tbuckley/cabot-search huggingface dataset:
Ratio of M2 tumor-associated macrophages as a better prognostic and predictive biomarkers for postoperative adjuvant chemotherapy in patients with stage II colon cancer.
Authors: Jianmin Xu, Qingyang Feng, Wenju Chang, Yihao Mao, Wentao Tang, Ye Wei, Li Ren, Guodong He, Yunshi Zhong, Dexiang Zhu, Jingwen Chen, Tuo Yi, Qi Lin, Meiling Ji
Journal: Journal of Clinical Oncology (2018)

e15582 Background: For stage II colon cancer, the effect of postoperative adjuvant chemotherapy is still controversial. M2 subtype of tumor-associated macrophages (TAMs) play an important role in promoting tumor progression. This study determined M2 TAMs as prognostic and predictive factor for adjuvant chemotherapy for stage II colon cancer. Methods: From 2009-07 to 2012-06, 521 patients with pathological stage II colon cancer were included. TAMs were detected using tissue microarray and immunohistochemistry (total TAMs by CD68; M2 subtype by CD206), also was MSI status. The density of total TAMs, M2 TAMs, and M2 TAMs / total TAMs ratio (M2 TAMs ratio) were calculated. Results: High M2 TAMs ratio was significantly associated with reduced disease-free survival (P < 0.001) and overall survival (P < 0.001), and had better prognostic power than M2 TAMs density, total TAMs density, and other clinicopathological high-risk factors. Furthermore, only patients with high M2 TAMs ratio can benefit from adjuvant chemotherapy, not only in total study population, but also in subgroup with clinicopathological high-risk factors (Table 1). Conclusions: For stage II colon cancer, M2 TAMs ratio was a good prognostic and predictive biomarker for postoperative adjuvant chemotherapy. It might facilitate patient counselling and individualise management. Table 1: M2 TAMs ratio as predictor for adjuvant chemotherapy Subgroup Total population T3 with high-risk factors or T4 M2 TAMs ratio Low High Low High Chemotherapy Yes n = 190 No n = 245 Yes n = 50 No n = 36 Yes n = 129 No n = 62 Yes n = 40 No n = 14 3-year DFS rate (%) 86.8 88.2 68.0 38.9 84.5 87.1 65.0 21.4 Log-rank P value 0.986 0.003* 0.660 0.001* HR 0.996 0.417 0.859 0.285 95% CI 0.614-1.615 0.225-0.771 0.435-1.696 0.132-0.616 Interaction P value 0.023* 0.024* 5-year OS rate (%) 90.3 91.5 75.8 47.8 88.8 89.5 74.7 37.5 Log-rank P value 0.706 0.029* 0.989 0.039* HR 1.129 0.460 0.996 0.389 95% CI 0.601-2.119 0.225-0.942 0.404-2.479 0.153-0.988 Interaction P value 0.063 0.136 HR: hazard ratio; CI: confidence interval; high-risk factors: according to NCCN guidelines for colon cancer; bold font: P < 0.1; *: P < 0.05.
Abstract 13921: Dysfunctional Bone Morphogenetic Protein Signaling Interlinks With Interleukin-1ß Mediated Inflammation in Pulmonary Arterial Hypertension
Authors: Josephine A Pickworth, Sheila Shay, Santhi Gladson, James Iremonger, Alex M Rothman, Sheila Francis, James West, Allan Lawrie
Journal: Circulation (2015)

