tbuckley/cabot-search huggingface dataset:
Molecular comparison of interval and screen-detected breast cancers.
Authors: Dane Anthony Cheasley
Journal: Journal of Clinical Oncology (2018)

12124 Background: Breast cancer diagnosed after a negative mammogram but prior to the next screening episode are termed an “interval breast cancer” (IBC) and account for ~20% of breast cancer diagnoses in women attending population-based screening programs. IBCs are a major issue limiting the effectiveness of mammographic screening particularly as IBCs are generally diagnosed at later stages and have a worse prognosis in compared to screen detected breast cancer (SDC). To understand if IBC are biologically distinct from SDC we assessed the frequency of germline and acquired somatic genomic aberrations in a prospective cohort is 1060 screen detected and interval breast cancers. Methods: Using the Lifepool cohort, an Australian prospective population-based cohort of over 54,000 women, 1001 cases of breast carcinoma (811 invasive and 180 in situ) with known screening status at time of diagnosis were identified. Clinicopathological information, mammographic density data, and family history data was recorded. Germline and tumour DNA was also collected where available and sequenced for breast cancer predisposition and driver genes. Results: IBCs were significantly associated with more aggressive tumour characteristics including higher grade, more advanced stage and higher proportion hormone receptor negative cancers. Women diagnosed with an IBC also had a higher frequency of actionable germline mutations in HBOC genes (4.4% versus 2.3%). Analysis of the breast cancers did not identify any significant differences in the somatic mutation spectrum or frequency, overall copy number profiles or homologous recombination deficiency scores. Conclusions: In the emerging era of clinical sequencing, it is timely to investigate the genomic alterations of IBCs, as they impose a major limitation on effective mammography screening and are associated with a high mortality burden. Within this study, Clinicopathological and molecular differences observed rather form the continuum from less aggressive (SDC) to more aggressive (IBC) cancers. Whilst analysis of an actionable germline mutations revealed subtle risk increases in IBCs (in particular BRCA2), additional cohorts will be required to define
Association of polymorphism in YB-1 regulating androgen receptor V7 expression with efficacy of androgen-deprivation therapy in metastatic prostate cancer.
Authors: Masaki Shiota, Naohiro Fujimoto, Kenjiro Imada, Akira Yokomizo, Ario Takeuchi, Hidetoshi Kuruma, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Yoshinao Oda, Seiji Naito, Masatoshi Eto
Journal: Journal of Clinical Oncology (2016)

e16562 Background: Although aberrant kinase activation has been proposed as a mechanism for obtaining castration resistance, comprehensive kinase profiles in castration-resistant prostate cancer (CRPC) remain unknown. Therefore, we aimed to elucidate the kinome in CRPC as well as the role of key molecules in the progression to CRPC among men treated with primary androgen-deprivation therapy for metastatic prostate cancer. Methods: We utilized kinome array to compare comprehensive phosphorylation status between androgen-dependent and castration-resistant cells. Also, the effect of Y-box binding protein-1 (YB-1) on androgen receptor (AR) expression was examined. The association between gene polymorphisms in the YB-1 gene and YB-1 expression in prostate cancer tissues as well as outcome in metastatic prostate cancer were investigated. Results: Various kinases, including ERK and RSK, were activated in CRPC cells, leading to increased phosphorylation of YB-1, which is a key molecule in the progression to CRPC. YB-1 signaling regulated AR V7 expression and YB-1 inhibition augmented anticancer effect of enzalutamide in 22Rv1 cells. Moreover, polymorphism (rs12030724) in YB-1 gene affected YB-1 expression in 93 prostate cancer tissues (YB-1 positive rate; 14.3% in TT, 40.0% in AT, and 52.9% in TT, AA, P = 0.04), as well as associated with progression-free survival in 104 metastatic prostate cancer cases (AA vs AT/TT, hazard ratio=2.02, 95% confidence interval=1.31–3.17, P = 0.001). Conclusions: YB-1 appears to be a promising target to inhibit the development of castration resistance even at the AR variant-expressing stage. Polymorphism in YB-1 gene may be a promising predictive biomarker in hormonal therapy. Progression-free survival rates between YB-1 polymorphisms*. Variable Gene SNP Major/ minor allele Secondary model (dominant) P value Secondary model (recessive) P value Major homozygote 1 or 2 minor allele 1 or 2 major allele Minor homozygote YB-1 rs10493112 C/A HR (95% CI) 1 1.06 (0.68- 1.64) 0.78 1 1.25 (0.31- 3.37) 0.71 rs12030724 A/T HR (95% CI) 1 0.49 (0.32 -0.77) 0.001* 1 0.75 (0.36- 1.39) 0.38 rs10493113 C/T HR (95% CI) 1 0.88 (0.53- 1.41) 0.60 - - -
Inhibition of hypoxia-inducible factor-1α by PX-478 as a potential targeted therapy in ESCC.
Authors: Yingming Zhu, Yuanwei Zang, Minghuan Li, Jinming Yu
Journal: Journal of Clinical Oncology (2017)

