tbuckley/cabot-search huggingface dataset:
Impact of metformin on survival and mTOR pathway in head and neck cancer patients: An updated analysis.
Authors: Shuchi Gulati, Vinita Takiar, Jonathan Mark, Randall Butler, Joshua NeCamp, Trisha Michel Wise-Draper
Journal: Journal of Clinical Oncology (2017)

e17500 Background: Metformin is hypothesized to suppress tumor cell growth by mTOR pathway inhibition, which mediates the phosphoinositide 3-kinase/Akt signaling pathway (frequently deregulated in human cancers). This effect is mediated by activation of the AMP protein kinase (AMPK). Despite knowledge of the mechanism, various retrospective studies show conflicting results about effect of metformin on survival in head and neck squamous cell carcinoma (HNSCC) patients (pts). Methods: We analyzed a retrospective cohort of 1500 consecutive pts (between 2009-2015) with HNSCC. We added about 1000 pts to previously presented data (e17514-ASCO 2016). These pts included those with diabetes (DM) on metformin (MET) or other anti-diabetic agents. Descriptive statistics were used for demographic and pt data. Kaplan-Meier method was used to calculate median overall survival (OS) and progression free survival (PFS), 95% CI. Cox model was used to test association between MET (or DM) and OS (or PFS) (using SPSS-24 (IBM)). Results: Of the 1500 pts with HNSCC, 329 had advanced cancer (stage III/ IV), and received definitive chemo-radiation (CRT). Of these, majority were Caucasian (90%), males (90%) and smokers (70%). Mean age at diagnosis was 57 years (SD 10). 53 pts had DM, of which 37 were on MET. Statistical results are shown in Table 1. Conclusions: This retrospective study showed no statistically significant difference between various subgroups described in the table. Given the low number of diabetics, and pts on MET, data is limiting. However, further subset analyses are ongoing to determine whether a difference in treatment (RT vs. cetuximab vs. cisplatin) had an impact on outcomes. Future experiments will utilize tissue microarrays to evaluate for association with mTOR pathway aberrations. [Table: see text][Table: see text]
P01.049 Prediagnostic presentations of glioma in primary care: a case-control study
Authors: M C M Peeters, L Dirven, M W M de Waal, M E Numans, M J B Taphoorn
Journal: Neuro-Oncology (2018)

Little is known about the symptoms and signs of glioma patients in the year(s) before diagnosis. This study aimed to assess the prevalence of clinical symptoms glioma patients may present with to the general practitioner (GP) in the five years prior to diagnosis, and whether these can be distinguished from two control groups, i.e. (1) patients with other central nervous system (CNS) disorders or (2) any other condition. Glioma patients were matched to patients in the two control groups based on age, sex and diagnosis date, using anonymized GP registries. Prevalences of nine prediagnostic symptoms (seizures, headaches, motor impairments, cognitive/mental impairments, visual disorders, mood disorders/fear, general symptoms, sensory complaints and metabolic/endocrine symptoms) were evaluated in the five years prior to diagnosis, both overall as well as divided into three time periods: 60-24 months, 24–6 months and <6 months. In addition, the number of visits to the GP per patient were calculated. Thirty-six glioma patients were matched with 72 control patients. In total, 2491 (range 0–102) visits to the GP were analyzed. There were no significant differences between groups in the number of visits over 5 years (711 versus 989 versus 791 in glioma, CNS and other patients respectively; p=0.381), or in each of the three time periods. In the 60-24 months before diagnosis 399 visits versus 582 versus 444 visits were made by glioma, CNS and other control patients respectively (p=0.187), in the 24–6 months 217 versus 264 versus 238 visits respectively (p=0.948) and in the 6 months prior to diagnosis 95 versus 132 versus 109 visits respectively (p=0.547). The prevalence of motor symptoms in the period 60-24 months was significantly higher in the CNS patients as opposed to the other groups (4 versus 0 in both other groups; both p=0.039). Moreover, <6 months prior to diagnosis CNS patients differed significantly in mood disorders/fear compared to other controls (8 versus 0, p=0.012), but not glioma patients versus CNS patients (5 versus 8, p=0.816) or glioma versus other patients (p=0.221). No differences between groups regarding the prevalence of symptoms were found in the period 24–6 months prior to diagnosis. In this sample, glioma patients could not be distinguished from CNS or ‘other’ control patients with respect to the number of GP visits before diagnosis or prediagnostic symptoms. Nevertheless, when mood disorders occur, all CNS disorders should be considered by the GP, including glioma.
TCT-439 Long-term Savings with Telemedicine STEMI Networks
Authors: Sameer Mehta, Roberto Botelho, Francisco Fernandez, Mauricio Prudente, Ricardo Cavalcanti, Jamil Cade, Cesar Dusilek, Fausto Feres, Marco Alcocer-Gamba, Alfredo Estrada, Mario Torres, Daniel Rodriguez, Haytham Aboushi
Journal: Journal of the American College of Cardiology (2018)
Abstract MP97: Physical Inactivity is a Strong Risk Factor for Stroke in the Oldest Old Findings From the Northern Manhattan Study
Authors: Joshua Z Willey, Yeseon Park Moon, Chensy E Marquez, Ralph L Sacco, Clinton B Wright, Mitchell S Elkind, Yuen K Cheung
Journal: Circulation (2016)

