tbuckley/cabot-search huggingface dataset:
Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067).
Authors: Jedd D. Wolchok, Vanna Chiarion-Sileni, Rene Gonzalez, Piotr Rutkowski, Jean Jacques Grob, C. Lance Cowey, Christopher Lao, Dirk Schadendorf, Pier Francesco Ferrucci, Michael Smylie, Reinhard Dummer, Andrew Hill, John B. A. G. Haanen, Michele Maio, Grant A. McArthur, Dana Walker, Joel Jiang, Christine E. Horak, James M. G. Larkin, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2016)

9505 Background: In CheckMate 067, NIVO (anti-PD-1) plus IPI (anti-CTLA-4) significantly improved progression-free survival (PFS) and objective response rate (ORR) vs IPI alone in pts with MEL (N Engl J Med 2015;373:23). We report updated efficacy and safety results from this study. Methods: Treatment-naïve pts (N=945) were randomized 1:1:1 to NIVO 1 mg/kg Q3W + IPI 3 mg/kg Q3W for 4 doses (followed by NIVO 3 mg/kg Q2W), NIVO 3 mg/kg Q2W + placebo, or IPI 3 mg/kg Q3W for 4 doses + placebo, until progression or unacceptable toxicity. Pts were stratified by PD-L1 status, BRAFmutation status, and M-stage. Co-primary endpoints were PFS and overall survival (data remain immature). Secondary endpoints included efficacy by PD-L1 status and safety. Results: At ≥18 months of follow-up, median PFS continued to be significantly longer for NIVO+IPI and NIVO vs IPI (P<0.001), and was numerically longer for NIVO+IPI vs NIVO alone (Table). Median duration of response in 181/314 (57.6%) NIVO+IPI responders has not been reached, and was 22.3 and 14.4 months in 138/316 (43.7%) NIVO and 60/315 (19.0%) IPI responders, respectively. Median PFS was also numerically longer with NIVO+IPI vs NIVO or IPI regardless of PD-L1 tumor expression (Table). For NIVO+IPI, NIVO, and IPI groups, median PFS was 15.5, 5.6, and 4.0 months in pts with a BRAF mutation and was 11.3, 7.1, and 2.8 months in pts with wild-type BRAF, respectively. The frequency and types of drug-related grade 3/4 AEs were consistent with earlier reports (NIVO+IPI, 56.5%; NIVO, 19.8%; IPI, 27.0%). Conclusions: NIVO+IPI and NIVO alone continue to demonstrate superior clinical activity vs IPI monotherapy. NIVO+IPI appears to have greater efficacy than either agent alone, regardless of PD-L1 expression or BRAF mutation status. Clinical trial information: NCT01844505.Median PFS (95% CI) NIVO+IPI NIVO IPI ITT population 11.5 (8.9–16.7) 6.9 (4.3–9.5) 2.9 (2.8–3.4) HR (95% CI) vs NIVO 0.76 (0.60–0.92)a — — PD-L1 expression ≥5% NR (9.7–NR) 22.0 (8.9–NR) 3.9 (2.8–4.2) HR (95% CI) vs NIVO 0.87 (0.54–1.41)a — — <5% 11.1 (8.0–22.2) 5.3 (2.8–7.1) 2.8 (2.8–3.1) HR (95% CI) vs NIVO 0.74 (0.58–0.96)a — — HR, hazard ratio; NR, not reached. aExploratory endpoint.
Early Antibiotic Exposure and Childhood Weight Gain
Authors: Susanna Esposito
Journal: JAMA (2016)

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The aging mouth: differentiating normal aging from disease
Authors: Ira B. Lamster, Lynda Asadourian, Tessa Del Carmen, Paula K. Friedman
Journal: Periodontology 2000 (2016)