Rationale: Bone morphogenetic protein receptor type 2 (BMPR2) mutations are found in heritable and idiopathic pulmonary arterial hypertension but disease penetrance is incomplete implying the necessity for a ‘second hit’. IL-1ß and IL-6 are increased in PAH patients and animal models and are proposed to play a critical role in disease. Objective: To determine pulmonary specific interplay between BMPR2 and IL-1ß signaling by exploring differences between pulmonary artery and aortic smooth muscle cells (PA / Ao SMC) in response to IL-1ß, and determine the effects of reduced BMPR2 expression using in vitro and in vivo disease models. Methods and Results: Microarray analysis of PASMC and AoSMC mRNA show reduced inflammatory pathway activation in response to IL-1ß in PASMC compared with AoSMCs. Pathway analysis identified an exaggerated inflammatory response to IL-1ß in PASMC lacking BMPR2 (siRNA). Significant up-regulation of IL-6, IL-1α and adhesion molecules (&gt;2-fold) shown by array analysis was validated by qPCR. In the absence of BMPR2 a 1.5-fold increase in proliferation was observed in response to IL-1ß that is not present in PASMC with functional BMPR2. To study this further, R899X+/- BMPR2 transgenic mice were fed western diet for six weeks and given daily injections of IL-1ß. Mice were assessed for inflammatory activation and PAH phenotype (catheter/echo). mRNA and protein changes were measured by TaqMan PCR, western blotting and serum ELISA. Mice treated with IL-1ß had significantly higher white blood cell counts (1.7-fold), and showed trends for increased mRNA of VCAM1, IL-1α (whole lung) and significantly raised serum protein levels of IL-6 and OPG matching in vitro data. IL-1ß treated mice had an increase in early pulmonary vascular remodelling and the full assessment of the inflammatory cell infiltrate in R899X+/- mice is currently underway. Conclusion: IL-1ß induces a pulmonary artery specific transcriptome that is altered by suppression of BMPR2 signaling in vitro. In vivo and in vitro IL-1ß drives an exaggerated inflammatory response under conditions of reduced BMPR2 signaling. This research highlights a mechanism by which increased IL-1ß may provide a “second hit” to reduced BMPR2 signaling and stimulate or potentiate the development of PAH.
Genetic mutation as biomarker for advanced cancer patients receiving apatinib: An analysis based on whole exome sequencing.
Authors: Yong Fang, Yulong Zheng, Jun Chen, Jieer Ying, Haizhou Lou, Enguo Chen, Da Li, Chuangzhou Rao, Fangmin Du, Jiawei Shou, Hongming Pan
Journal: Journal of Clinical Oncology (2018)

e24219 Background: Apatinib, a VEGFR-2 inhibitor, has shown significant anti-tumor effects in the treatment of advanced solid tumors. However no biomarkers identified to predict the benefits treated with apatinib. In this retrospective analysis, using whole exome sequencing (WES) analysis based on the next-generation sequencing (NGS) detection, the gene mutation was assessed to identify the possible biomarkers associated with survival benefit. Methods: 39 pts with advanced solid cancer resistant to routine chemotherapy or radiotherapy were enrolled. All the pts were divided into 2 groups, 26 pts with PFS≥90days and 13 pts with PFS < 90 days. WES was performed to depict the comprehensive genomic features. The captured sequencing data was further processed to identify somatic mutations. The FISHER Exact statistical test was used to find significant differentially genes between 2 groups. Results: Based on the WES detection, ERICH3, CNTNAP3 and MUC6 p.G1946D mutation only detected in pts with PFS≥90 days, while no mutation of these 3 genes in pts with PFS < 90 days. Pathway analysis showed that ERICH3 and CNTNAP3 mutation could induce the change of drug target or affect the intake of drug through the cell membrane, the MUC6 mutation could change the cell adhesion signal pathway. The differences were also observed in the following gene mutation between 2 groups. 1. COL6A3, MYLK, and BMPR1B, could activate bypass vascular signaling pathway; 2. SLC2A3 and YME1L1, could influence the concentration of reactive oxygen species in tumor tissues; 3. ICAM5, could affect tumor invasion signal pathway. All the above 3 signal pathways with gene mutation were related to drug-resistance. Conclusions: The ERICH3, CNTNAP3 and MUC6 gene mutation might be associated with longer PFS. The mutation in drug-resistant related pathway might affect the survival benefit. Further prospective study is needed to discover the possible biomarker of Apatinib. Table 1 Mutant status of ERICH3, CNTNAP3 and MUC6 p.G1946D. N PFS≥90 n (%) PFS < 90, n (%) P ERICH3 wild type 32 0 (0) 32(100) < 0.0001 mutation 7 7 (100) 0 (0) CNTNAP3 wild type 32 0 (0) 32(100) < 0.0001 mutation 7 7 (100) 0 (0) MUC6 p.G1946D wild type 32 0 (0) 32(100) < 0.0001 mutation 7 7 (100) 0 (0)
TCT-418 Association between Body Mass Index and 1-year MACCE after Acute Myocardial Infarction
Authors: Dae-Won Kim, Sung-Mi Kim, Kyun Young Kim, Dong-Bin Kim, Sung-Ho Her, Jee Hyuk Kim, Myun Hee Lee, Byung-Hee Hwang
Journal: Journal of the American College of Cardiology (2018)
First-in-human phase 1 study of TAK-931, an oral cell division cycle 7 (CDC7) inhibitor, in patients (pts) with advanced solid tumors.
Authors: Toshio Shimizu, Toshihiko Doi, Shunsuke Kondo, Hideaki Takahashi, Noboru Yamamoto, Emily Sheldon-Waniga, Xiaofei Zhou, Brittany Bahamon, Hongmei Li, Yasutoshi Kuboki
Journal: Journal of Clinical Oncology (2018)