Introduction: The fastest growing segment of the population is those over age 80, in whom there is the highest incidence of stroke. Few clinical trials, however, have targeted this population, and management of risk factors is complicated by higher rates of side effects and polypharmacy. We aimed to characterize whether the risk factors for stroke are different in those age &gt;80 versus &lt;80 in a multi-ethnic prospective cohort study. Methods: The study sample derives from the Northern Manhattan Study (n=3298), a prospective cohort study among an urban dwelling multi-ethnic population. At enrollment risk factors were assessed by self-report, physical examination, and laboratory data. Leisure-time physical activity (LTPA) was assessed by validated questionnaire and categorized as none versus any. Participants are followed annually for incident stroke which is adjudicated by study neurologists after review of all records and imaging. We fit Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association of cardiovascular disease risk factors (LTPA, reported alcohol use, fasting HDL-C and LDL-C, history of diabetes, hypertension, heart disease, and tobacco use) with risk of stroke. Multi-variable models also included two-way interaction terms between the primary exposures and age (&lt;80 and ≥80) and stratified models are presented if p-interaction &lt; 0.05. Results: The mean age was 69 years and 562 (17%) were age ≥80 years. Physical inactivity was common (41%) and did not differ by age. Subjects were followed for a median of 14 years, and there were 391 total strokes. We found a statistically significant interaction of age ≥80 on the risk of stroke with physical inactivity (p=0.02), diabetes (p=0.04), hypertension (p=0.005), and LDL-C (p=0.03). In stratified models no LTPA versus any (adjusted HR 1.61, 95%CI 1.06-2.43) was associated with an increased risk of stroke among those age ≥80 but not in those younger; LDL-C, hypertension and diabetes were mainly associated with risk of stroke in those below age 80. Conclusion: Lack of leisure-time physical activity is a potentially modifiable stroke risk factor and was more notable than hypertension, diabetes or dyslipidemia among those older than age 80. Improving activity may reduce the risk of stroke in this segment of the population.
Rituximab, lenalidomide, and ibrutinib alone and combined with dose adjusted chemotherapy for patients with high risk diffuse large B-cell lymphoma.
Authors: Jason R. Westin, Yasuhiro Oki, Luis Fayad, Loretta J. Nastoupil, Francesco Turturro, Frederick B. Hagemeister, Vishwanath Sathyanarayanan, Ken H Young, Timothy McDonnell, Hubert Chuang, Shouhao Zhou, Sattva Swarup Neelapu, Richard Eric Davis
Journal: Journal of Clinical Oncology (2016)

