tbuckley/cabot-search huggingface dataset:
Phase I-Ib trial of tivantinib in combination with carboplatin and pemetrexed as first-line treatment in patients (pts) with advanced nonsquamous NSCLC or malignant pleural mesothelioma (MPM).
Authors: Paolo A. Zucali, Matteo Simonelli, Fabio De Vincenzo, Giuseppe Fatuzzo, Monica Bertossi, Matteo B. Suter, Matteo Perrino, Laura Giordano, Armando Santoro
Journal: Journal of Clinical Oncology (2014)

TPS7610 Background: Dysregulation of MET signalling has been reported as a key event in several malignancies and has been identified as a promising therapeutic target. Strong preclinical data on MPM and NSCLC showed that MET inhibition blocks tumor cell growth and migration (Jagadeeswaran et al, Cancer Res 2006; MA et al, Cancer Res 2005). Tivantinib (T) is a selective non-ATP competitive oral inhibitor of MET receptor. In a randomized phase III trial, the combination of T plus erlotinib improved overall survival in a subset of pts with non-squamous NSCLC and high MET expression (Scagliotti G, ESMO/ECCO 2013 abst. n°:3410). Adding T to first-line chemotherapy (CT) may improve efficacy. Methods: This Phase I-Ib study is designed to assess the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of escalating doses of T in combination with fixed doses of carboplatin (AUC 5 i.v. d1-q21) and pemetrexed (500 mg/m2 i.v. d1-q21) as first line treatment for pts with advanced MPM or non-squamous NSCLC. Eligible pts must be CT naïve with ECOG Performance Status <2 and adequate bone marrow, liver and kidney functions. Sequential cohorts of 3 pts per dose level are recruited according to a standard 3 + 3 dose-escalation design starting from level 0 (T 240 mg BID). In case of DLTs in the first 3 pts, a dose level -1 (T 120 mg BID) will be investigated; in absence of DLTs, dose escalation will continue at dose level +1 (T 360 mg BID). The MTD is defined as the highest dose level at which no more than 1 of 6 pts experiences a DLT during the first cycle. If the frequency of DLTs encountered at dose-level +1 will not fulfil the MTD definition it will be accepted as the recommended dose for phase II trials. Additional pts (in order to reach 13 pts with MPM and 18 with NSCLC) will be enrolled at the MTD in an expansion cohort, to evaluate the preliminary anti-tumor activity in terms of 3-month PFS% for MPM pts and 5-month PFS% for NSCLC pts. Enrollment has begun in October 2013. The first dose level has been completed without DLTs and the first pt at dose level + 1 started treatment in January 2014. Clinical trial information: NCT02049060.
Early predictors of improved long-term outcomes in first-line antiangiogenics plus chemotherapy (anti-ANG/CT) in metastatic colorectal cancer (mCRC): Analysis of individual patient (pt) data from the ARCAD database.
Authors: Everardo D. Saad, Elisabeth Coart, Dirkje Willemien Sommeijer, Qian Shi, John Raymond Zalcberg, Tomasz Burzykowski, Jeffrey P. Meyers, Paulo Marcelo Hoff, J. Randolph Hecht, Herbert Hurwitz, Jolien Tol, Niall C. Tebbutt, Charles S. Fuchs, Eduardo Diaz-Rubio, John Souglakos, Alfredo Falcone, Fairooz F. Kabbinavar, Daniel J. Sargent, Aimery De Gramont, Marc E. Buyse
Journal: Journal of Clinical Oncology (2014)