2506 Background: TAK-931 is an oral selective inhibitor of CDC7, a protein kinase with key roles in DNA replication and DNA damage response. TAK-931 has demonstrated potent antitumor activity in various preclinical models. Methods: We evaluated safety, dose limiting toxicity (DLT), maximum tolerated dose (MTD), and preliminary antitumor activity of TAK-931 in pts with advanced solid tumors. Four schedules are being tested, and we report data from Schedule A: TAK-931 QD for 14 days on/7 days off in 21-day cycles. A Bayesian logistic regression model with overdose control was used to guide dose escalation and MTD estimation. Results: As of 14-Nov-2017, 25 Japanese pts (60% male; median age 59 [range 42–75] years) were treated with TAK-931 30 mg (n = 3), 40 mg (n = 3), 60 mg (n = 3), and 50 mg (n = 16: 7 pts in dose escalation, 9 pts in expansion). Pts received a median of 3 cycles (range 1–12). Most common any-grade adverse events (AEs) were nausea (n = 15), neutropenia (n = 12), decreased white blood cells (WBCs) (n = 8), decreased appetite, vomiting, and diarrhea (each n = 7). Most common grade ≥3 AEs were neutropenia (n = 11), decreased WBCs (n = 3), leukopenia, and decreased appetite (each n = 2). DLTs (grade 4 neutropenia) were observed in 2 of 3 pts at 60 mg; 50 mg was considered the MTD. Preliminary pharmacokinetics (PK) showed increased systemic exposure of TAK-931 in a dose proportional manner between 30 and 60 mg, with minimal accumulation and mean terminal elimination half-life of 5.4 hours (15% CV). Dose-dependent inhibition of pMCM2, a direct substrate of CDC7, was observed in skin biopsies from most pts treated with TAK-931, which correlated well with drug exposure (R2= 0.6598). Partial responses were observed in pts with duodenal, esophageal, and cervical cancers (1 pt each) as well as prolonged stable disease of ~6 months in a bladder cancer pt and ~9 months in a pancreatic cancer pt. Conclusions: TAK-931 demonstrated an acceptable safety profile with early signs of clinical antitumor activity. Isolated neutropenia was the DLT with the tested schedule. Strong pharmacodynamic (PD) effects and PK-PD correlation provide clinical evidence of target engagement of TAK-931 in pts. Clinical trial information: NCT02699749.
Somatic, psychological, and social complaints after surgery: The perspective of breast cancer survivors.
Authors: Monika Klinkhammer-Schalke, Brunhilde Steinger, Michael Koller, Patricia Lindberg
Journal: Journal of Clinical Oncology (2016)

