF4) are still under debates. Human FLYWCH1 has been first characterized and identified in our lab as a novel transcription factor, which interacts with nuclear β-catenin and modulates its transcriptional activity (Muhammed et al., under publication). FLYWCH1 differentially expressed between normal as well as between different stages of colorectal cancers. However, we have just started exploring the biological functions and mechanisms of FLYWCH1 in colon/ intestinal development, homeostasis and tumor formation. Methods: Loss- and gain-of-function analysis, CRISPR-Cas9, RNA-Seq, Western blotting, Immunoprecipitation, qRT-PCR, and immunofluorescence techniques. Results: Endogenous β-catenin physically interacts with the C-terminal domain of FLYWCH1 protein in human CRC cell lines. FLYWCH1 overexpression negatively regulates the expression of some but not all bβ- catenin/TCF4 target genes in CRC cell lines. R-spondin1 synergizes with Wnt-3A in repressing of FLYWCH1 in CRC cell lines. Conclusions: a) FLYWCH1 protein binds to the endogenous bβ-catenin protein while negatively regulates the transcription of a specific-subset of bβ-catenin /TCF target genes, regardless of Wnt signaling status. b) Activation of Wnt signaling forms a negative feedback loop during FLYWCH1 repressed β-catenin/TCF4 target gene in carcinogenesis. c) Our current and future studies with focuses on the in vivo role(s) of FLYWCH1 will provide insights on a novel molecular mechanism mediated by FLYWCH1 and the canonical Wnt/bβ-catenin pathway in CRC carcinogens, where may offer a new potential approach(s) and implications for future therapeutics. Legal entity responsible for the study: University of Nottingham. Funding: Saudi Government. Disclosure: The author has declared no conflicts of interest.
Tolerability and activity of tepotinib in Asian patients with advanced hepatocellular carcinoma (HCC).
Authors: Shukui Qin, Ho Yeong Lim, Baek-Yeol Ryoo, Cindy Li, Wenfeng Chen, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2016)

4072 Background: Patients (pts) with advanced HCC have a poor prognosis, particularly if tumor c-Met activity is aberrant. Current first-line therapy is sorafenib, which has limited efficacy and is not widely used in Asia. Tepotinib (MSC2156119J) is a highly selective c-Met inhibitor with favorable safety and promising antitumor activity, particularly in c-Met+ tumors. Translational modeling established a recommended phase II dose (RP2D) of 500 mg/day. All patients enrolled into a phase Ib trial of tepotinib in Asian pts with HCC have completed the dose-limiting toxicity (DLT) evaluation period and data are reported. Methods: Asian adults with confirmed HCC of BCLC Stage C, Child-Pugh Class A liver function without encephalopathy, and ECOG PS 0–2 were recruited to this 3+3 dose-escalation study (tepotinib 300 or 500 mg/day, 21-day cycle; protocol amendment added a 1,000 mg/day cohort, n = 6). In total, 12 patients were to be enrolled at the RP2D. c-Met expression was retrospectively determined by IHC. PK was analyzed by non-compartmental methods. Results: 27 pts were enrolled (median age 57 [38-69]; male 23; ECOG PS 0/1 11/15). 7 received tepotinib 300 mg/day, 14 500 mg/day, and 6 1,000 mg/day. No DLTs were observed. 22 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs); most were grade ≤ 2. The most common TRTEAEs were diarrhea (n = 10), elevated AST (7), nausea (7), and elevated ALT (6). 15 grade ≥ 3 TRTEAEs occurred, including grade 3 increased lipase levels (n = 3) and grade 3 diarrhea (n = 2). Best overall response (BOR) in pts with c-Met+ (n = 7) tumors was partial response (n = 2), stable disease (SD; n = 2), and progressive disease (PD; n = 3). The 2 pts with PRs were treated with tepotinib 500 and 1,000 mg/day, respectively; AFP levels in these pts were at least stabilized during response to tepotinib. Of 18 pts with c-Met– tumors, 6 had a BOR of SD, 10 PD, and 2 were not evaluable. Conclusions: Data indicate that tepotinib at doses of up to 1,000 mg/day is well tolerated by Asian pts with HCC. Efficacy appeared to be greatest in the c-Met+ population. The ongoing phase II part of this study is comparing the efficacy and safety of first-line tepotinib and sorafenib in pts with c-Met+ HCC. Clinical trial information: NCT01988493.