TPS7575 Background: Diffuse large B-cell Lymphoma (DLBCL), the most common lymphoid malignancy, is categorized by the putative cell of origin (COO) classification system into germinal center (GCB) and non-GCB subtypes. Both the immunomodulatory agent lenalidomide (L) and BTK inhibitor ibrutinib (I) have shown activity in the non-GCB DLBCL subtype as single agents and in combination with chemotherapy. Separate randomized phase III trials of RCHOP alone and +L or +I are ongoing in non-GCB DLBCL. Preclinical studies demonstrate L+I results in synthetic lethality in non-GCB DLBCL via interferon signaling (Yang et al, Cancer Cell, 2012), but no trials have evaluated the efficacy in newly diagnosed patients. We present the first "window of opportunity" trial to use targeted therapy (rituximab, R+L+I) alone prior to chemotherapy in newly diagnosed DLBCL. Methods: In this investigator initiated phase II trial, patients receive standard R dosing q 21 days (d), L 25mg po d1-10, I 560mg po d1-21, and after two 21d RLI cycles or earlier if disease progression will start RLI-EPOCH q 21d for 6 cycles, without maintenance therapy. EPOCH will be dose adjusted based on standard criteria, capped at level +2. L+I dosing may be reduced if significant toxicity criteria are met. Key eligibility criteria include histologically confirmed, treatment-naïve non-GCB DLBCL, age ≥ 18, adequate performance status and organ function, and measurable disease. COO will be determined via immunohistochemistry for eligibility, and NanoString (Scott et al, Blood. 2014) for confirmation. Patients will be restaged with PET/CT using Lugano criteria (Cheson et al, JCO 2014). The primary objectives are to determine the overall response rate after two RLI cycles and complete response rate after 6 RLI+EPOCH cycles. Secondary objectives include safety and survival outcomes. Exploratory objectives include evaluation of baseline and therapy induced changes in gene and protein expression, mutations, minimal residual disease monitoring, and immune cell subsets in comparison with clinical outcomes. The trial will accrue 60 patients, and employs Bayesian futility and toxicity monitoring rules. Clinical trial information: NCT02636322.
Public Health England’s capture by the alcohol industry
Authors: Ian Gilmore, Linda Bauld, John Britton
Journal: BMJ (2018)

As in many rich countries, public health in the United Kingdom is blighted by harms caused by consumption of unhealthy commodities such as tobacco, alcohol, and foods high in fat, sugar, or salt. 1 In England, responsibility for tackling these problems lies with Public Health England (PHE), an executive branch of the Department for Health and Social Care. 2 It is a challenging task: consumption of these commodities is driven by powerful transnational companies 3 with a history of cooperation in opposing health legislation and adopting similar tactics to influence and restrict controls on their market environments. 4 The launch on 10 September of a health promotion partnership 5 between PHE and Drinkaware, an organisation that is funded by the alcohol industry, indicates that PHE is struggling to rise to the challenge.
SECOMBIT (sequential combo immuno and target therapy study): A three arms prospective, randomized phase II study to evaluate the best sequential approach with combo immunotherapy [ipilimumab (I) /nivolumab (N)] and combo target therapy [encorafenib (E)/binimetinib (B)] in patients with metastatic melanoma and BRAF mutation.
Authors: Paolo Antonio Ascierto, Reinhard Dummer, Ignacio Melero, Giuseppe Palmieri, Diana Giannarelli, Elena Abrami, Marcello Curvietto, Ester Simeone, Antonio Maria Grimaldi
Journal: Journal of Clinical Oncology (2017)

TPS9598 Background: Treatment of BRAF-mutated metastatic melanoma has dramatically changed with the introduction of targeted therapy (BRAF and MEK inhibitors) and immune-checkpoint blockade (anti-CTLA4, anti-PD-1, and anti-PD-L1). Target therapy has been associated with high response rates, but short-term responses. Conversely, treatment with immune checkpoint inhibitors was found to present with lower response rates, but long-term responses. Synergism has been demonstrated when targeted therapy is combined with immunotherapy. The risk of a high rate of toxicity limits the simultaneous combination of all the four compounds (target agents and immunomodulating monoclonal antibodies). Sequencing of these different combinations seems to be more feasible; finding the right treatment sequence represents an important issue to be addressed. Methods: Approximately, 230 patients with untreated, histologically-confirmed advanced melanoma (measurable disease by RECIST v1.1) and carrying the BRAF V600 mutation will be randomized to Arm A [E+B until disease progression (PD), followed by I+N], or Arm B (I+N until PD, followed by E+B) or Arm C (E+B for 8 weeks, followed by I+N until PD, followed by E+B until PD). Patients will receive the combo treatments with the following schedules: target therapy, E 450mg p.o. od + B 45mg p.o. bid; immunotherapy, I 3mg/kg + N 1mg/kg Q3w x 4 cycles, followed by N 3mg/kg Q2w. The OS (time from the date of randomization until death from any cause) is primary efficacy endpoint of the study. Secondary endpoints include total PFS (time from randomization until the second progression), survival at 2 and 3 years, best overall response rate, duration of response. About 90 patients will take part in the ancillary study for the evaluation of biomarkers on the biological samples available (biopsies + blood samples). 30 Sites in Europe will concur to enroll the patients in the trial. This study is open and currently enrolling patients. Clinical trial information: NCT02631447.
Natural killer cells as a predictive biomarker for response to anti-PD-1 therapy in patients with advanced solid tumors.
Authors: Bixia Tang, Zhihong Chi, Xinan Sheng, Lu Si, Chuanliang Cui, Yan Kong, Si Ming Li, Xieqiao Yan, Li Li Mao, Bin Lian, Xue Bai, Xuan Wang, Li Zhou, Dan Li, Jiayi Yu, Jun Guo
Journal: Journal of Clinical Oncology (2017)