e21564 Background: The subjective experiences of survivors of breast cancer shape the concept of the illness in their social environment. We combined qualitative and quantitative methods to investigate how long-term survivors remember their postoperative complaints. Methods: Long-term follow-up (6-8 years after diagnosis) was conducted with participants of an earlier randomized trial on quality of life of female primary breast cancer patients (eligible patients n= 166). Survivors received a questionnaire package including a question about their ‘worst postoperative complaints (somatic/ psychological/ social) at discharge from hospital’ (multiple answers possible). A category system was created and answers were categorized by two independent raters. Descriptive statistics were used to analyze frequencies of categories. Results: 133 women (age M= 64.2 years, SD= 10.8; time since surgery M= 84.8 months, SD= 5.6) returned the questionnaire with 107 answering the question about worst postoperative complaints. Of those, 54% (n= 58) named psychological complaints, with anxiety as the most common subcategory (n= 39, 36%; e.g. fear of recurrence n= 11; fear of adjuvant therapies n= 11; uncertainty about the future n= 8), followed by depression (n= 3, 3%). Half of the survivors (n= 53) reported somatic complaints, particularly pain (n= 14, 13%) and impairments of the arm/ shoulder movement (n= 13, 12%), followed by the loss of a breast after mastectomy (n= 6, 6%), chemotherapy with side-effects (n= 5, 5%), and weakness/ fatigue (n= 3, 3%). Social complaints were mentioned only by eleven women (10%; e.g. expected limitations in work/ household n= 3; worries of family n= 2; separation from family n= 2; financial difficulties n= 2). Ten survivors (9%) reported that they had no severe postoperative complaints and four answered they could not remember (4%). Conclusions: The most prominent postoperative complaints recollected by breast cancer survivors were anxiety in the psychological domain and pain and impaired arm/ shoulder movement in the somatic dimension whereas social aspects were hardly mentioned. This knowledge should be used to provide specific support in primary medical treatment.
Induction capecitabine and cisplatin followed by hypofractionated radiotherapy in locally advanced head and neck cancer.
Authors: Quratul Ain Hashmi, Abdul Mateen, Muhammad Saqib Khan, Allah Rakha Adil, Arif Moin Duraishi, Famya Abdullah
Journal: Journal of Clinical Oncology (2018)

e18012 Background: Induction chemotherapy (IC) in locally advanced head and neck cancer (HNC) has not shown any survival benefit in spite of higher response rates in these patients. We tested IC using capecitabine and cisplatin (CC) in these patients having in mind two things. Firstly, reduction in IC treatment duration leading to less chance of resistant clonogens to repopulate and secondly reduce the burden of indoor patients in overloaded department. Hypofractionated radiotherapy (HRT) was used to reduce the overall treatment time. Methods: A total of 75 patients with biopsy proven HNC were included. Patients having primary tumor in oropharynx (19), larynx (24) and hypopharynx (32) with TNM stage III to IVB were selected. The patients were planned for three cycles of CC every three weeks in a dose of 1000 mg/m² twice in a day for 14 days and 80 mg/m² on D1 of each cycle respectively. After three cycles of chemotherapy, patients were planned for HRT. A total of 55 Gray (Gy) was planned with 2.75 Gy per fraction and five fractions a week. Spinal cord dose was limited to 33 Gy. Response Evaluation Criteria in Solid Tumor (RECIST) was used to assess various response rates using computed tomography (CT) after IC and six weeks after completion of HRT. Results: 69 patients (92%) were available for assessment. Rest were excluded due to inability to complete planned treatment. Six patients (8%) showed disease progression during treatment and were switched to other treatment. 11 patients (16%) showed grade 3 mucosal toxicity and needed treatment interruption. 8 patients (12%) showed hematological related grade 1-2 toxicity. The complete response (CR) was seen in 23 (31%), partial response (PR) in 35 (47%) and stable disease SD in 11 (15%) patients. There was no statistically significant difference in response rate between male and female, and according to age. There was significant difference in response rates between stage III and IV patients. Conclusions: Induction CC followed by HRT is a reasonable in locally advanced HNC but a longer follow up with comments on disease free and overall survivals must be reported before any recommendations.
OS5.6 Issues and needs experienced by adolescent and young adult brain tumour survivors and their caregivers: A systematic review
Authors: E Nicklin, G Velikova, C Hulme, F Boele
Journal: Neuro-Oncology (2018)