e14083 Background: Hypoxia is a unique microenvironment in solid tumors, including ESCC. We aim to investigate the interaction between hypoxia-inducible factor-1α (HIF-1α), COX-2 and programmed cell death ligand-1 (PD-L1) and uncover the role of HIF-1α inhibitor PX-478 as a potential targeted therapy in ESCC. Methods: Immunohistochemical staining was performed to investigate the levels of HIF-1α, COX-2 and PD-L1 from 133 pT3N0M0 ESCC patients after radical resection. The prognostic value of the expression of HIF-1α, COX-2 and PD-L1 and the correlation with clinicopathologic features was evaluated. Knockdown assay, CCK-8 assay, Western blot, real-time polymerase chain reaction (RT-PCR), flow cytometry and Transwell migration assays were used in cells experiment. Results: HIF-1α and PD-L1 are independent prognostic factors in pT3N0M0 ESCC. Further data showed that HIF-1α plays an important role in regulation of COX-2 and PD-L1 expression. Our in vitro studies demonstrated that HIF-1α inhibitor, PX-478, induced G2 phase arrest, increased apoptosis, and inhibited migration and invasion of esophageal carcinoma cells, and thus significantly inhibit ESCC cells proliferation. Conclusions: Our results provide new insight into the potential role of HIF-1α inhibitors, PX-478 and open up the possibility of PX-478 for targeted therapy of ESCC.
Inferior vena cava leiomyosarcoma: A single-institution experience.
Authors: Brittany Siontis, Laurence H. Baker, William Burns, Scott Schuetze, Rashmi Chugh
Journal: Journal of Clinical Oncology (2018)

e23556 Background: Vascular leiomyosarcomas (LMS) are rare tumors that often arise from the inferior vena cava (IVC). Despite several surgical case series in the literature, there remains little data on outcomes of patients who undergo multimodal therapy. We review the University of Michigan (UM) experience with IVC LMS. Methods: We identified patients (pts) > 18 years (yr) with IVC LMS treated at UM using an institutional database. We extracted clinical, pathologic and treatment-related data. Survival curves were generated using the Kaplan-Meier method. Results: We identified 27 pts with IVC LMS with a median follow-up of 3 yr (0.1-7.3). Results displayed in Table 1. Median overall survival (OS) was and 44 months (mo). 4 pts had metastases (mets) at dx. 10 additional pts developed mets at a median of 12 mo (2-50 mo) after dx. 18 pts (67%) underwent resection with significantly improved OS (65 vs 43 mo, p = 0.007). Pre-surgical biopsy (bx) and surgical grade were discordant in 2/8 pts (25%). Chemotherapy was administered to 17 pts (63%, median 4 lines (range 1-6)). Stable disease or better > 6 mo with: A-based (n = 3/15), GD (n = 2/14) and trabectedin (n = 2/7). Conclusions: In our series, patients able to undergo resection had improved OS. The majority of pts developed metastases, yet OS for all pts was relatively favorable at 44 mo. Tumor grade upgraded in 25% of pts after surgery suggesting heterogeneity and potential failure to identify high-grade disease on bx. Table 1. Variable P - value Age, median (range) 61 (26-81) Female, n (%) 19 (70) Tumor Size (cm), median (range) 7.5 (2.6-16.5) Grade, n (%) Bx (n = 8) Surgical (n = 18) G1 2 (25) 1 (5.5) G2 1 (12.5) 2 (11) G3 5 (62.5) 15 (83.3) Treatment, n (%) Resection 18 (67) Metastasectomy 8 (30) Chemotherapy 17 (63) Radiation 9 (33) PFS (mo), median (IQR) Yes No 0.002 Resection 25 (12-88) 4 (1-14) 0.813 Chemotherapy 14 (11-25) 9 (11-25) OS (mo), median (IQR) Yes No 0.007 Resection 65 (35-72) 43 (35-72) 0.490 Chemotherapy 61 (35-67) 36 (1-70) 1st Line Chemotherapy Intent, n (%) Neoadjuvant 2 (11.7) Adjuvant 7 (41.2) Palliative 8 (47.1) 1st Line Chemotherapy Regimen, n (%) Anthracycline-based 11 (64.7) Gemcitabine-Docetaxel 6 (35.3) Location of Metastases, n (%) Liver 9 (64.3) Lung 9 (64.3) Retroperitoneum 6 (42.9)
A phase Ib study of JS001, a humanized IgG4 mAb against programmed death-1 (PD-1) combination with axitinib in patients with metastatic mucosal melanoma.
Authors: Jun Guo, Xinan Sheng, Lu Si, Yan Kong, Zhihong Chi, Chuanliang Cui, Bixia Tang, Xieqiao Yan, Li Li Mao, Bin Lian, Xuan Wang, Siming Li, Li Zhou, Xue Bai, Jie Dai
Journal: Journal of Clinical Oncology (2018)

