tbuckley/cabot-search huggingface dataset:
Results from a pilot of an innovative 4R Cancer Care Delivery Model: Impact on patient self-management.
Authors: Julia Rachel Trosman, Christine B. Weldon, Claudia B. Perez, Swati Kulkarni, Seema Ahsan Khan, Nora M. Hansen, Valerie Nelson, Jennifer Stein, Melissa A. Simon, Cathy Spagnoli, Jennifer Tepper, Kay Pearson, William John Gradishar
Journal: Journal of Clinical Oncology (2018)

224 Background: Under the “NCI ASCO Teams” Project, we proposed a 4R Model of teamwork and patient self-management (pSM) (Trosman JOP ’16). 4R is Right Info / Care / Patient / Time. It enables patient (pt) and care team to manage interdependent care along the care continuum with an innovative multimodality personalized 4R Care Project Plan. We piloted 4R at 3 centers (academic, community, safety net) and assessed its impact on pSM. Methods: 4R Plans were administered to breast cancer pts stage 0-III Sep ’16 – Aug ’17 (4R cohort). We surveyed the 4R cohort and a comparable historical cohort of pts who received care pre-4R, Jun ’15 – May ’16 (control). We used simple frequencies and Fisher’s exact test in analyses. Results: Survey response rates: 68%, 185/271 (4R cohort); 47%, 241/410 (control). 75% of 4R respondents reported 4R Plans very useful / useful in overall understanding and organizing their care; 68% found 4R’s novel “project” component, very useful / useful in managing timing &amp; sequencing of interdependent care. Care complexity impacted 4R usefulness: 67% of pts who received &gt; 6 care services found 4R very useful / useful vs. 47% of pts who received &lt; = 6 services, p = .01. Pts with lower care complexity suggested how to make 4R more useful to them, eg focus on endocrine therapy. Table compares pSM metrics in the 4R and control cohort. Care complexity was a significant factor of feeling overwhelmed for pts in the control cohort (51% of pts receiving &gt; 6 care services felt overwhelmed vs. 31% of pts receiving &lt; = 6 services, p = .02), but not a significant factor for pts in the 4R cohort (30% vs. 28%, p = .9). Conclusions: The 4R model significantly improved pt self-management in early breast cancer and reduced the impact of care complexity on pts, but provider factors of pSM need improvement. A 4R pilot at additional 12 cancer centers across the U.S. is in progress.[Table: see text]
P02.11 Fluorescence imaging of meningoma cells with somatostatin receptor ligands - a in vitro study
Authors: S Linsler, R Ketter, J Oertel, S Urbschat
Journal: Neuro-Oncology (2018)

Five-aminolevulinic acid (5-ALA) staining of malignant glioma cells increased the radicality significantly in the last decade. Until today there is no comparable selective fluorescent substance available for meningiomas. Nevertheless, there is a demand for intraoperative fluorescent identification of e.g. invasive skull base meningiomas or at dural tail to increase radicality. Meningiomas show high expression of the somatostatin receptor subtype 2 offering the possibility of receptor-targeted imaging. The authors used a somatostatin receptor labeled fluorescence dye for the identification of meningiomas in vitro. The aim of this study was the evaluation of possibility to identify meningioma cells with fluorescent techniques selectively. 24 primary human meningioma cell cultures were analysed. The tumor cells were incubated with FAM-TOC (5,6-Carboxyfluoresceine-Tyr3-Octreotide). As a negative control, four human dura pieces were cultured in vitro and incubated with the same somatostatin receptor labeled fluorescence substance as negative control. After incubation fluorescence signal and intensity in all cell cultures was analysed at three different time point using a fluorescence microscope with 488nm epi-illumination. Sixteen WHO I, six WHO II, two WHO III meningioma primary cell cultures and four dura cell cultures were analysed. Fluorescence was detected in all meningioma cell cultures (22 cell culture:strong, 2 cell cultures: moderate) directly after incubation until 4 hours later. The different meningioma grades revealed no different quality or quantity of fluorescence. The fluorescence signal persisted unchanged during the analysed period. In the negative control, dura cell cultures remained unstained. It could be demonstrated that FAM-TOC can be used for the selective fluorescent identification of meningioma cells in vitro. For further evaluation of the used somatostatin receptor ligand and fluorescence dye the chemical kinetic has to be analysed more in detail. As the next step, an experimental animal model is needed to evaluate these previous promising results in vivo and to identify the best application form in vivo.
Distress among breast cancer patients treated with adjuvant radiotherapy.
Authors: Orit Kaidar Person, Lauren Terzo, Jayne Camporeale, Allison Mary Deal, Timothy Zagar, Lawrence B. Marks
Journal: Journal of Clinical Oncology (2016)