Aging is the physiologic change that occurs over time. In humans, this change occurs at different rates and are related to lifestyle, environment and genetics. It can be challenging to differentiate normal aging from disease. In the oral cavity, with increasing age the teeth demonstrate wearing of the enamel, chipping and fracture lines, and a darker color. The pulp chamber and canals are reduced in size as a result of the deposition of secondary dentin. Coronal or root caries, however, represent disease. A limited amount of periodontal attachment loss occurs in association with aging, usually manifesting as recession on the buccal surface of teeth. Severe periodontitis occurs in 10.5-12% of the population, with the peak incidence being observed at 35-40 years of age. Changes to the mucosal tissue that occur with age include reduced wound-healing capacity. However, environmental factors, such as smoking, dramatically increase the risk of mucosal pathology. Reduced salivary gland function is often seen in association with medication usage, as well as with disorders such as diabetes mellitus. Both medication use and chronic disorders are more common in older adults. Masticatory function is of particular importance for older adults. Maintenance of a nutritionally complete diet is important for avoiding sarcopenia and the frailty syndrome. Successful oral aging is associated with adequate function and comfort. A reduced, but functional, dentition of 20 teeth in occlusion has been proposed as a measure of successful oral aging. Healthy oral aging is important to healthy aging from both biological and social perspectives.
Abstract 2085: Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize tumor killing effect of an anti-VISTA monoclonal antibody in tumor bearing mice
Authors: Xiling Jiang, Jocelyn Leu, Indrajeet Singh, Linda A. Snyder, Weirong Wang
Journal: Cancer Research (2016)

Abstract The V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a recently discovered co-inhibitory molecule that shares limited sequence homology with the IgV domain of immune regulators of the B7 family. A first-in-class monoclonal antibody (mAb) that targets VISTA is currently in development for evaluation in patients with non-small cell lung cancer and other types of cancer. Data from a preclinical mouse model (in human VISTA knock-in mice) showed that treatment with its surrogate antibody demonstrated tumor growth inhibition, which is believed to be associated with modulation of the myelomonocytic and T cell compartments. A mechanistic pharmacokinetic/ pharmacodynamic (PK/PD) modeling approach was applied that integrated the in vitro and in vivo information (PK, target occupancy (TO) and tumor growth), and incorporated key physiological processes. A one-compartment pharmacokinetic model with Michaelis-Menten elimination kinetics was used to characterize the nonlinear clearance of the surrogate antibody. The growth and killing of tumor cells was described with a cell distribution tumor growth/ killing model. Tumor killing effects can be described well by a linear relationship to VISTA TO. The developed PK/PD model captured the observed data in mice. This work also presents the potential of how mechanistic modeling and simulation can support first-in-human dose selection and dosing regimen optimization for immunomodulatory mAbs for anticancer immunotherapy. Citation Format: Xiling Jiang, Jocelyn Leu, Indrajeet Singh, Linda A. Snyder, Weirong Wang. Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize tumor killing effect of an anti-VISTA monoclonal antibody in tumor bearing mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2085.
Abstract 2853: Apoptosis and proliferation in micropapillary structures of colorectal polyps and carcinomas
Authors: Madhura Patankar, Sara Vayrynen, Anne Tuomisto, Markus Makinen, Tuomo Karttunen
Journal: Cancer Research (2016)

Abstract Background: Micropapillary structures (MIP) can be defined as focal piles of epithelial cells in columnar epithelium. MIP's are found in many cancers, but they are characteristic for serrated colorectal carcinomas. Suprabasal cells of MIP show no contact with extracellular matrix (unpublished). Objective: To evaluate whether MIP cells in colorectal polyps and cancers would show evidence for anoikis inhibition we assessed proliferation and apoptosis indexes (PI and AI, respectively) in MIP and non-MIP epithelium. Materials and methods: We stained human colorectal lesions: non-serrated adenomas (n = 15), serrated polyps (n = 29), conventional adenocarcinomas (n = 32), and serrated adenocarcinomas (n = 30) with antibodies to Ki67 and M30. To obtain PI and AI two independent observers counted proportions of positive cells separately in the cells of MIP and in non-MIP epithelium. Results: In carcinomas, AI was lower in the cells of MIP (M30; median 0, range 0-40) than in the non-MIP cells (median 2, range 0-40; p&amp;lt;0.001, Wilcoxon). Similarly, PI was lower in the MIP cells (Ki67; MIP: median 17, range 0-93; non-MIP: median 30, range 1-93; p&amp;lt;0.001). Similar patterns were evident in subsets of serrated lesions, in both carcinomas (p&amp;lt;0.001) and polyps (p&amp;lt;0.001), and in non-serrated carcinomas (p&amp;lt;0.004). Apoptosis/proliferation (AI/PI) ratio was lower in the MIP cells than in the non-MIP epithelium in both cancers and their precursor lesions (P&amp;lt;0.01). Conclusion: Apoptosis rate was lower in MIP's than in other tumor epithelium indicating ability of these cells to survive without matrix contact, i.e. Anoikis is inhibited in them. Lower PI could suggest that cells in the MIP are in some kind of quiescent stage. However, significantly lower AI/PI ratio in the MIP infers that these structures may form a fast growing subpopulation of tumor cells. Further studies are in progress to dissect mechanism of formation of MIP and matrix independent survival of tumor cells in them. Citation Format: Madhura Patankar, Sara Vayrynen, Anne Tuomisto, Markus Makinen, Tuomo Karttunen. Apoptosis and proliferation in micropapillary structures of colorectal polyps and carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2853.
An observational cohort study on terminal cancer survivors practicing falun gong (FLG) in China.
Authors: Yuhong Dong, Chian-Feng Huang, Jim Liao, Alex Chih-Yu Chen, Jason G. Liu, Kai-Hsiung Hsu
Journal: Journal of Clinical Oncology (2016)