9528 Background: There was no standard treatment for metastatic mucosal melanoma. Preclinical data showed that axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model. JS001 is a humanized IgG4 mAb against programmed death-1 (PD-1) with clinical activity in metastasis melanoma.This study is a phase Ib dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of JS001 combination with axitinib in patients with metastatic mucosal melanoma. Methods: Eligibility criteria include: histologically confirmed metastatic mucosal melanoma, archival or fresh tumor biopsy, ECOG PS 0-1, no prior system treatment. The patients will receive JS001 (1mg/kg or 3 mg/kg IV Q2W) combined axitinib (5 mg BID) in dose-finding and dose-expansion parts and treatment will be given until confirmed disease progression, unacceptable toxicity, withdrawal, or study termination. After the MTD or the optimal biological dose is identified, an expansion cohort of 30 patients were enrolled to further characterize the safety and efficacy. Other objectives include pharmacokinetics, pharmacodynamics, immunogenicity and tumor tissue biomarkers. Results: Enrollment began in April 2017. The majority of melanomas is mucosal origin included esophagus, nasopharynx, rectal melanoma and vaginal melanoma. As of February 10, 2018, enrollment has been completed with 33 patients. No dose-limiting toxicities (DLTs) were reported during dose escalation. 30 patients were treated with JS001 (3 mg/kg) combined axitinib (5mg Bid). The most common treatment-related AEs were grade 1/2, including hypertension, hand-foot skin reaction, oral ulcer, hypo-thyroidism and fever. Among 24 evaluable patients, no patient have complete response, 12 patients have partial response, and 9 pts achieve stable disease, for an ORR of 50% and a DCR of 87.5%. 10 out of 12 PR pts still have ongoing response. Conclusions: JS001 combined with axitinib may benefit for patients with metastatic mucosal melanoma.we will report all results during 2018 asco annual meeting. Clinical trial information: NCT03086174.
Molecular prediction of lymph node metastases using immunohistochemical analysis of primary oral tongue squamous cell carcinomas.
Authors: Furrat Amen, Michael Eden, Alison Marker, Bill Barrett, Philip Wilson, Ann Sandison, Silvana DiParma, Mahir Petkar, Kevin J. Harrington, Christopher Nutting, Cyrus Kerawala, Peter Clarke, Haitham Mirghani, Eamon Shamil, Khin Thway, Kikkeri Naresh, Gordon William Stamp, Peter Rhys-Evans
Journal: Journal of Clinical Oncology (2018)