e21599 Background: Early stage breast cancer is a potentially curative disease, yet many patients experience distress that may affect their well-being. The aim of this retrospective study, among patients receiving adjuvant radiotherapy, is to identify factors associated with patients’ distress. Methods: A retrospective search was conducted of all breast cancer patients who were treated from November 2014 to October 2015 with adjuvant radiotherapy. Data collected from medical records included demographics, tumor related factors, stage, treatment, mood/anxietylytic and sleep medications, and referral to supportive services (CCSP). Male patients, recurrent/synchronous, inoperable or metastatic disease, known psychiatric disorder, or mood medication for hot flashes were excluded from the analysis. Distress was measured by referrals to CCSP and the use of medication. Wilcoxon Rank Sum, Fisher’s exact, and Jonckheere’s trend tests were used to evaluate associations. Results: 121 patients were included. The median age was 60 years (range 30-82), 17% ductal carcinomas in situ (DCIS) and 83% invasive carcinomas (IC); 82% underwent lumpectomy. 44% were taking medications, 40% were referred to CCSP. Overall, 60% were either taking medications or referred to CCSP. Patients with IC had higher rates of medications than those with DCIS (49% v 19%, p = 0.01). Mastectomy was not associated with higher medication intake but was associated with more referrals to CCSP compared to lumpectomy (62% v 35%, p = 0.02). Patients taking medications were younger (mean 55 v 62 years, p = 0.001), and had more advanced T stage (p = 0.004) and N stage (p = 0.0004). Increased T and N stage were also associated with increasing rates of CCSP referrals (both p = 0.03). Conclusions: Mood/anxietylytic and sleep medications intake and referrals to supportive services were associated with young age and advance disease. The high use of mood/anxietylytic and sleep medications in this young and curative population should be further studied. Measures need to be taken to better identify patients who are at need for support to allow early intervention and better coping skills.
Abstract 20432: Phosphorylated Cardiac Myosin Binding Protein-C Alters Signaling Response to Improve Survival in Heart Failure With Reduced Ejection Fraction
Authors: Yang Liu, Paola C Rosas, David T Kidwell, Carl W Tong
Journal: Circulation (2016)

Introduction: Cardiac myosin binding protein-C (cMyBP-C) is a heart muscle thick filament protein. Phosphorylated cMyBP-C increases cross-bridge cycling rate to enhance contractility and lusitropy. Hypothesis: Phosphorylated cMyBP-C can mitigate heart failure with reduced ejection fraction (HFrEF), which have both systolic and diastolic dysfunctions. Methods: We tested our idea by challenging WT equivalent cMyBP-C(tWT), phosphorylation deficient cMyBP-C(t3SA):S273A/S282A/S302A, and phosphorylation mimetic cMyBP-C(t3SD):S273D/S282D/S302D mouse models with trans-aortic constriction (TAC) to induce HFrEF. Results: Increasing phosphorylation levels of cMyBP-C provided 5-week survival advantage (t3SA 40/69 58%, tWT 35/46 76%, t3SD 39/44 89%, p=0.001). We then examined cardiac function and signaling cascades to elucidate contributory mechanisms at the 3rd week, where survival curves separated. The phosphorylation mimetic t3SD model showed better preservation of diastolic function by echocardiography (smaller E/...
The relationship of pharmacodynamics (PD) and pharmacokinetics (PK) to clinical outcomes in a phase I study of OX40 agonistic monoclonal antibody (mAb) PF-04518600 (PF-8600).
Authors: Anthony B. El-Khoueiry, Omid Hamid, John A. Thompson, Willeke Ros, Ferry Eskens, Toshihiko Doi, Siwen Hu-Lieskovan, Jeffrey Chou, Ken Liao, Bishu J Ganguly, Catherine Fleener, Tenshang Joh, Adi Diab
Journal: Journal of Clinical Oncology (2017)