Long term issues following diagnosis and treatment of a childhood brain tumour often become apparent as the survivor enters adolescence and young adulthood. These issues can spillover to the survivors’ informal caregivers with emotional and psychological impacts. This systematic review aimed to identify and synthesise evidence on the issues and unmet needs of adolescent and young adult (14–39 y) survivors of a brain tumour diagnosed in childhood (0–14 y) and their caregivers. Medline, Embase, PsycINFO, Web of Science, Pubmed, CINAHL, NICE evidence database and the Cochrane Library were searched from inception to August 2017. All studies reporting on issues or needs of brain tumour survivors (aged 14–39) and their caregivers were included. A random sample (20%) was independently screened by a second reviewer. Quality was assessed using the Mixed Methods Appraisal Tool. Narrative synthesis methods were used to summarise, integrate and interpret the findings of the articles included within the review. In total, 3768 unique articles were identified, of which 645 were reviewed in full text. 56 were included. Quality of articles was varied, many studies scored poorly in acceptable response rates (defined as under 60%). Social issues (isolation, relationships) were most commonly reported by survivors, followed by cognitive (attention, memory) and physical issues (appearance, fitness). Medulloblastoma survivors and those with more invasive treatment experienced more challenging issues than other subgroups. Caregivers similarly reported concerns around survivors’ ability to succeed socially, academically and their current/ future health. Caregivers themselves had little time and energy to maintain their own wellbeing or that of other family members. Unmet supportive care needs were less frequently reported. Survivors expressed a need for educational support and age-specific psychosocial services; including face-to-face/virtual support groups and opportunities to socialise with other survivors. Caregivers felt a loss of support as the survivor moved further away from their treatment into young adulthood. They most frequently mentioned the need for caregiver support groups, survivorship education classes, and age-matched social support groups for survivors. Surviving a childhood brain tumour can be particularly challenging for adolescent and young adult patients and their caregivers. Survivors and caregivers continue to report long-term issues and unmet needs throughout follow-up. More research is needed on the specific unmet support needs of both survivors and their caregivers and how support services can best meet these needs. This could improve quality of life in survivorship.
The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling
Authors: Fabiana Csukasi, Ivan Duran, Maya Barad, Tomas Barta, Iva Gudernova, Lukas Trantirek, Jorge H. Martin, Caroline Y. Kuo, Jeremy Woods, Hane Lee, Daniel H. Cohn, Pavel Krejci, Deborah Krakow
Journal: Science Translational Medicine (2018)

Disrupting the PTH/PTHrP-SIK3 pathway impairs degradation of DEPTOR, affects mTOR signaling, and leads to abnormalities in skeletal development.
Prospective comparison of invasive circulating tumor cells (iCTCs) vs PSA and mpfs in prostate cancer (PC) treated with SM-88.
Authors: Wen-Tien Chen, Terence W. Friedlander, Huang Dong, Qiang Zhao, Giuseppe Del Priore
Journal: Journal of Clinical Oncology (2018)