e21055 Background: Assessment of PD-L1 expression in tumor biopsy has been widely used for predicting anti-PD-1 therapy. Several factors, including tumor heterogeneity, false negative staining and unavailability of biopsy samples limit the application. Natural killer (NK) cells exert cytotoxicity against cancer cells. Therefore, we explored using NK cells percentage in peripheral blood (PB) as a biomarker to identify pts who are more likely to benefit from anti-PD-1 therapy. Methods: Pts treated with anti-PD-1 antibody (JS001) 1 mg/kg, 3mg/kg or 10mg/kg every 2 weeks in a Phase I clinical trial (ClinicalTrials.gov Identifier: NCT02836795) had PB collected at baseline and at time of radiographic evaluation performed every 8 wks. Disease status (shrinking stable disease, growing stable disease, partial response, complete response, or progressive disease) was characterized using RECIST v1.1 and immune-related response criteria. Frequencies of NK cells (CD3 - CD16 + CD56 + ) were measured by flow cytometry. Results: Thirty-six patients were enrolled in this trial, including 22 melanoma, 9 urothelial carcinoma and 5 renal cell carcinoma. As of 1/27/2017, median treatment duration: 3.92 months. Radiographic tumor evaluation has been performed in 32 pts: 1/32 CR, 6/32 PR, 6/ 32 shrinking SD, 4/32 growing SD and 15/32 PD. Pts with high NK cells at baseline observed 60% (6/10) Clinical Benefit Rate (CR/PR/ shrinking SD) versus 40% (13/32) in overall pts. Patients with clinical benefit had higher frequency of NK cells at baseline compared to pts with radiographic growing SD and PD (mean 24.3% vs. 17.9%, P = 0.076). Furthermore, pts with NK cell level consistently above UN or increasing above UN during treatment are more likely to get clinical benefit than those under UN (7/10 vs 3/22, P = 0.013). Conclusions: Baseline high NK cells frequency may predict a favorable response to anti-PD-1 therapy, which provides a non-invasive way to monitor response to PD-1 blockade. These results are being validated in a phase II trial. Clinical trial information: NCT02836795.
P04.27 Silence of Hippo pathway induces pro-tumoral immunity: New therapeutic target of glioblastomas
Authors: E Kim, J Lee
Journal: Neuro-Oncology (2018)

The Hippo pathway plays a critical role in various cancers, but its role in glioblastoma (GBM) has not been properly addressed. We assessed the clinical relevance of the Hippo pathway in GBM. We generated a core gene expression signature from four previously established gene signatures reflecting silence of the Hippo pathway (SOH) in colorectal, liver, ovarian, and stomach cancers. The association of the core SOH signature with copy number variation, mutations, proteomics, and mRNA expression data, as well as overall survival, was assessed in GBM patient samples from The Cancer Genome Atlas (TCGA) and validated in a separate cohort. Immune signature score (ISS) was generated based on the previously established algorithm to access immune signature of each sample. Gene expression signatures reflecting host immune activity and the transforming growth factor beta (TGF-β) pathway were also assessed in TCGA samples. The SOH signature was associated with poor prognosis in GBM in both cohorts. Expression levels of CTGF and CYR61, the most reliable and well-known downstream targets of YAP1 (a target of the Hippo pathway), were markedly increased in GBM with the SOH signature. GBM showing the SOH signature was associated with an increased ISS, suggesting that these patients might be good potential candidates for immunotherapy. Genes differentially expressed between samples with the SOH signature and samples with an active Hippo signature showed that many inhibitory immune checkpoint genes, such as CTLA4, PD-1, and PD-L2, were upregulated in the SOH subgroup, suggesting that YAP1/TAZ may induce resistance of cancer cells to host immune response in GBM. Also, many M2-polarized microglial markers and innate immune pathways were activated in the SOH subgroup. The SOH signature was strongly correlated with the TGF-β signature, which was also associated with a high immune signature score and mesenchymal features. SOH is significantly associated with poor prognosis of patients with GBM and increased immune activity. Many inhibitory immune checkpoint genes are upregulated in the SOH subgroup, suggesting that YAP1/TAZ may induce resistance of cancer cells to host immune response in GBM. M2 polarized microglia may be another important component of pro-tumoral immunosuppression in GBM with possible association with SOH.
Impact of lifestyle habits on patient-reported concerns among breast cancer survivors
Authors: Moaath Khader Mustafa Ali, Machelle Moeller, Lisa A. Rybicki, Halle C. F. Moore
Journal: Journal of Clinical Oncology (2016)