Efficacy and toxicities of gemcitabine and cisplatin combination chemotherapy in advanced thymoma and thymic carcinoma.
Authors: Jian Fang, Yang Wang
Journal: Journal of Clinical Oncology (2017)

e20007 Background: Thymoma and thymic carcinoma are rare thymic epithelial tumours. This study investigated the efficacy of first-line gemcitabine and cisplatin combination chemotherapy in advanced thymoma and thymic carcinoma Methods: Retrospective review of patients with histologically-confirmed invasive, metastatic thymoma or thymic carcinoma treated with gemcitabine plus cisplatin as a first-line therapy between August 2008 and February 2016 at the Department of Respiratory Medicine II Peking University Cancer Hospital and Institute. The objective response rate was the primary end point. Results: Forty patients, 13 with thymoma and 27 with thymic carcinoma, were identified. Nine received gemcitabine and cisplatin combined with Endostar (injectable recombinant human Endostatin); 31 received gemcitabine and cisplatin only. Of the 13 patients with thymoma, four (30.8%) achieved a partial response (PR) and nine (69.2%) had stable disease (SD); no patients had a complete response (CR) or progressive disease (PD). Among the 27 patients with thymic carcinoma, 13 (48.1%) achieved a PR, 12 (44.4%) had SD and two (7.4%) had PD; no patients had a CR. In thymic carcinoma, progression free survival (PFS) was 25 months and median survival (OS) was 41 months; in thymoma, median PFS was 29 months and median OS was 77 months. As no patients achieved a complete response, objective response was defined as partial response in this study. Conclusions: This retrospective analysis indicates gemcitabine plus cisplatin has moderate efficacy and could represent a suitable first-line therapy for thymic carcinoma and thymoma, especially for patents who cannot tolerate anthracyclines. [Table: see text]
Noradrenaline for Hepatorenal Syndrome in Patients With Acute on Chronic Liver Failure: Hope Remains!
Authors: Sandeep Satsangi
Journal: Hepatology (2018)

To the Editor: I read with great interest the article published recently by Arora et al.1 Hepatorenal syndrome (HRS) is a grave complication occurring in patients with acute on chronic liver failure (ACLF) and is associated with high short‐term mortality. It thus becomes extremely crucial to start appropriate and timely medical therapy in order to reverse this potentially lethal complication. The authors of this study have demonstrated terlipressin to be significantly better when compared to noradrenaline in causing reversal of HRS (40% versus 16.7%) in patients presenting with ACLF. In a study by Piano et al.2 response to terlipressin was noted in 53% of patients with ACLF having HRS, and the incidence of mortality was significantly lower in responders to therapy when compared to nonresponders (28% versus 57%). These data clearly emphasize the reversal of HRS as an important prognostic indicator in patients with ACLF. In clinical practice, it is quite common for the treating physician to encounter patients who are terlipressin‐intolerant despite using an infusion protocol as suggested by Cavallin et al.3 Profuse diarrhea is one of the most common side effects, leading to stoppage of terlipressin therapy. In the study by Arora et al.1 adverse events requiring discontinuation of the drug were reported in 15% of patients in the terlipressin arm compared to only 8% in the noradrenaline arm. It is this subset of patients which is extremely difficult to manage. I would be intrigued to know how the authors managed patients who were intolerant to terlipressin in their study and whether any such patients switched to noradrenaline therapy. In a study by Singh et al.4 noradrenaline was noted to be as effective as terlipressin at causing reversal of HRS. Though this study did not target sick patients with ACLF, it does provide clinically meaningful insight on the use of noradrenaline in patients with HRS. It would be extremely interesting and clinically meaningful to study the efficacy of noradrenaline in the subset of patients with ACLF having HRS who are intolerant to terlipressin. As reversal of HRS should be one of the prime foci in patients presenting with ACLF, future studies in this area are urgently needed. Potential conflict of interest Nothing to report.