6054 Background: Patients that present with oral tongue squamous cell carcinoma (OTSCC) may have a clinically and radiologically N0 neck at presentation. Should we observe these patients without treatment to the neck, waiting for lymph node metastases to occur, or should they be treated with a prophylactic neck dissection or irradiation, with their associated mortality and morbidity? Methods: This is translational research, using a tissue microarray constructed from formalin-fixed paraffin-embedded glossectomy specimens from 186 patients with OTSCC treated in 7 cancer centers in the United Kingdom. Full clinical follow up for at least 5 years and pathology data were obtained for all patients retrospectively. Up to 3 cores were taken from the centre of the tumour, 3 from the periphery, 3 from areas of perineural or vascular invasion and 1 core from normal tissue surrounding the tumor. 30 antibodies were selected from a previous cDNA microarray study (novel antibodies) and previous research studies, for confirmation of these reports. We standardized and performed immunohistochemistry using 19 antibodies: p16, FAS, desmoglein, P4HA1, involucrin, MMP8, S100, orniithine, SRP19, MRP2, LLGL2, laminin 5, FTH1, CD44, IL22, p53, Kif2a, anticollagen V, and VEGF. Results: Nodal metastases were related to central cores being P4HA1 negative and p53 positive, and peripheral cores being MMP8 positive and VEGF positive. SRP19 expression in the centre (56% vs 78% 5-year survival p = 0.004) and periphery of tumor (60% vs 78% 5-year survival p = 0.015) predicted significantly worse survival. VEGF expression in the periphery of tumor predicted significantly worse survival (60% vs 80% 5-year survival p = 0.001). All other tumor and patient specific predictors of metastases and survival will also be presented. Conclusions: The “Amen signature” (P4HA1 central negative, MMP8 peripheral positive and VEGF peripheral positive), in the primary tumor, is highly predictive of nodal metastases (p = 0.000). This will help predict which patients need a neck dissection. Poor survival can also be predicted so that these patients can have aggressive therapies or be entered into therapeutic trials of new regimens.
FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal Morphogenesis in Adult Neurogenesis
Authors: Iris Schäffner, Georgia Minakaki, M. Amir Khan, Elli-Anna Balta, Ursula Schlötzer-Schrehardt, Tobias J. Schwarz, Ruth Beckervordersandforth, Beate Winner, Ashley E. Webb, Ronald A. DePinho, Jihye Paik, Wolfgang Wurst, Jochen Klucken, D. Chichung Lie
Journal: Neuron (2018)
ECHO palliative care in Africa (ECHO-PACA): Improving access to quality palliative care.
Authors: Sriram Yennu, Charles E Amos Jr, John Weru, Edwina Beryl Victoria Naa Deedei Addo, Joseph Anthony Arthur, Olaitan Soyannwo, Runcie C.W. Chidebe, Eduardo Bruera, Suresh Reddy
Journal: Journal of Clinical Oncology (2018)

6545 Background: There is limited access to quality Palliative Care (PC) for advanced cancer patients being treated in Sub Saharan Africa due to limited PC knowledge among health care providers in the region. The goal of this innovative project was to improve access by offering cost-effective training to these providers using Project ECHO (Extension for Community Healthcare Outcomes), an established telementoring and support program.Our aim was to evaluate feasibility, attitudes, knowledge, and efficacy of participants of ECHO-PACA to deliver PC. Methods: An interdisciplinary team at the UT MD Anderson Cancer Center, guided by PC providers in Sub Saharan Africa, developed a standardized curriculum based on PC needs in the region. Participants were then recruited and monthly telementoring sessions consisting of case presentations, discussions, and didactic lectures began in July 2016. Program participants included 14 clinics and teaching hospitals from Ghana, Kenya, Nigeria, South Africa, and Zambia, with sessions offering participants the ability to interact and learn new skills in PC. Participants were surveyed at the beginning, mid-point and end of the 16 month program to evaluate changes in self-perceived efficacy in pain assessment and management, Identification of signs/symptoms of imminent death, Identifying and addressing challenging communication issues related to end of life. Results: Median participation per session was 30. Median duration of monthly meetings was 90 minutes. 33 of 40 initial participants (83%) completed the survey. There was significant improvement in appropriate use of non-opioid analgesics for persistent pain (p = .03), titrating opioids to optimize pain control (p = .03), Identification of signs/symptoms of imminent death (p = .05), and Identifying and addressing challenging communication issues related to end of life (p = .02). Conclusions: ECHO-PACA was a feasible, cost effective, pragmatic approach to disseminate PC knowledge without the need for travel, which has the potential to increase access to quality PC through enhancing the skills of providers in resource challenged areas of Sub Saharan Africa. Further studies are needed to evaluate ECHO-PACA impact on patient outcomes.
Correlation of pre- and post-induction plasma mutant allele fraction with progression-free survival (PFS) in STEAM, a prospective, randomized, multicenter study in metastatic colorectal cancer (mCRC).
Authors: John J. Lee, John F. Palma, Lijing Yao, Alexander F. Lovejoy, Stephanie Yaung, David Zhang, Nasiema Wingate-Pearse, May Yau, Carolyn Williams, Monica Pimentel, Abraham Munoz, Katrina Mayol, Christoph Mancao, Alan Nicholas, Nicolas Sommer, Herbert Hurwitz, Johanna C. Bendell, Ulrich Peter Rohr
Journal: Journal of Clinical Oncology (2017)

