tbuckley/cabot-search huggingface dataset:
STING-dependent preventive effect by ablative hyperfractioned radiotherapy and delayed delivery of a CSF-1R inhibitor.
Authors: Xiaowen Sun, Lei Deng, Limei Yin, Mengqian Li, Jianxin Xue, You Lu
Journal: Journal of Clinical Oncology (2019)

e14190 Background: It has been reported that hyperfractioned radiotherapy can bring out abscopal effects when combined with checkpoint inhibitors and radiation-induced myeloid-derived suppressor cells (MDSCs) infiltration can lead to radioresistance. Our prior work has shown that ablative hypofractionated radiotherapy (AHFRT) alone can not trigger significant abscopal effects in three mouse tumor models. The goal of this study was to figure out whether the AHFRT play a preventive role in different tumor models and can be enhanced by a CSF-1R inhibitor. Methods: In experiment exploring the preventive effect of AHFRT, on Day 0, B16/ CT26/ MC38 tumor cells or PBS were inoculated s.c. in the left-side thigh of mice, respectively. Then, control mice and mice with established tumors were irradiated by AHFRT (12Gy*3f*3days). When the AHFRT accomplished, mice randomly divided into different groups and the second tumors inoculated s.c. in the right-side thigh, respectively: 1 day/ 3 days/ 7 days after AHFRT accomplished. Besides, “1 day after AHFRT accomplished” mice, both established MC38/CT26 tumors and PBS controls, were divided into 4 groups: control, a-CSF-1R, AHFRT, AHFRT+a-CSF-1R. And MC38 tumor cells were irradiated. The mice and cells followed for tumor growth and further analyses (mainly flow cytometry, western-blotting and qPCR). Results: We found that AHFRT alone could trigger significant preventive effects in” 7 days after AHFRT accomplished” group in B16 tumor model and “ 1 day/ 3 days/ 7 days after AHFRT accomplished” groups in CT26/ MC38 tumor models. In CT26/ MC38 tumor models, all the second tumors were cured which inoculated in “7 days after AHFRT accomplished” groups because of the preventive effects. And these cured mice keep survival without tumors when rechallenged at 180 days after AHFRT accomplished. AHFRT induced CD11b + CD11c + MHC-II + antigen presenting cells at the 1 st day after AHFRT accomplished and effector CD8 + T cells at 3rd day after AHFRT accomplished. AHFRT could active cGAS, STING, CXCL10 and IRF3 in the irradiated MC38 cells. And with a STING inhibitor, the growth of second tumors lost the preventive effect from AHFRT. And a delayed delivery of a small-molecule CSF-1R inhibitor decreased monocyte-MDSC(CD11b + CD11c - Gr1 - ) and delay the growth of second tumors inoculated 1 day after AHFRT accomplished. Conclusions: We show thatAHFRT triggers in situ vaccination and subsequent prevention effect. The prevention effect is STING-dependent and can be enhanced by a delayed delivery of CSF-1R inhibitor.
Leveraging Signaling Pathways to Treat Heart Failure With Reduced Ejection Fraction
Authors: Miguel Pinilla-Vera, Virginia S. Hahn, David A. Kass
Journal: Circulation Research (2019)

Advances in the treatment of heart failure with reduced ejection fraction due to systolic dysfunction are engaging an ever-expanding compendium of molecular signaling targets. Well established approaches modifying hemodynamics and cell biology by neurohumoral receptor blockade are evolving, exploring the role and impact of modulating intracellular signaling pathways with more direct myocardial effects. Even well-tread avenues are being reconsidered with new insights into the signaling engaged and thus opportunity to treat underlying myocardial disease. This review explores therapies that have proven successful, those that have not, those that are moving into the clinic but whose utility remains to be confirmed, and those that remain in the experimental realm. The emphasis is on signaling pathways that are tractable for therapeutic manipulation. Of the approaches yet to be tested in humans, we chose those with a well-established experimental history, where clinical translation may be around the corner. The breadth of opportunities bodes well for the next generation of heart failure therapeutics.