Phase 1/2 open-label, multiple ascending dose trial of AGEN2034, an anti-PD-1 monoclonal antibody, in advanced solid malignancies: Results of dose escalation.
Authors: Kathleen N. Moore, Charles Dresher, Joyce Liu, David M. O'Malley, Edward Wenge Wang, Judy Sing-Zan Wang, Vivek Subbiah, Breelyn A. Wilky, Guojun Yuan, Christopher D Dupont, Ana M Gonzalez, David Savitsky, Sara Coulter, Olga Shebanova, Ed Dow, Igor Proscurshim, Jennifer Buell, Robert Benjamin Stein, Hagop Youssoufian
Journal: Journal of Clinical Oncology (2018)

3086 Background: Agenus AGEN2034 is a fully-human IgG4 monoclonal antibody antagonist targeting Programmed Cell Death Protein-1 (PD-1). The objective was to assess safety, MTD, pharmacokinetic (PK) and pharmacodynamics (PD) characteristics of AGEN2034 in patients (pts) with advanced, refractory malignancies. Analyses of PD-1 receptor occupancy on circulating CD8+ and CD4+ effector memory T lymphocytes was completed. Methods: Thirty pts were enrolled in escalating dose cohorts of 1, 3, and 10 mg/kg. AGEN2034 is administered intravenously Q2W for up to 2 years with cohorts evaluating q3wk dosing at 6 and 10 mg/kg are underway. Results: Ten subjects were enrolled at each dose level. Median age was 58 years (range 23–77) with ECOG 0–1. No DLTs were observed. Immune-related adverse events consistent with this drug class were observed of pneumonitis, colitis, diarrhea, rash and pruritus. 21 of 30 pts had treatment-related adverse events (TRAEs). 13 subjects (43%) discontinued (d/c) due to disease progression and 2 pts d/c due to TRAEs of hepatitis (n = 1) and pneumonitis (n = 1). In 25 evaluable heavily pre-treated pts, three partial responses (two confirmed) were noted in patients with cervical, ovarian and breast cancers in 1mg/kg and 3mg/kg cohorts. At the time of data cut-off, 13 patients had stable disease, including 5 of 5 with ovarian cancer. AGEN2034 demonstrates a dose-proportional Cmax of 19.6 µg/mL at 1 mg/kg and 73.6 µg/mL at 3 mg/kg in 12 patient samples analyzed in the first two cohorts. Average PD-1 receptor occupancy on circulating CD8+ and CD4+ effector memory T lymphocytes (n = 18) demonstrated > 59% saturation at all dose levels at day 15. Conclusions: AGEN2034 is a pharmacologically active, well-tolerated PD-1 antagonist antibody, demonstrating early signals of clinical activity in cervical and ovarian cancers. PK and RO results are comparable to commercial PD-1 antagonists. A phase 2 expansion in pts with relapsed/refractory cervical cancer is underway. Clinical trial information: NCT03104699.
Classifying lung cancer stage from health care claims with a clinical algorithm or a machine-learning approach.