3578 Background: Early tumor shrinkage (ETS, ≥20% decrease from baseline) is associated with improved progression-free survival (PFS) and overall survival (OS) in mCRC pts treated with epidermal growth factor receptor inhibitors. We compared the relative merits of ETS and early objective tumor response (EOTR; CR/PR by RECIST) vs. standard Best Overall Response (BOR) and Confirmed Response (ConfR) in mCRC pts treated with 1st-line anti-ANG/CT. Methods: Data were available from 4,776 pts enrolled on 8 randomized trials of bevacizumab (N=6), cediranib (N=1), or both (N=1). ETS, EOTR, BOR and ConfR were assessed at 6, 8/9 and 12 weeks (wks). Associations were assessed by stratified Cox models with a landmark approach. The relative prediction accuracy of distinguishing pts at high vs. low risk of progression/death was compared by C-index (c, higher values indicate better accuracy). Results: All response endpoints were significantly associated with PFS and OS (P≤0.001 for all hazard ratios [HRs]) (see Table). Adjusting for age, performance status, # of metastases and prior therapy, significance remained. ETS showed larger effect size than EOTR. For PFS, the prediction accuracy was similar across time points or endpoints. For OS, compared with earlier time points, ETS and EOTR at 12 wks produced larger risk reduction, with similar prediction accuracy as BOR. Conclusions: Early response-based endpoints are significantly associated with improved PFS and OS in mCRC pts treated with anti-ANG/CT. The prediction performance of early response based on tumor measurement is as good as for standard RECIST response. Assessment of these endpoints as surrogates for PFS/OS at the trial level is ongoing. Wks ETS EOTR BOR ConR HR (95% CI) c HR (95% CI) c HR (95% CI) c HR (95% CI) c PFS 6 .77 (.69-.86) .55 .80 (.71-.91) .53 .72 (.67-.79) .55 .86 (.78-.94) .52 8/9 .74 (.67-.82) .55 .81 (.72-.91) .53 12 .74 (.66-.84) .54 .80 (.71-.90) .54 OS 6 .63 (.54-.73) .58 .64 (.54-.76) .56 .45 (.40-.49) .61 .60 (.53-.69) .56 8/9 .58 (.50-.66) .59 .63 (.53-.74) .56 12 .51 (.44-.59) .59 .53 (.46-.62) .60 Abbreviations: CI, confidence interval.
Prevalence of iron deficiency in severe anemia for cancer patients admitted in the emergency unit for acute onset symptoms.
Authors: Arif Alibay, Mansouriah Merad, Sylvie Khan, Mario Di Palma, Sami Antoun
Journal: Journal of Clinical Oncology (2014)

e20706 Background: Anemia in cancer is a common biological abnormality and etiological research is often not conducted. Iron deficiency (ID) is rarely explored. The objective is to determine the prevalence and the characteristics of severe anemia for cancer patients. Methods: All cancer patients who visited the emergency unit for acute symptoms were included prospectively during 22 months if haemoglobin level was <10 g/dl. Four groups were defined using serum ferritin (SF) (ng/ml) and transferrin saturation (TSAT) (%): Absolute ID (AID) (TSAT<20 and SF<100); Functional ID (FID) (TSAT<20 and SF between 100 and 1000); Unknown ID (UID) (TSAT<20 and SF>1000); Group without ID (WID) (TSAT>20). The cut-off value of SF at 1000 was chosen because beyond this level the ferritin in the tissues and SF are no more correlated. Data are expressed as mean ± standard error (SE). Comparisons between two means by Student’s test were made. The level of significance was p< 0.01. Results: Anemia was observed for 125 patients; 30% had hemoglobin<8; 8% of the patients had AID, 47 % had a FID, 17% were UID and 28% were WID. Asthenia and dyspnea were reported in 82% and 54% of the patients, respectively. A gastrointestinal localization was found for only 20% of the patients with AID. No difference between groups was observed for Vitamin B9 and Vitamin B12 levels. Surprisingly, C reactive Protein (CRP) (mg/l) levels were significantly higher for FID (131 ± 95) than WID (50 ± 58) (p< 0.001) while SF was significantly lower for FID (442 ± 243) than WID (1050 ± 830) (p<0.001). For 80% of FID and 86% of UID, inflammatory syndrome (CRP level>50 mg/ml) might explain TSAT less than 20%, but for 20% and 14% respectively there are maybe other explanations. Conclusions: Absolute ID was rarely observed in cancer patients visiting for acute onset symptoms and 64% (FID + UID) of the patients are with an ID status difficult to determine. The reticulocytosis response after an iron supplementation could be a help for diagnosis and understanding the underlying mechanisms.
BIM expression in EGFR-mutant non-small cell lung cancer (NSCLC) patients (pts) treated with erlotinib in Colombia.
Authors: Andres F. Cardona, Niki Karachaliou, Ana Drozdowskyj, Ana Gimenez Capitan, Miguel Angel Molina-Vila, Oscar Arrieta, Hernan Carranza, Carlos A. Vargas, Jorge M. Otero, Rafael Rosell
Journal: Journal of Clinical Oncology (2014)