Comprehensive molecular profiling of metastatic melanoma to predict response to monotherapy and combination immunotherapy.
Authors: Ines Esteves Domingues Pires Da Silva, Alexander M. Menzies, Felicity Newell, James S. Wilmott, Matteo S. Carlino, Peter M. Ferguson, Jarem Edwards, Andrew Spillane, Kerwin Shannon, Robyn Saw, John F. Thompson, Helen Rizos, Graham J. Mann, Peter Johansson, Nicholas Hayward, Richard A. Scolyer, Nic Waddell, Georgina V. Long
Journal: Journal of Clinical Oncology (2019)

9511 Background: Several factors have been proposed as biomarkers for response to PD1 therapy, including tumor mutational burden (TMB), immune gene expression, PD-L1 expression and TILs, while few specific mechanisms of resistance have been identified. The relative importance of these factors or detailed examination of biomarkers of response to combination immunotherapy have yet to be explored. Methods: Cutaneous metastatic melanoma (MM) patients (pts) treated with anti-PD-1 (PD1) +/- anti-CTLA-4 (CTLA4) were selected. Pre-treatment tumors underwent whole genome sequencing (WGS), RNA sequencing (RNAseq) and immunohistochemistry (IHC; TILs and PD-L1). Results: Tumors from 77 pts treated with PD1 (n = 53) or PD1+CTLA4 (n = 24) underwent WGS. Higher TMB (p = 0.0001), lower structural variant (SV) burden (p = 0.001) and higher neoantigen load (p = 0.001) were associated with response. There was no difference in the expression of specific genes reported to confer resistance (JAK1/2, PTEN or BAF/PBAF complex members) or response (SERPINB3/4, ARID) in responders vs non-responders. RNAseq was performed on 53/77 samples; IFN and TCR signalling pathways were enriched in responders. Cytolytic activity (CYT, p = 0.002), T cell proportion estimated by CIBERSORT (p = 0.002) and confirmed by IHC (p = 0.033), and PD-L1 expression (IHC, p = 0.026) were also higher in responders. Multivariate analysis including DNA (TMB, SV count), RNA (six gene IFN expression signature - IFNG.6; effector T cell gene expression signature; chemokine gene expression; CYT), IHC (PD-L1, TILs) and clinical factors (sex, age, RECIST Sum of diameters, LDH) identified TMB and IFNG.6 as independent predictors of response (AUC = 0.83). 15 outliers with discordant molecular features and clinical outcomes had varying profiles, including 5 non-responders with high TMB, but low IFNG.6 expression, suggestive of a failure of immune activation. Conclusions: Comprehensive clinical and genomic analysis demonstrated that TMB and IFNG expression independently predict response, suggesting defects in both immune recognition or activation in non-responders.
Integrating CRISPR screening with tumor genomic analyses to identify therapeutic targets in hepatocellular carcinomas (HCC) independent of P53.