3027 Background: PF-8600 is a novel fully human IgG2 agonistic mAb against human OX40, a TNF receptor superfamily member expressed primarily on activated T cells. This ongoing phase 1 study (NCT02315066) is investigating the safety, efficacy, PK and PD of PF-8600 in patients (pts) with solid tumors. Methods: PF-8600 (0.01–10 mg/kg) was given IV every 14d. Expression of free/total OX40 receptor, proliferation marker ki67 and activation markers HLA-DR/CD38 were measured in T cell subsets in peripheral blood by flow cytometry in all pts. CD4, CD8, OX40 and FOXP3 were evaluated in paired tumor biopsies (bx), collected from a subset of pts (≥0.1 mg/kg) at baseline (BL) and Wk6, by immunohistochemistry. Results: As of 21Sep2016, 48 pts with melanoma (n = 14), hepatocellular carcinoma (HCC, n = 19), head and neck squamous cell (n = 6) or renal cell carcinoma (n = 9) enrolled in the dose-escalation cohorts (0.01-3 mg/kg). No immune related adverse events (AE) were reported. The most frequent treatment related AEs in &gt; 3 pts were fatigue (27.1%) and nausea and vomiting (8.3% each); all Gr 1-2. 2 pts had a partial response: melanoma at 0.1 (Pt1) and HCC at 0.3 (Pt2) mg/kg. 25 pts had best ORR (BOR) of stable disease (SD; 3 pts ≥24 wks). A majority of pts at 0.1, 0.3, and 3 mg/kg, including Pt1 and Pt2, had increases in ki67 and HLA-DR/CD38 expression in peripheral CD4+ central memory T cells. Pt1, Pt2 and all pts at ≥0.3 mg/kg had full receptor occupancy. Paired bx were only available from pts with BOR of SD or progressive disease. In 10 pts with available paired tumor bx and defined date of radiographic progression (rPD), longer time to rPD correlated with increases in %OX40+ in bx from BL to Wk6, regardless of dose level, tumor type or prior immunotherapy (R 2 = 0.52, p = 0.0188); no correlation between rPD and CD4+, CD8+ or FOXP3+ expression changes was observed. Updated efficacy, safety, PK and PD data will be presented. Conclusions: PF-8600 is well tolerated with evidence of single agent efficacy. Initial observations of PD markers that change with treatment and correlate with rPD support efforts to confirm these findings as more clinical outcomes and larger sample sizes become available. Clinical trial information: NCT02315066.
Violations of the proportional hazards assumption in randomized phase III oncology clinical trials.
Authors: Rifaquat Rahman, Geoffrey Fell, Lorenzo Trippa, Brian Michael Alexander
Journal: Journal of Clinical Oncology (2018)

2543 Background: The hazard ratio is the most common measure of treatment effect in oncology trials, but many trials commonly violate the underlying Cox proportional hazards assumption. We aimed to evaluate the prevalence of non-proportionality of hazards in phase III oncology clinical trials. Methods: We performed a PubMed search for randomized phase III trials in breast cancer, lung cancer, prostate cancer and colorectal cancer published in high-impact journals between 2014 and 2016. To be included, studies were required to report on a cancer-directed intervention and provide Kaplan-Meier (KM) curves of a time-to-event outcome. We generated individual patient data for time-to-event outcomes for overall survival (OS) and non-survival endpoints. We reanalyzed trials with our reconstructed individual patient data and evaluated for evidence of violation of the proportional hazards assumption with the Grambsch-Therneau test with a p-value threshold of < 0.1. Results: We identified 157 publications with 115 KM curves of overall survival (OS) and 139 KM curves of a non-survival time-to-event outcome. There was evidence of non-proportionality of hazards in a total of 62 (24%) time-to-event outcomes including 20 of 115 (18%) OS KM curves and 42 of 139 (30%) non-survival KM curves. Immunotherapy (50%) and endocrine/hormonal therapy (50%) trials had the highest prevalence of KM curves with evidence of non-proportional hazards, and this was less common in KM curves of targeted therapy (25%), radiation therapy (19%), and chemotherapy (15%) trials. Conclusions: A notable proportion of time-to-event outcomes reported in oncology clinical trials demonstrates evidence of violating the assumption of proportional hazards. Non-survival time-to-event outcomes were more likely to show evidence of non-proportionality of hazards. Consideration of violation of the proportional hazards assumption is warranted in designing clinical trials.
Efficacy and dosimetry of 125I radioactive seed implantation for locally recurrent rectal cancer.
Authors: Hao Wang, Junjie Wang, Yuliang Jiang, Suqing Tian, Ruijie Yang, Haitao Sun
Journal: Journal of Clinical Oncology (2016)

e15143Background: To evaluate the efficacy of 125I radioactive seed implantation for locally recurrent rectal cancer (LRRC), and analyze the associated prognostic factors, the relationship between ...
The first-in-class anti-cancer agent ABTL0812 is effective in preclinical models of human endometrial cancer.
Authors: Eva Colàs Colàs, Nuria Eritja, Pau Muñoz-Guardiola, Sonia Sole-Sanchez, Cristian Moiola, Isidre Felip, Antonio Gil-Moreno, Hector Perez-Montoyo, Jose Alberto Alfon, Carles Domenech, Jose M Lizcano, Xavier Matias-Guiu
Journal: Journal of Clinical Oncology (2017)