e21568 Background: In China, cancer patients may choose to practice FLG -- the most popular Qigong since 1992 -- after treatment failure, arousing great interest in the medical society. Methods: We collected reports from Chinese cancer patients between 2000 and 2015 via a web platform, including diagnosis, FLG practice duration, Actual Survival (AS) till report date, symptom improvement, and Quality of Life (QoL). All reports were reviewed by 2 physicians. Predicted Survival (PS) was assessed using the NIH SEER data if the treating physician’s Clinical Prediction of Survival (CPS) was unavailable. Reports of terminal cancer patients (PS ≤ 12 months) with sufficient and verifiable medical information were considered eligible. Symptom Free Survival (SFS) was also calculated. Results: In the web database, using the search terms
Surgical outcome for pulmonary metastasis of colorectal cancer in the modern chemotherapy era: Results of a retrospective Japanese multicenter study.
Authors: Tomoyuki Hishida, Takehiro Okumura, Narikazu Boku, Yasuhisa Ohde, Yukinori Sakao, Katsuo Yoshiya, Masahiko Higashiyama, Kotaro Kameyama, Hirofumi Adachi, Kazu Shiomi, Masato Kanzaki, Kazuya Uchino, Motoki Matsuura, Yoshinobu Hata, Fengshi Chen, Kazuo Yoshida, Hidefumi Sasaki, Ichinosuke Hyodo, Keita Mori, Haruhiko Kondo
Journal: Journal of Clinical Oncology (2014)

3528 Background: There have been few reports of surgical outcome for pulmonary metastasis (PM) of colorectal cancer (CRC) (CRC-PM) in the era of modern effective chemotherapy including oxaliplatin. Methods: Clinical and survival data of patients undergoing first metastasectomy for CRC-PM between 2004 and 2008 were collected from 46 institutions. Data cut-off date was August 31, 2013. Results: A total of 1,237 patients' (pts’) data were collected. After exclusion of ineligible cases including non-R0, 898 pts’ data were analyzed. Of these, 161 (18%) pts had synchronous PM with primary tumor. Median number of resected PMs was 1 (range, 1–10) and 124 (14%) had bilateral PMs. The five-year overall survival (OS) and disease-free survival (DFS) were 65.7% (95% CI, 62.3–69.2) and 35.3 % (32.1–38.8) after median follow-up period of 61 months, respectively. According to the status of pre or postoperative adjuvant chemotherapy (Pre- / Post-C), pts were classified into four groups: A (-/-, n=417), B (-/+, n=368), C (+/-, n=55), and D (+/+, n=58). There were substantial differences in background among four groups. Independent prognostic factors for OS and DFS were elevated carcinoembryonic antigen (CEA) level at the time of lung resection (OS: HR=2.03, 95% CI, 1.61–2.57; DFS: 1.58, 1.32–1.88), and the number of resected PMs (OS: 1.20, 1.10–1.30; DFS: 1.21, 1.13–1.29). The five-year OS and DFS after surgery alone (group A) were 66.8% (62.1–72.0), and 39.3% (34.6–44.6), respectively. After adjusting by above prognostic and background factors among four groups, overall perioperative use of chemotherapy (B+C+D vs. A) was not statistically associated with prolonged OS (HR=0.95, 0.66–1.35) and DFS (0.93, 0.71–1.20). HR of Pre-C (group C vs. A) was 2.26 (95% CI, 1.06–4.81) for OS and 2.26 (1.28–3.98) for DFS. On the other hand, HR of Post-C (B vs. A) was 0.81 (0.55–1.19) for OS and 0.87 (0.66–1.14) for DFS. Conclusions: Modern surgical resection for CRC-PM demonstrated favorable prognosis. This retrospective study did not reveal a relevant effect of perioperative chemotherapy on survival. However, HR of Post-C prompted further investigation for adjuvant chemotherapy after resection of CRC-PM.
Abstract 1315: Nanoparticles targeting RAF/ERK-driven cell-autonomous resistance to sorafenib for effective treatment of hepatocellular carcinoma
Authors: Yunching Chen, Ya-Chi Liu, Ts-Ting Lin, Rakesh Ramjiawan, Dan Duda
Journal: Cancer Research (2016)