Authors: Ankur Sheel, SuetYan Kwan, Wen Xue
Journal: Journal of Clinical Oncology (2019)

e14659 Background: Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer with few effective treatments. Moreover, the underlying mechanisms that drive HCC pathogenesis remain poorly characterized. Identifying genes and pathways essential for HCC cell growth will aid the development of new targeted therapies for HCC. Furthermore, the P53 pathway is frequently mutated in HCC therefore identifying targets with therapeutic efficacy irrespective of P53 status is warranted. Methods: To identify kinases essential for HCC proliferation, we performed a kinome wide CRISPR screen in human HCC cell lines with varying P53 mutations and validated our findings using CRISPR-Cas9 mediated genetic manipulations in human HCC cell lines in-vitro and in-vivo. Furthermore, we performed an integrated cancer genomics analyses using patient data from TCGA and the NCI to validate the relevancy of our findings. Results: We identified transformation/transcription domain-associated protein (TRRAP) as an essential gene for HCC cell proliferation. we show that depletion of TRRAP or its co-factor, histone acetyltransferase KAT5, inhibits HCC cell growth via induction of P53, P21 and RB-independent senescence in-vitro and in-vivo. Furthermore, we find that TRRAP is upregulated in HCC patient samples independent of TP53 mutations. Integrated cancer genomics analyses using both HCC patient data derived from TCGA and from RNA-sequencing of our in-vitro model identified a chromosomal instability signature that was regulated by TRRAP/KAT5 in-vitro. Furthermore this chromosomal instability signature was also upregulated in HCC patients. Finally, we identify TOP2A as a target in this pathway as genetic depletion of TOP2A inhibited cell growth via induction of senescence. Conclusions: Our results uncover a role for TRRAP/KAT5 in promoting HCC cell proliferation via activation of mitotic genes in order to potentiate a chromosomal instability signature. Our findings suggest that targeting the TRRAP/KAT5 complex and TOP2A is a therapeutic strategy for HCC, even in tumors that have escaped P53 and RB tumor suppressive programs.
Does neutrophil to lymphocyte ratio correlate with toxicities and outcome of patients with genitourinary cancers treated with checkpoint inhibitors?
Authors: Marco Maruzzo, Francesco Pierantoni, Umberto Basso, Filippo Maria Deppieri, Michele Dionese, Evelina Lamberti, Marina Gardiman, Enrico Pizzirani, Mario Gardi, Angelo Porreca, Filiberto Zattoni, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2019)

e16032 Background: Few data are available concerning the role of neutrophil and lymphocyte counts in predicting toxicities and outcome in patients (pts) with genitourinary cancer treated with recent immunotherapy. Methods: We retrospectively reviewed the clinical charts of all pts with metastatic renal cell (RCC) or urothelial cancer (UC) treated at our Institute with immunotherapy(Nivolumab with or without Ipilimumab, Atezolizumab, Durvalumab, Pembrolizumab), having at least one response assessment after starting treatment. Results: We identified 117 pts treated from May 2015 onwards, median age: 68 years (range 39-84), 72% males, 53% with UC. Incidence of G3/4 toxicities was 17%, while 23.9% of pts needed an high dose steroid treatment because of immune-related toxicities (IrT). Median PFS and OS were 7.0 and 24.1 months, respectively for RCC, and 2.8 and 7.1 months, respectively for UC. 56 pts had progressive disease at best response. Baseline value of neutrophils or lymphocytes does not correlate with IrT (t test, p = 0.399, p = 0.728, respectively). In the IrT events, no significant increase of lymphocytes was detected (p = 0.160). The incidence of a IrT which needed steroid treatment positively impact in PFS (p = 0.03) but not in OS (p = 0.74). The use of steroid therapy was not associated with a different outcome in terms of OS (p = 0.49 for UC and p = 0.18 for RCC) and associated with a better PFS in RCC (p = 0.018). Steroid use was associated with the probability of non-progressive disease at first assessment (Chi-squared test, p = 0.015). In our cohort, baseline neutrophil to lymphocyte ratio (NLR) ≥ 3 correlate with a shorter PFS and OS in UC (p = 0.026 and p = 0.003 respectively), while it does not in RCC (p = 0.104 and p = 0.678 respectively). In our cohort, baseline neutrophil to lymphocyte ratio (NLR) ≥ 3 correlate with a shorter PFS and OS in UC (p = 0.026 and p = 0.003 respectively), while it does not in RCC (p = 0.104 and p = 0.678 respectively). In UC, the positivization of NLR after 2 cycles predicts a shorter PFS for UC (p = 0.008) and a trend for OS. Conclusions: In our retrospective single-center experience, NLR confirms its role in UC even in a cohort treated with immunotherapy and its variation predicts shorter outcome, while neutrophils or lymphocytes do not relate with IrT. The use of steroid for IrT is safe since it does not impact on survival and is associated with a higher probability of non-progressive disease at first assessment.