10095 Background: In a cohort of breast cancer survivors, we observed differences in patient-reported symptoms and comorbidity based on age, treatment, and time since end of treatment. Here we sought to evaluate the impact of modifiable lifestyle behaviors on symptoms and concerns reported by survivors. Methods: We conducted a retrospective and prospective IRB-approved cohort study evaluating 34 symptoms and comorbidities reported by stage 0-III breast cancer patients at an initial survivorship visit. Using logistic regression analysis, we studied the association of symptoms and comorbidities with exercise behavior (exercised before cancer, started after cancer, no exercise), smoking status (current, former, never) and alcohol intake ( > 3 drinks/week [moderate], 1-3 [mild], none). Results: Between 4/2009 and 11/2015, 1126 eligible survivors were seen. Median time from treatment to survivorship visit was 18 (range 0-300) months. On multivariable analysis, mild alcohol consumption was associated with more hot flashes, amenorrhea, insomnia and depression but less osteoporosis and diabetes. Moderate alcohol consumption was associated with more hot flashes but less extremity swelling and diabetes. Patients who exercised before cancer diagnosis experienced less paresthesia, fatigue, dyspnea, concerns about weight, hair loss, extremity swelling, anhedonia, depression, anxiety, diabetes, difficulty focusing, and unintentional weight loss but experienced more vaginal dryness (all P < 0.05). Patients who started to exercise after diagnosis reported less anhedonia (P < 0.05). Former smokers were more likely to report hair loss, gastrointestinal symptoms and depression than never-smokers while current smokers were more likely to experience anhedonia (all P < 0.05). Current smokers reported 6-fold more coronary artery disease (95% CI: 1.6-25.9, P = 0.008). Conclusions: Breast cancer survivors who exercised before cancer reported less symptoms and comorbidities. Smoking and alcohol intake were associated with an increase in some patient-reported concerns. The impact of smoking cessation and initiation of exercise after diagnosis on symptom burden merits further investigation.
Effect of combination of ONC201 and bevacizumab on colorectal cancer (CRC) growth and metastasis in vivo.
Authors: Wafik S. El-Deiry, Jessica Wagner
Journal: Journal of Clinical Oncology (2016)

e15155 Background: ONC201 is a small molecule anti-tumor agent that upregulates endogenous TRAIL and activates the integrated stress response (ISR), increasing DR5 expression. ONC201 completed a phase I clinical trial in advanced solid tumors and is currently in multiple phase I/II clinical trials in select advanced cancers. Advanced CRC has a 5-yr survival of 13%. Bevacizumab (Avastin), a monoclonal antibody that targets VEGF, is an important therapeutic option for patients with advanced metastatic CRC. Because ONC201 has activity in preclinical models against CRC, we investigated the efficacy of ONC201 in combination with chemotherapy or bevacizumab in CRC models. Methods: HT-29 xenograft mice were treated with doses of ONC201 at 25, 50, or 100 mg/kg at 1 or 2 week frequencies as a single agent or in combination with Avastin at 5 mg/kg every 2 weeks. Bio-luminescence imaging and pathology-analyzed tissue sections demonstrated if metastatic lesions where present. Angiogenic marker CD31 staining in ONC201-dosed xenografts was performed, and analysis of the combinational therapy performed. Results: ONC201 did not demonstrate synergy with 5-FU or irinotecan used to treat CRC. However, a potent ONC201 plus bevacizumab anti-tumor effect was observed in vivo. ONC201 decreased CD31 levels in CRC xenografts. While each agent showed single agent efficacy, the combination was synergistic in creating significant suppression of CRC xenograft growth and occasional complete tumor regressions. The ONC201 combination with bevacizumab also suppressed metastasis of CRC in vivo. Colorectal PDX models are ongoing including a BRAF-mutant CRC PDX model from CTCs. Mechanistic studies and angiogenesis imaging studies are ongoing to demonstrate the importance of the combination on tumor growth, migration, and invasion. Conclusions: Our results demonstrate that combining anti-angiogenic bevacizumab with ONC201 enhances anti-tumor efficacy in preclinical models of CRC and provides a rationale for further testing in the clinic.