e24072 Background: SM-88 is a relatively non-toxic novel combination of dysfunctional tyrosine and repurposed agents (CYP3a4 inducer, mTOR, oxidative stress catalyst) with activity in PC. PSA, mPFS and iCTCs were assessed in a Phase Ib/II trial. Methods: Blood from men treated with SM-88 for biochemically recurrent non-metastatic PC (nmPC) was prospectively examined for iCTCs and PSA at each cycle. A cell adhesion matrix (CAM)-based platform, Vita-Assay™ plate (two-step) and Vita-Cap™ tube (single-step), were used to enrich metastasis-initiating cells from blood. Isolated cells were identified and enumerated by flow cytometry using tumor progenitor and epithelial markers plus negative hematopoietic lineage markers to identify iCTCs. Serial changes in iCTCs and PSA were measured in 124 blood and 305 serum samples, respectively, from 13 PC patients to assess their concordance and relationship with radiographic or metastasis progression free survival (mPFS). Results: Among 13 subjects with Vita-Assay™ iCTC results, there were 11/13 with reduction within the 1st cycle (28 days). Thereafter all 11 had continued reduction of iCTCs with median of 6 wks to nadir, and 5 having undetectable levels a median of 7 wks on treatment. Two of 124 iCTC assays had high background red cell due to microclots in transit. Correlation of the iCTC assays enriched by Vita-Assay™ vs Vita-Cap™ was r2= 0.78 (P < 0.0001). 83% (10/12 subjects with ≥ 3 cycles of treatment) had an improvement in PSA velocity and at least one decrease in PSA. There were 2 biochemical progressions (PCWG3 criteria), one of which also had radiographic progression. iCTC results matched PSA PD and local PD was confirmed by CT 12 wks later. The other progression was predicted 8 wks earlier by iCTCs than PSA (iCTC sensitivity and specificity for PD = 100%). Other biomarkers (LDH, uNTX, neutrophil:lymphocyte, bsAlkP) did not predict mPFS or PSA rise. Conclusions: Treatment with SM-88 in patients with nmPC in a phase Ib/II cohort was associated with iCTC reduction, and PSA stability. iCTCs prospectively correlate with prolonged mPFS despite equivocal PSA results, and predicted both biochemical and radiographic progression. Clinical trial information: NCT02796898.
CCGs win right to offer patients Avastin for wet AMD
Authors: Deborah Cohen
Journal: BMJ (2018)

A group of 12 clinical commissioning groups in the north of England have won a legal battle to offer patients a choice to use off-label bevacizumab to treat wet age related macular degeneration, which they say will save the NHS millions of pounds.

In November last year the drug companies Novartis and Bayer brought legal proceedings against the CCGs because they had decided to offer bevacizumab (Roche’s Avastin), which is not licensed for treatment of wet AMD, alongside ranibizumab (Lucentis, marketed by Novartis) and aflibercept (Bayer’s Eylea), which are approved by the UK National Institute for Health and Clinical Excellence for treating the condition in the NHS.1

The companies opposed the policy on four grounds: they said that the supply of bevacizumab was unlawful because it was not licensed for ophthalmic use; it undermined drug regulation; it undermined patients’ right to have a NICE approved drug; and the patient information sheet accompanying the policy was misleading.

However, in the High Court Mrs Justice Whipple dismissed the application for judicial review on all grounds and found in favour of the CCG’s policy. She said that the companies’ arguments that the NHS could not consider bevacizumab unless Roche applied for a licence for …
Abstract 17650: Outcomes Of Critically Ill Peripartum Cardiomyopathy Treated With Extracorporeal Membrane Oxygenation
Authors: Hansie M Mathelier, Satya Shreenivas, Jesus E Rame, Michael A Acker, Nimesh D Desai
Journal: Circulation (2013)

Introduction: Severe refractory cardiogenic shock (SRCS) has in-hospital mortality approaching 60-80%. Treatment of SRCS with temporary circulatory support options such as peripheral ventricular as...