e15118 Background: STEAM (NCT01765582) evaluated the efficacy and safety of concurrent (c) and sequential (s) FOLFOXIRI-bevacizumab (BEV) versus FOLFOX-BEV for first-line treatment of mCRC. Methods: The AVENIO ctDNA Expanded Kit (Research Use Only) was used to identify somatic mutations in 77 cancer-related genes by next-generation sequencing (NGS) in both pre- and post-induction plasma samples (n = 118 for both groups) from STEAM. Demographics for patient tested were similar to the overall cohort. The mutant allele fraction (mAF) represents the mutation frequency in ctDNA for single nucleotide variants (SNVs) and indels detected per patient. Results: Overall, patients with a pre-induction mAF below the median had longer PFS compared to patients with mAF above the median (13.4 vs 9.5 mo, HR 0.49, p = 0.002). A similar trend was seen for overall survival (OS). Within the below median mAF group, longer PFS was observed in patients treated with cFOLFOXIRI-BEV versus FOLFOX-BEV (25.2 vs 9.5 mo, HR 0.34, p = 0.020). In contrast, no differences in PFS were observed in the treatment arms in the above median mAF group. Patients with a post-induction mAF below the median had longer PFS compared to patients with mAF above the median (15.3 vs 8.1 mo, HR 0.51, p = 0.0064). Correlations of post-induction genomic changes with outcomes, according to treatment groups, will also be presented. Conclusions: The level of pre- and post-induction mAF appears to correlate with PFS in STEAM overall. Furthermore, a lower median pre-induction mAF suggests PFS benefit for cFOLFOXIRI-BEV versus FOLFOX-BEV. Thus, plasma analysis of mAF via the AVENIO ctDNA Expanded Kit may identify patients who benefit from specific treatment in mCRC. These results are hypothesis generating and require further clinical validation. Clinical trial information: NCT01765582.
UK experience of combined BRAF and MEK inhibition with dabrafenib and trametinib (D+T) in the metastatic melanoma (MM) named patient programme.
Authors: Sarah Gabrielle Ellis, Lalit Pallan, Mirela Hategan, Nicola Price, Hendrik-Tobias Arkenau, Neil Steven, Marianne Nicolson, Philippa Corrie, Ioannis Karydis, Christian H.H Ottensmeier, Matthew James Wheater
Journal: Journal of Clinical Oncology (2016)

e21027 Background: Combination BRAF and MEK inhibition in mm has demonstrated improved Overall Survival (OS) and Progression Free Survival (PFS) compared to single agent BRAF inhibition (BRAFi) in phase III testing. Access to the combination in the UK was through a named patient programme for patients with unresectable stage III or IV BRAF mutant melanoma from July 2013. We report on outcome and toxicity data for the cohort. Methods: Retrospective data was collected from casenote and database review of patients treated in 5 UK centers. Physician assessment of response and toxicity was recorded. PFS and OS were calculated from the date of start of treatment to progressive disease or death. Patients still alive or progression free were censored at last clinical review. Results: 73 patients were treated with a median age 55, (range 20 -77). 31 were treatment naïve, 13 had prior immunotherapy. A large proportion (49.3%) received prior BRAFi with Vemurafenib. 20.5% of patients had brain metastases at initiation of D+T and 19% developed brain metastases during treatment. In 66 patients evaluable for response; 1.5% had complete, 74% partial responses and 12% stable disease. Median PFS was 7.3 months, OS 15.2 months with median follow up of 10.3 months. The most common adverse events (AEs) of all grades (G) were fevers and rigors (46.6%), skin toxicity (34.2%), lethargy (19.2%), arthralgia (13.7%), nausea and vomiting (13.7%). Most were G1-2. Twelve patients had G3-4 fevers and rigors requiring treatment breaks or addition of steroids. There were 7 cases of G3-4 neutropenia, with 1 neutropenic sepsis and 2 cases of thrombocytopenia. We observed one G3-4 reduction in LVEF. 4 patients stopped drugs due to toxicity. 26 patients received immunotherapy after progression (20 Ipilimumab, 6 Pembrolizumab). Conclusions: D+T has significant activity in a real world unselected population although our data do not match those of phase III trials. RR was high and the AEs were manageable and predictable. A number offactors likelyinfluenced the reduction in observed PFS/OS including prior exposure to BRAFi, higher percentage of M1c disease, and inclusion of patients with active brain metastases.
TCT-704 Feasibility of overlapped Magnesium-made bioresorbable scaffold implantation in long lesions: results from the multicenter italian registry (MAGIC)
Authors: Giorgio Quadri, Enrico Cerrato, Alfonso Ielasi, Salvatore Geraci, Francesco Tomassini, Fabio Ferrari, Cristina Rolfo, Nadia Garro, Massimo Leoncini, Simone Bellucca, Giuseppe Caramanno, Chiara Bernelli, Paolo Sganzerla, Francesco Granata, Umberto Barbero, None Giorgio Sacchetta, Mario Iannaccone, Gianluca Campo, None Claudio Rapetto, Maurizio Tespili, Diego Milazzo, Gerlando Pilato, Giovanni Vaccaro, None Ferdinando varbella
Journal: Journal of the American College of Cardiology (2018)