Authors: Gabriel A. Brooks, Nancy Lynn Keating, Savannah L Bergquist, Mary Beth Landrum, Sherri Rose
Journal: Journal of Clinical Oncology (2018)

6589 Background: Cancer stage is a critical determinant of cancer outcomes, however stage is not available in claims-based data sources used for evaluating real-world outcomes. We compare two new methods for classifying lung cancer stage from claims data. Methods: We used the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data to identify patients with lung cancer diagnosis in 2011-‘12 who received chemotherapy within 6 months of diagnosis. We developed two approaches for using claims records to classify stage group (AJCC stage 1-3 vs. stage 4), using SEER stage as the gold standard. The first method was a clinical algorithm that assigned stage group based on treatment received (inclusive of surgery, radiation, and chemotherapy). The second method employed an ensemble of machine learning algorithms and analyzed an expanded set of claims-derived variables that considered treatments received, inpatient and outpatient visits, diagnosis codes, and demographic variables. We then used the Least Absolute Shrinkage and Selection Operator to select parsimonious variable sets of ≤ 10, 15, 20, 30, 40, and 50 variables. Classification methods were evaluated and compared on the basis of sensitivity, specificity, and accuracy, in reference to the stage 1-3 group. Results: The study sample included 14,743 patients with a mean age of 72.1 years. 54.6% were male. The best performing machine-learning classifier was the random forests algorithm. Sensitivity, specificity, and accuracy for the clinical algorithm were 53% (95% CI = 52-54%), 89% (88-90%), and 71% (71-72%), vs. 91% (90-92%), 89% (88-90%), and 90% (90-91%) for the random forests with 15 variables. Key variables for the random forest algorithm included secondary malignancy codes, treatments received (including type of surgery, number of radiation fractions, and specific chemotherapies), presence of COPD, and geographic region. Conclusions: Compared with a clinically derived algorithm, a machine-learning classifier demonstrated substantially improved sensitivity and accuracy. Improved accuracy of claims-based stage classification can support clinically relevant, real-world analyses of cancer care quality and outcomes.
Factors associated with the growth of ground-glass opacity nodules on chest computed tomography.
Authors: Jin Hwa Lee, Ji Yun Bae, Ye ji Han, Yon Ju Ryu, Sung Shine Shim, Yookyung Kim, Jung Hyun Chang
Journal: Journal of Clinical Oncology (2017)

e20051 Background: Chest computed tomography (CT) has become increasingly popular for screening and various reasons, and many cases of ground-glass opacity pulmonary nodules (GGN) that cannot be detected by simple chest radiography have been found incidentally. However, the natural history of GGN is not well understood and guidelines for the evaluation and follow-up of GGN have not yet been established yet. The purpose of this study was to investigate the clinical and CT scan characteristics associated with the growth of GGNs. Methods: We retrospectively reviewed GGN on chest CT performed between March 2011 and February 2014 at a tertiary referral hospital. Data were collected for the patient's age, sex, underlying lung disease, history of malignancy or comorbidities, size, border, number of GGN and presence of solid portion in GGN. For each GGN, an increase in size over time was investigated. We applied a Cox regression analysis to identify factors associated with the growth of GGN. Results: In a total of 504 patients, 916 GGN were found on chest CT. The mean age of the subjects was 59.6 years and 37% of men. The mean follow-up was 17.1 months. Cox regression analysis was performed on age, sex, history of malignancy, maximum diameter of GGN, number of GGN, margins of GGN, and presence of solid portion in GGN. History of malignancy (adjusted hazard ratio [HR] 1.770, 95% confidence intervals [CI] 1.049-2.986, p = 0.032), solitary nodule (adjusted HR 2.335, 95% CI 1.401-3.867, p = 0.001), and nodules with the longest diameter of 10 mm or more (adjusted HR 1.833, 95% CI 1.032-3.253, p = 0.039) were associated with the growth of GGN. Conclusions: A history of malignancy, solitary nodule, and nodules with the longest diameter of 10 mm or more may increase in size in the future. Therefore, the history of malignancy and the size and number of nodules should be considered to determine the duration of follow-up and appropriate biopsy timing.
TCT-773 Procedural Volume and Outcome With Radial or Femoral Access for Percutaneous Coronary Intervention in Patients With ST-segment Elevation Myocardial Infarction
Authors: Nam Kyun Kim, Jang Hoon Lee, Yoon Jung Park, Bo Eun Park, Hong Nyun Kim, Se Yong Jang, Myung Hwan Bae, Dongheon Yang, Hun Sik Park, Yongkeun Cho, Shung Chull Chae
Journal: Journal of the American College of Cardiology (2018)