Abstract Sorafenib is the only systemic therapy approved for advanced hepatocellular carcinoma (HCC). Sorafenib's efficacy has been attributed in part to inhibition of cancer cell proliferation due to B- and CRAF targeting in HCC cells. However, cell autonomous mechanisms promote evasion from sorafenib treatment, leading to moderate survival benefit. Herein, we demonstrated that the effects of sorafenib on HCC cell viability were initially independent of RAF kinase inhibition and were mediated in part by p38MAPK inhibition. Moreover, sorafenib treatment led to RAF heterodimerization (BRAF/CRAF) and subsequent ERK activation and thus converted HCC cell dependence for survival signaling to the RAF/ERK pathway. Inhibition of ERK pathway by the MEK inhibitor AZD6244 significantly enhanced the therapeutic efficacy of sorafenib efficacy on HCC in vitro and in vivo. Furthermore, we developed HCC-targeted nanoparticles (NPs) to efficiently co-deliver both sorafenib and AZD6244 into HCC, downregulate RAF/ERK pathway, suppress angiogenesis and enhance anti-cancer effect in the orthotopic HCC model. In conclusion, sorafenib treatment leads to rapid MAPK activation due to BRAF heterodimerization as a cell-autonomous mechanism of treatment resistance. Co-delivery of sorafenib and MEK inhibitor AZD6244 using HCC targeted NPs downregulates the compensatory activated RAF/ERK pathway and overcomes resistance to sorafenib in HCC. Citation Format: Yunching Chen, Ya-Chi Liu, Ts-Ting Lin, Rakesh Ramjiawan, Dan Duda. Nanoparticles targeting RAF/ERK-driven cell-autonomous resistance to sorafenib for effective treatment of hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1315.
Abstract 786: Project Survival: Interrogative Biology® platform mediated discovery of molecular markers for detection, stratification and outcomes in pancreatic cancer
Authors: Niven R. Narain, A James Moser, Ramesh Ramanathan, John Crowley, Amy Stoll-D’Astice, Yezhou Sun, Leonardo O. Rodrigues, Eric M. Grund, Emily Chen, Vivek K. Vishnudas, Michael A. Kiebish, Viatcheslav R. Akmaev, Rangaprasad Sarangarajan
Journal: Cancer Research (2016)

Abstract Pancreatic adenocarcinoma generally presents with a poor prognosis and an extremely low response rate to first line therapies. There is a critical unmet need to discover and implement effective diagnostic panels to stratify outcomes and tailor treatment strategies to improve survival. The BERG Interrogative Biology® platform utilizes Artificial Intelligence to analyze and integrate multi-omic profiles with clinical annotation to define novel biomarkers and improve treatment interventions. Herein, we analyzed the serum proteome, signaling lipidome, structural lipidome, and metabolome of 163patients at multiple timepoints (pancreatic cancer: 115; pancreatitis: 15; and age-matched healthy controls: 33). Utilizing the power of the Bayesian Network learner, bAIcis™ (BERG Artificial Intelligence Clinical Information System), multi-omic profiles were aligned to the longitudinal clinical information and subjected to AI-algorithms to infer probabilistic cause-and-effect relationships among molecular and clinical variables explicitly explaining pancreatic cancer status, cancer progression, and survival, and defining the interconnectivity of molecular features with clinical phenotype. Network features linking into clinical endpoints and key network pressure points were identified as molecular drivers. The drivers of clinical endpoints were analyzed to rank potential biomarkers. Novel biomarkers were discovered that demonstrate diagnostic potential for pancreatic cancer detection, disease prognosis including metastatic disease progression, patient stratification associated with survival, and response to standard chemotherapy agents like Gemcitibine. A prospective study is underway to validate the biomarkers and discover additional diagnostic and therapeutic molecules to improve the outcomes for patients affected by adenocarcinoma of the pancreas. Citation Format: Niven R. Narain, A James Moser, Ramesh Ramanathan, John Crowley, Amy Stoll-D’Astice, Yezhou Sun, Leonardo O. Rodrigues, Eric M. Grund, Emily Chen, Vivek K. Vishnudas, Michael A. Kiebish, Viatcheslav R. Akmaev, Rangaprasad Sarangarajan. Project Survival: Interrogative Biology® platform mediated discovery of molecular markers for detection, stratification and outcomes in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 786.
Abstract 2199: TLR3-induced immune response using PLGA nanoparticles for dendritic cell-based cancer immunotherapy
Authors: HEEDONG HAN.
Journal: Cancer Research (2016)