Safety and efficacy of aspirin for primary prevention of cancer: A meta-analysis of randomized controlled trials.
Authors: Tarek Haykal, Mahmoud Barbarawi, Yazan Zayed, Babikir Kheiri, Anitha Yelangi, Harsukh Dhillon, Sowmya Goranta, Adam Chahine, Varun Samji, Ghassan Bachuwa, Khalil Katato
Journal: Journal of Clinical Oncology (2019)

1533 Background: In the United States, cancer is the second leading cause of mortality, and millions more battle cancer worldwide. As such, primary prevention of cancer is a major interest globally. Aspirin has been studied as a primary prevention method for multiple diseases, mainly cardiovascular disease and various forms of cancer. The role of aspirin as a primary prevention of cancer is still controversial and may be more beneficial in certain cancers over others. With rapidly surfacing large randomized controlled trials (RCTs) studying this subject, we aimed to evaluate the efficacy and safety of aspirin as a primary prophylaxis for cancer. Methods: A comprehensive electronic database search was conducted for all RCTs that compared aspirin versus placebo for the prevention of any type of disease, and where cancer incidence or mortality was reported. The primary outcome was cancer-related mortality. Secondary outcomes were cancer incidence, all-cause mortality, major bleeding, any bleeding and gastrointestinal (GI) bleeding. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model at the longest follow-up period. Results: We included 16 RCTs with 104,018total patients, mean age of 60.51 years, mean follow-up of 5.48 years, and a male percentage of 38.72%. We found that aspirin was not associated with a significant reduction of cancer-related mortality compared with placebo (RR 0.99; 95% CI: 0.87-1.12; P = 0.85: I 2 = 41%). Compared with placebo, aspirin was not associated with significant reduction of all-cause mortality (RR 0.97; 95% CI: 0.92-1.02; P = 0.19; I 2 = 13%) or cancer incidence (RR: 0.98; 95% CI: 0.92-1.04; P = 0.43; I 2 = 16%). However, aspirin treatment was associated with significantly increased risks of any bleeding (RR 1.63; 95% CI: 1.31-2.03; P &lt; 0.01), major bleeding (RR 1.41; 95% CI: 1.26-1.57; P &lt; 0.01), and GI bleeding (RR 1.85; 95% CI: 1.38-2.48; P &lt; 0.01) compared with placebo. Conclusions: Our study did not find any significant reductions in cancer-related mortality or cancer incidence when compared with placebo. Our study also highlights the dangers of aspirin for primary prevention of cancer as aspirin was found to cause higher rates of bleeding (any bleeding, major bleeding, and GI bleeding) compared to placebo at the longest follow-up period with no significant benefit in cancer primary prevention.
Rethinking breast cancer surveillance in women with BRCA-associated ovarian cancer in the post-solo trial era.