e19098 Background: Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with EGFR-mutated NSCLC. However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. BIM is a pro-apoptotic member of the BCL2 family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. Previous reports have linked BIM to response and progression-free survival (PFS), and its polymorphism was sufficient to confer intrinsic resistance in Asian population. Methods: We study the impact of BIM mRNA expression on response and OS in 29 EGFR-mutant pts treated with erlotinib in Colombia. Results: 55% of pts were >60 years old, 79% (n = 23) were women and overall response rate to TKIs was 58.6%. Response was 70% for erlotinib-treated pts with high total BIM levels, compared to 52.9% with low/intermediate total BIM levels (P=0.4475). OS was 32.9-mo for pts with high and 18.1-mo for those with low BIM (P=0.23). Conclusions: From our knowledge this is the first attempt to establish the relevance of BIM mRNA expression in patients with EGFR mutations in a LATAM population. The results define the potential usefulness of this biomarker to predict the response to TKIs.
The nationwide Danish CancerBiobank: Future possibilies.
Authors: Estrid V. Høgdall, Beth Bjerregaard
Journal: Journal of Clinical Oncology (2014)

e22196 Background: Through Danish CancerBiobank (DCB) to ensure collection of blood and tissues optimal for translational research from all patients diagnosed with primary cancer. Methods: The infrastructure was established through the Departments of Pathology and Departments of Clinical Biochemistry at the six University hospitals in Denmark. All departments agreed on national technical recommendations. A national on-line database was established to registry information such as pre-analytical factors, laboratory procedures and verification of the diagnosis of the colleted tissues. The database is linked to the national pathology register (www.patobank.dk) and the data can be combined with Danish clinical databases and other registers relevant for research. Results: DGC was implemented in January 2010. In 2012 biological materials from 9.609 patients have been collected, a total of 11.121 blood samples and 6.814 tissue samples equivalent to a 30% coverage of all patients with primary cancer. From 3.056 tissue samples a corresponding blood sample was collected. A twofold increase of material collected is observed from 2010 to 2012. Today DCB is responsible for collecting biological materials for 35 research projects. Conclusions: The DCB is unique nationally and internationally, due to: 1) National recommendations for handling of biological materials 2) Centralized nationwide data registration 3) Information of both blood and tissue for the single patient 4) Connection to the final diagnosis through Patobanken and 5) Connection to the nationwide clinical databases and other national registries. The success for DCB will be translational research results of clinical importance for cancer patients.
Long Term Follow-up on Phase 2 Study on the Efficacy and Safety of Blinatumomab in Adult Patients with Relapsed Refractory B-Precursor Acute Lymphoblastic Leukemia
Authors: Iman Aboudalle, Hagop M. Kantarjian, Nicholas J Short, Farhad Ravandi, Koji Sasaki, Guillermo Garcia-Manero, Guillermo Montalban-Bravo, Jorge E. Cortes, Christopher B. Benton, Ghayas C. Issa, Maria Khouri, Patrice Nasnas, Susan M. O'Brien, Elias J. Jabbour
Journal: Blood (2018)
Solving Homelessness from a Complex Systems Perspective: Insights for Prevention Responses
Authors: Patrick J. Fowler, Peter S. Hovmand, Katherine E. Marcal, Sanmay Das
Journal: Annual Review of Public Health (2019)

Homelessness represents an enduring public health threat facing communities across the developed world. Children, families, and marginalized adults face life course implications of housing insecurity, while communities struggle to address the extensive array of needs within heterogeneous homeless populations. Trends in homelessness remain stubbornly high despite policy initiatives to end homelessness. A complex systems perspective provides insights into the dynamics underlying coordinated responses to homelessness. A constant demand for housing assistance strains service delivery, while prevention efforts remain inconsistently implemented in most countries. Feedback processes challenge efficient service delivery. A system dynamics model tests assumptions of policy interventions for ending homelessness. Simulations suggest that prevention provides a leverage point within the system; small efficiencies in keeping people housed yield disproportionately large reductions in homelessness. A need exists for policies that ensure reliable delivery of coordinated prevention efforts. A complex systems approach identifies capacities and constraints for sustainably solving homelessness.
Association of Patient Sex With Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers
Authors: Christopher J. D. Wallis, Mohit Butaney, Raj Satkunasivam, Stephen J. Freedland, Sandip P. Patel, Omid Hamid, Sumanta K. Pal, Zachary Klaassen
Journal: JAMA Oncology (2019)