Abstract Dendritic cells (DCs) are potent professional antigen presenting cells (APCs) capable of initiating a primary immune response and activating T cells, and they play a pivotal role in host immune responses to cancer. Prior to antigen presentation, efficient antigen and adjuvant uptake by DCs is necessary to induce their maturation and cytokine generation. Nanoparticles (NPs) are capable of intracellular delivery of both antigen and adjuvant to DCs. Here, we developed an advanced poly(lactic-co-glycolic acid) (PLGA)-NP encapsulating both ovalbumin (OVA) as model antigen and poly I:C as adjuvant to increase intracellular delivery, and promote DC maturation. These NPs were taken up by mouse primary DCs and their uptake greatly facilitated MHC class I antigen presentation in vitro. Moreover, vaccination with PLGA-NP treated DCs led to the generation of OVA-specific CD8+ T cells, and the resulting antitumor efficacy was significantly increased in EG.7 tumor-bearing mice compared to control (p &amp;lt; 0.01). Taken together, we demonstrate that this PLGA-NP platform may be an effective method for delivering tumor-specific antigens or adjuvant to DCs. Citation Format: HEEDONG HAN. TLR3-induced immune response using PLGA nanoparticles for dendritic cell-based cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2199.
Abstract SY38-02: Immune-related changes in breast tumor evolution
Authors: Kornelia Polyak
Journal: Cancer Research (2016)

Abstract Increasing evidence supports a role for the immune system in tumor initiation and progression. Immune cells shape tumor evolution directly (e.g., anti-tumor immune response) and indirectly (e.g., changing the microenvironment) by selecting for cancer cells with certain properties. Immunotherapy is one of the most promising current therapeutic options and almost the only one that can effectively cure metastatic disease. However, thus far its success has been limited to a subset of patients. This may be a consequence of heterogeneity among tumors for mechanisms by which they escape immune surveillance. We hypothesized that the in situ to invasive carcinoma transition is a critical tumor progression step for immune escape in breast cancer that defines subsequent tumor evolution. This is due to the fact that in DCIS (ductal carcinoma in situ) cancer cells are still physically separated from the stroma by the basement membrane and myoepithelial cell layer, and tumor-infiltrating leukocytes are rarely detected in direct contact with cancer cells. In contrast, with invasive progression, cancer cells and leukocytes are intermingled, thus, only cancer cells that can survive in this environment will play a role in disease progression. To begin dissecting mechanisms of immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, DCIS, and invasive ductal carcinomas (IDC) by polychromatic FACS and found significant changes in multiple cell types. We also analyzed the gene expression profiles of T cells from each of these tissue types and found that T cells in DCIS are different from those in normal breast and invasive tumors. We validated some of these changes by multicolor immunofluorescence. We also performed high throughput sequencing of T cell receptor (TCR) of T cells in DCIS and found potential clonal expansions shared among patients. Lastly, we performed multicolor immunofluorescence analysis of checkpoint proteins in DCIS and IDC of different subtypes, and detected significant differences in expression patterns. Our results imply that analyzing immune-related changes during DCIS to IDC transition will identify novel targets for immunotherapy in breast cancer. Citation Format: Kornelia Polyak. Immune-related changes in breast tumor evolution. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY38-02.