e17070 Background: ABTL0812 is a first-in-class anti-cancer agent with a unique mechanism of action currently in Phase Ib/IIa clinical development for endometrial cancer and squamous NSCLC. ABTL0812 successfully culminated a Phase I clinical trial showing a high safety profile and long disease stabilizations, including 14-months stabilization in a patient with platinum-unresponsive Grade IIIC endometrial cancer with mutated PI3KCA and Akt. Methods: ABTL0812 synergy with paclitaxel and carboplatin was tested in vitro on Ishikawa cells by MTT assay. ABTL0812 in vivo anti-tumor activity was assessed in a PTEN-null inducible mouse model of endometrial adenocarcinoma development upon tamoxifen injection. In vivo synergy between ABTL0812 and paclitaxel was validated in a xenograft model orthotopically implanted with Ishikawa cells and between ABTL0812 and paclitaxel/carboplatin (P/C) in xenografts derived from a patient (PDX) with grade IIIC2 endometrial carcinoma with mutated PI3KCA. Results: ABTL0812 reduced paclitaxel and carboplatin IC50 by 1.5 and 2.1 times respectively in Ishikawa cells. Synergy with paclitaxel was found in Ishikawa orthoxenografts, showing a maximum Tumor Growth Inhibition (maxTGI) of 56,7±16,9% compared with 34.6±33.2% of paclitaxel group. ABTL0812 alone was effective reducing endometrial intraepithelial neoplasia formation in a mouse model of endometrial adenocarcinoma. Additionally, in an endometrial cancer PDX, ABTL0812 alone showed similar efficacy with reduced toxicity when compared with P/C and improved maxTGI when given in combination (ABTL0812: 45,2±17,5%; C/P*: 38,7±26,9%; ABTL0812+C/P*: 59.3±8.8%; *p=0.031). Conclusions: ABTL0812 has shown efficacy as a single agent and in combination with chemotherapy in preclinical models of endometrial cancer with mutations on PI3K/Akt pathway, which appears frequently over-activated in patients with these cancers. These results supported the application of ABTL0812 as a first line therapy in combination with chemotherapy for the Phase Ib/IIa clinical trial currently ongoing, positioning ABTL0812 as a potential therapeutic agent in the treatment of endometrial cancers bearing these genetic alterations.
Influence of a STAT3 inhibitor on tumor infiltrating lymphocytes in malignant pleural mesothelioma.
Authors: Seiji Matsumoto, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa
Journal: Journal of Clinical Oncology (2017)

e23078 Background: Patients with malignant pleural mesothelioma have elevated IL-6 levels in their blood and pleural fluid. IL-6 activates the JAK-STAT pathway and promotes transcriptional activation. Our previous work on a STAT3 inhibitor (BBI-608: napabucasin) as a molecular target drug for malignant pleural mesothelioma confirmed its antitumor effect. In this study, the effect of napabucasin on tumor immunity, specifically on tumor infiltrating lymphocytes, was evaluated. Methods: A mouse-derived malignant pleural mesothelioma cell line (AB22; 1.0 × 10 5 cells) was subcutaneously injected into BALB/cAJcl mice. When the tumors grew to 250 mm 3 , the mice were divided into three groups (five mice per group): untreated control, 5 mg/kg napabucasin, and 20 mg/kg napabucasin groups. The drug was orally administered twice daily. Tumor volumes were measured twice weekly, and the subcutaneous tumors were removed 15 days after treatment initiation. Tumor infiltrating lymphocytes were extracted from the tumors, and the CD8+ cell percentage was measured using FACS. Results: The subcutaneous tumors of the mice in the untreated control, 5 mg/kg napabucasin, and 20 mg/kg napabucasin groups grew to 2318 mm 3 , 1764 mm 3 , and 1383 mm 3 , respectively, after 15 days of treatment. Suppression of subcutaneous tumor growth was observed, and the inhibitory effect was greater in the 20 mg/kg than in the 5 mg/kg napabucasin groups. The CD8+ cell percentage of tumor infiltrating lymphocytes for the untreated control, 5 mg/kg napabucasin, and 20 mg/kg napabucasin groups was 8.6%, 6.9%, and 19.0%, respectively. The CD8+ cell percentage increased with the increase in drug dosage. Conclusions: We had previously confirmed the antitumor effect of napabucasin by STAT3 inhibition in malignant pleural mesothelioma. In this study, 20 mg/kg napabucasin increased the CD8+ cell percentage of tumor infiltrating lymphocytes, indicating that the drug appears to enhance tumor immunity and that it may be used in combination with an antitumor immune antibody.
Glycoprotein nmb Is Exposed on the Surface of Dormant Breast Cancer Cells and Induces Stem Cell–like Properties
Authors: Chen Chen, Yukari Okita, Yukihide Watanabe, Fumie Abe, Muhammad Ali Fikry, Yumu Ichikawa, Hiroyuki Suzuki, Akira Shibuya, Mitsuyasu Kato
Journal: Cancer Research (2018)