Sex-associated differences in immune response are known, but a meta-analysis suggested men, compared with women, derive greater value from immunotherapy for advanced solid-organ malignant neoplasms. However, methodologic concerns and subsequent trials have placed these results in doubt.To perform an updated, comprehensive meta-analysis that assesses the efficacy of immunotherapy in advanced cancers according to patient sex.A systematic review of studies (n = 23) indexed in MEDLINE (PubMed), Embase, and Scopus from inception of these databases to October 2, 2018, was conducted. Randomized clinical trials that compared immunotherapy with standard of care in the treatment of advanced solid-organ malignant neoplasms were included if overall survival was reported as an outcome and if data stratified by patient sex were available. Observational studies, editorials, commentaries, review articles, non-peer-reviewed publications, studies that compared various immunotherapy regimens, studies that reported other measures of oncologic response, and studies that reported subgroup analyses for 1 sex only were excluded.Overall survival, with a test for heterogeneity between women and men, to assess the null hypothesis that no difference in the survival advantage of immunotherapy exists by patient sex.This meta-analysis included 23 randomized clinical trials that reported on 9322 men (67.9%) and 4399 women (32.1%); the age of most patients was in the 70s. An overall survival benefit of immunotherapy was found for both men (hazard ratio [HR], 0.75; 95% CI, 0.69-0.81; P < .001) and women (HR, 0.77; 95% CI, 0.67-0.88; P = .002). Random-effects meta-analysis of study-level differences in response to immunotherapy demonstrated no statistically significant difference between the sexes (I2 = 38%; P = .60). Subgroup analyses according to disease site, line of therapy, class of immunotherapy, study methodology, and representation of women recapitulated these findings.Stratified analyses demonstrated no statistically significant association of patient sex with the efficacy of immunotherapy in the treatment of advanced cancers using overall survival as the outcome.
Anticoagulation Therapy in Non–ST-Segment Elevation Acute Coronary Syndrome
Authors: Gregory Curfman
Journal: JAMA Internal Medicine (2018)

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Abstract 18008: Skeletal Muscle SIRT3 is Required for Nitrite- and Metformin-Mediated Reduction of PH-HFpEF
Authors: Yen-Chun Charly Lai, Jeff Baust, Ana L Mora, Mark T Gladwin
Journal: Circulation (2017)

Introduction: Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is the most common cause of PH worldwide and has no proven effective therapies. Our recent data show that SIRT3 activation levels are specifically decreased in skeletal muscle, concomitant with robust increase of pulmonary pressures and vascular remodeling. Restoration of SIRT3 in skeletal muscle with nitrite and metformin therapies improve metabolic syndrome and reduces disease phenotypes. However, it is unknown whether SIRT3 activation in skeletal muscle is critical for the beneficial effects of nitrite and metformin on both metabolic abnormalities and cardiopulmonary defects underlying PH-HFpEF. Methods and Results: Using skeletal muscle-specific SIRT3 KO (SIRT3skm-/-) mice with 16 weeks of high-fat feeding (HFD, 60% fat in Kcal), which induces a PH-HFpEF phenotype in mice, in the presence or absence of nitrite (100 mg/L) and metformin (300 mg/kg), we examined the impact of skeletal muscle SIR...
SAT0216 The addition of colchicine to metotrexate might help achieve low disease activity in patients with early rheumatoid arthritis by downregulating the activity of caspase-1.
Authors: D. Ramos-Bello, A. J. Pedro-Martínez, G. Aguilera Barragán-Pickens, E. S. Acevedo-Castañeda, H. López-Ferretis, G. Martínez-Flores, T. A. Luna-Zúñiga, E. Santillán-Guerrero, R. Moreno-Valdés, M. Saldaña-Baard, E. Cuevas-Orta, C. Álvares-Quiroga, R. González-Amaro, C. Abud-Mendoza
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> NLRP3 inflammasome is an intracellular protein complex involved in the production of pro-inflammatory cytokines as IL-1β and IL-18, which has been reported to have a role in the pathogenesis of RA<sup>1,2</sup>. Since colchicine (CCH) is a potent inhibitor of NLRP3<sup>3</sup>, we hypothesized that it may significantly modify the expression and function of this molecular complex, reducing the inflammatory phenomenon in early rheumatoid arthritis (eRA). <h3>Objectives:</h3> To evaluate the possible effect of CCH administration on the expression and activity of NLRP3 in patients with eRA and evaluate if it has an effect on disease activity. <h3>Methods:</h3> Inflammasome expression by monocytes was assessed by two-color flow cytometry (CD14<sup>+</sup>NLRP3<sup>+</sup> cells), and its function was estimated through the analysis of caspase-1 activity (colorimetric assay). Clinical activity was assessed by HAQ-DI, CDAI, SDAI and DAS28ESR at 0, 4 and 12 weeks. <h3>Results:</h3> Twenty DMARD naive patients were recruited, 18 women, mean age 47.55 (30–72), mean time with symptoms 20 months and seropositive (RF/ACCP) in 60% of patients; all described in table 1. All patients had increased levels of caspase-1 activity and NLRP3 in week 0. At week 12, MTX+CCH patients showed decreased activity of caspase-1 and numerical difference in the expression of NLRP3. Patients with MTX+CCH at week 12 had significant clinical improvement, with low disease activity in 6/10 patients vs 2/10 patients with MTX (p&lt;0.05). Mean change in HAQ was -0.64 in patients with MTX compared with -1.5 in patients with MTX+CCH (p&lt;0.05). <h3>Conclusions:</h3> The data suggest that CCH administration is associated with decrease in the expression NLRP3 inflammasome and activity of caspase-1. This phenomenon contributes to decrease inflammation and may help to achieve low disease activity. The administration of CCH might block additional targets in patients with eRA. <h3>References</h3> [1]Choulaki C, et al. Arthritis Research &amp; Therapy2015;17:257. [2]Lasithiotaki I, et al. Eur Respir J. 2016Mar;47(3):910–8. [3]Martinon F, et al. Nature2006Mar 9;440(7081):237–41. [4]Aletaha D, et al. Arthritis Rheum2010Sep;62(9):2569–81. <h3>Disclosure of Interest:</h3> None declared
The role of protein tyrosine phosphatase non-receptor 11 (<i>PTPN11</i>) mutations in lung squamous cell carcinoma (SQCC).
Authors: Yasir Elamin, Sinead Toomey, Aoife Carr, Kenneth O'Byrne, Shereen Rafee, Kathy Gately, Oscar S. Breathnach, Sinead Cuffe, William Grogan, Patrick Glyn Morris, Bryan Hennessy
Journal: Journal of Clinical Oncology (2014)