Authors: Catherine S. John, Farin F. Amersi, Abigail Fong, Jessica Gillen, Kathleen N. Moore, Christine S. Walsh, Andrew John Li, Bj Rimel, Ilana Cass
Journal: Journal of Clinical Oncology (2019)

5565 Background: Patients with BRCA mutations are at increased risk of developing both breast (BC) and epithelial ovarian cancer (EOC). Optimal breast cancer surveillance guidelines for BRCA mutation carriers following EOC has not been defined due to high risk of EOC recurrence. The recent SOLO-1 trial demonstrated a survival benefit of olaparib maintenance therapy for newly diagnosed women with advanced stage EOC. Olaparib reduced the risk of disease-progression or death by 70% compared to placebo with a median progression-free survival (PFS) of 36 months. Methods: An IRB-approved, multi-institutional study retrospective chart review was performed. Patients had BRCA-associated EOC diagnosed between 1990-2015 without a history of prior BC or mastectomy. All women received combination chemotherapy for EOC. The observed breast cancer free survival was adjusted to reflect the enhanced 3-year PFS observed in olaparib-treated women from the SOLO-1 trial. Kaplan-Meier survival curves were performed. Results: 191 patients with BRCA-associated EOC were included (135 BRCA1, 55 BRCA2, 1 BRCA1 and BRCA2). Median age was 53 years. Most women had advanced stage, high-grade serous EOC (75%). The median overall survival was 7.7 years for BRCA 1, and 9.7 years for BRCA2 mutation carriers. Annual mammography and MRI were performed in 43% and 34% of women, respectively, with a median of 4 mammograms and 3 MRI per patient. 16 women (8.3%) were diagnosed with BC over a median follow up of 80 months: 7 (44%) DCIS and 9 (56%) invasive ductal carcinoma. 14 (88%) women had early stage (0-2) BC. 28 (15%) of women had risk-reducing mastectomy performed an average of 2.1 years following their EOC diagnosis. The incidence of BC increased from 5.6% to 11% at 5- and 10-years post EOC, and in the predicted model with olaparib, from 10% to 17% at 5- and 10-years, assuming olaparib does not impact breast cancer incidence. Conclusions: The risk of metachronous BC following BRCA-associated EOC increases over time. In the post SOLO trial era, BC surveillance strategies in women with EOC should be optimized to reflect improved outcome. [Table: see text]
Introduction of a variable electrostatic field for targeted drug application following intraperitoneal aerosol chemotherapy (PIPAC).
Authors: Veria Khosrawipour, Haris Chaudhry, Agata Mikolajczyk, Justyna Schubert, Alessio Pigazzi, Tanja Khosrawipour
Journal: Journal of Clinical Oncology (2019)

e14211 Background: In the treatment of Peritoneal Metastasis, the delivery of pressurized chemo-aerosols into the capnoperitoneum has been reported to show superior qualities to the application of conventional liquid chemotherapy. However, there is little basic knowledge on how aerosol particle motion within the abdominal cavity may be influenced and directed by means of an electrostatic field. This study aims to investigate aerosol motion within the abdominal cavity using an ex-vivo model. Material and Methods: All experiments were performed in an ex-vivo box as well as on postmortem swine abdomen, both established ex-vivo PIPAC models previously introduced by our research team. Extra-abdominally created, unipolar charged aerosols are introduced to the abdominal cavity. A modulated electrostatic field within the abdominal cavity is established to examine aerosol particle collision via fluorescence microscopy and photography. Results: Aerosol particle collision was observed on the peritoneum in the varying electric field. Preliminary data suggests that tissue penetration rates change with a varying electric field (p &lt; 0.05). Drug distribution pattern showed a significant improvement with a varying electric field vs. without (p &lt; 0.05). Conclusions: Our data suggest that extra-abdominally created, highly drug concentrated aerosol particles have the capacity to achieve high drug penetration rates in the peritoneum. The addition of a varying electric field enhances particle collision as well as significantly improves drug distribution patterns. Further studies are required to investigate the in-vivo safety and efficacy of a varying electric field and the significance of extra-abdominally created chemo-aerosols with regards to possible clinical applications.
Analysis of plasma biomarker and tumor genetic alterations from a phase II trial of lenvatinib in patients with advanced endometrial cancer.