Glycoprotein nmb (GPNMB) is a type I transmembrane protein that contributes to the initiation and malignant progression of breast cancer through induction of epithelial-mesenchymal transition (EMT). Although it is known that EMT is associated with not only cancer invasion but also acquisition of cancer stem cell (CSC) properties, the function of GPNMB in this acquisition of CSC properties has yet to be elucidated. To address this issue, we utilized a three-dimensional (3D) sphere culture method to examine the correlation between GPNMB and CSC properties in breast cancer cells. Three-dimensional sphere cultures induced higher expression of CSC genes and EMT-inducing transcription factor (EMT-TF) genes than the 2D monolayer cultures. Three-dimensional culture also induced cell surface expression of GPNMB on limited numbers of cells in the spheres, whereas the 2D cultures did not. Therefore, we isolated cell surface-GPNMBhigh and -GPNMBlow cells from the spheres. Cell surface-GPNMBhigh cells expressed high levels of CSC genes and EMT-TF genes, had significantly higher sphere-forming frequencies than the cell surface-GPNMBlow cells, and showed no detectable levels of proliferation marker genes. Similar results were obtained from transplanted breast tumors. Furthermore, wild-type GPNMB, but not mutant GPNMB (YF), which lacks tumorigenic activity, induced CSC-like properties in breast epithelial cells. These findings suggest that GPNMB is exposed on the surface of dormant breast cancer cells and its activity contributes to the acquisition of stem cell-like properties.Significance: These findings suggest that cell surface expression of GPNMB could serve as a marker and promising therapeutic target of breast cancer cells with stem cell-like properties. Cancer Res; 78(22); 6424-35. ©2018 AACR.
Phase II study of everolimus, letrozole, and metformin in women with advanced/recurrent endometrial cancer.
Authors: Pamela T. Soliman, Shannon Neville Westin, David A Iglesias, Mark F. Munsell, Brian M. Slomovitz, Karen H. Lu, Robert L. Coleman
Journal: Journal of Clinical Oncology (2016)

5506 Background: The combination of everolimus and letrozole has shown promising results in the treatment of recurrent endometrioid endometrial cancer (EEC). Both pre-clinical data and experience from a previous clinical trial suggest the addition of metformin may enhance this response, particularly in the presence of a KRAS mutation. We conducted a phase 2 study evaluating everolimus, letrozole, and metformin in patients (pts) with advanced/recurrent ECC. Molecular testing was performed to determine KRAS mutation status. Methods: A Simon two-step design was employed, with interim analysis after 25 pts. Women with incurable advanced/recurrent EEC and up to 2 prior chemotherapy regimens for recurrence were eligible. A pre-treatment biopsy was performed, followed by everolimus 10 mg PO daily, letrozole 2.5 mg PO daily, and metformin 500 mg PO BID. One dose reduction for everolimus was permitted. Pts were treated until progression or toxicity. The primary endpoint was clinical benefit (CB) rate, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) (confirmed at 8 wks), by RECIST 1.1. Fisher's exact was used to compare pts with and without KRAS mutation. Results: To date, 58 pts have been enrolled (median age 62; range: 40–77) and 194 cycles completed. Forty-eight pts were evaluable for response with a CB rate of 66.7% (32/48). Best overall response to date was 29% (14/48) PR and 38% (18/48) SD with a median of 6 cycles (range: 1–18). Seven patients have received > 14cycles (5 PR, 2 SD). Thirteen pts are on active treatment. There was no difference in CB based on KRAS mutation status; 19/26 (73.1%) pts without KRAS mutation and 9/14 (64.3%) pts with KRAS (p=0.72). Most common drug related toxicities were diarrhea, anemia, fatigue, nausea, mucositis, hypertriglyceridemia, and elevated aspartate aminotransferase. Two pts with SD after 2 cycles withdrew from the study for perceived toxicity. One patient who had a PR after 1 cycle was removed due to increased liver enzymes. Conclusions: The combination of everolimus, letrozole, and metformin results in a 67% CB rate in pts with recurrent, previously treated EEC. Further development in recurrent EEC of this combination is warranted. Clinical trial information: NCI2013-00960.