e22174 Background: In contrast to lung adenocarcinoma, there are no known targetable oncogenes in lung SQCC. Herein, we thus screened for mutations in 49 kinome-related genes in lung cancer including SQCCs to find novel potential treatment targets. Methods: DNA was extracted from tumor and matched adjacent normal tissue of surgical resection samples of a cohort of Irish non-small cell lung cancer (NSCLC) patients. A novel mass spectrometry-based approach developed by Sequenom (Hamburg Germany) was applied to DNA extracted from tumor and matched normal tissue to screen for a panel of 547 mutations in 49 genes. Results: We analyzed 152 surgical resection NSCLC samples, 86 SQCCs and 66 adenocarcinomas. Among the SQCCs 16 (18.6%) were found to have novel somatic mutations in the PTPN11 gene (that encodes for Shp2, a positive regulator of the MAPK pathway), compared to 1 (1.5%) of the adenocarcinoma samples (p<.01). Three hotspot somatic PTPN11 mutations were found in our lung SQCC samples, E76A, E76G, and A72D. All these mutations occur in exon 3 of PTPN11 We have validated these mutations in the SQCCs using a 2nd sequencing technology (pyrosequencing), and confirmed that these mutations are somatic (by demonstrating their absence in matched adjacent normal tissue through sequenom analysis) and likely functional (using AVSIFT analysis) Pairwise exclusivity analysis showed that KRAS and PIK3CA mutations were statistically significantly (P<.01) enriched in lung SQCCs harboring novel PTPN11 mutations. In the setting of SQCC surgical resection alone, PTPN11 mutations were associated with RFS and OS times of 23.8 and 26.9 months, respectively compared with 21.6 and 23.3 in patients with PTPN11-wild type SQCCs, p=0.4 and 0.9 respectively. Conclusions: Novel somatic PTPN11 mutations occur in 18.6% of Irish lung SQCCs. We hypothesize that PTPN11 mutations are important events in the pathogenesis of mutated SQCCs and, significantly, may represent a new treatment target in this difficult-to-treat disease. We are currently exploring the pre-clinical efficacy of PTPN11/Shp2 inhibitors that have recently been developed (one of which is already in clinical trial in polycystic ovarian syndrome) in PTPN11 mutated lung SQCC.