Authors: Yasuhiro Funahashi, Richard T. Penson, Matthew A. Powell, David S. Miller, Jean Fan, Min Ren, Nicole Meneses, Pallavi Sachdev, Tadashi Kadowaki, James P. O'Brien, Ignace Vergote
Journal: Journal of Clinical Oncology (2013)

5591 Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. A phase 2 study in patients with advanced endometrial cancer following 1 or 2 prior platinum-based treatments was performed and is presented in a separate abstract. Here we report potential predictive markers of clinical benefit. Methods: Pre- and post-treatment plasma samples collected from 122 of 133 treated subjects were analyzed for 50 circulating cytokine and angiogenic factors (CAFs) using ELISA and multiplex assay platforms; 107 archival tumor tissues obtained from 133 enrolled subjects were analyzed for gene mutation (mut) (81 samples) and gene expression profiling (GEP) (64 samples). For GEP analysis, the NanoString nCounter platform was used to measure the expression level of approximately 300 genes identified preclinically as relevant. Correlation with clinical outcome measures including maximal tumor shrinkage (MTS), objective response rate (ORR), PFS, and OS was performed. Results: Clinical correlation identified baseline levels of 7 CAFs related to angiogenesis (Ang-2, IL-8, HGF, VEGFA, PlGF, Tie-2, and TNFa) that associated with survival. Only baseline levels of Ang-2 associated with greater MTS (R=0.36 [Spearman], P&lt;0.001), ORR (61% vs 18%), mPFS (9.5 vs 3.7 mos), and mOS (23 vs 8.9 mos) as determined using a defined cut-off value for baseline Ang-2. In gene mut analysis, no significant correlations were observed among the genes tested. Mut in PIK3CA showed a trend toward shorter OS (p = 0.085). In GEP analysis, expression levels of approximately 90 genes correlated with clinical outcome. Combination of GEP and CAF signatures identified signaling pathways, including Ang-2, that associated with OS. Clinical and preclinical GEP analysis identified overlapping gene signatures involving MAPK and PI3K signaling pathways that contributed to lenvatinib resistance. Conclusions: Baseline circulating Ang-2 levels may potentially predict outcomes in patients with advanced endometrial cancer and require further examination. This may provide a basis for stratification of patients in future clinical trials. Clinical trial information: NCT01111461.
Nationwide treatment patterns of oropharyngeal cancer in the human papillomavirus era.
Authors: Kailin Yang, Matthew C. Ward, Chandana A. Reddy, Brian B. Burkey, David J. Adelstein, Shlomo A. Koyfman
Journal: Journal of Clinical Oncology (2019)

e17521 Background: Human papillomavirus-mediated (HPV+) oropharyngeal cancer is now defined as a clinically distinct entity from HPV-unrelated (HPV-) disease in the 8th edition AJCC staging system, which more accurately informs prognosis for HPV+ patients. Treatment decisions are currently made according to the AJCC 7th ed staging. HPV+ patients are associated with favorable outcome. This study aims to analyze the national pattern of practice for HPV+ disease. Methods: Patients with oropharyngeal squamous cell carcinoma (OPSCC) diagnosed from 2010-2012 were identified from the National Cancer Database (NCDB). Patients were staged using the AJCC 7th system. Chemotherapy, radiotherapy and surgery were counted as treatment modalities. Fisher’s exact test and chi-squared test were used to assess treatment patterns over time. Overall survival (OS) was compared with Cox proportional hazards model. Results: 5,928 HPV+ OPSCC patients were identified. Single modality (surgery or radiation) was the most common treatment choice, used in 53.6% of stage I and 48.8% of stage II patients. For stage I, the use of dual modality therapy (70.8% received surgery with radiation) decreased from 36% in 2010 to 19% in 2012 (p = 0.05), though no significant difference in OS was seen between dual modality and single modality. Dual modality with chemoradiation was the main approach for stage III (58.6%) and stage IVA (67.5%) disease. Use of trimodality decreased from 2010 to 2012 in both stage III (p = 0.03) and stage IVA (p &lt; 0.01). Conclusions: Using a national cohort of HPV+ patients from the NCDB, we showed that single modality was the most common for stages I/II and dual modality was the mainstay for stages III/IVA. Usage of aggressive approaches (dual modality for stages I/II and trimodality for stages III/IVA) decreased over time. Prospective studies would be needed to determine the optimized therapeutic choice for HPV+ patients given favorable outcome.