tbuckley/cabot-search huggingface dataset:
Efficacy and safety of endostar combined with whole brain radiotherapy in patients with NSCLC brain metastases.
Authors: Xiaorong Dong, Fan Tong, Lingjuan Chen, Pengcheng Li, Gang Wu
Journal: Journal of Clinical Oncology (2018)

e14002 Background: Brain metastasis (BM) is the leading cause of poor prognosis, recurrence, and death in non-small-cell lung cancer (NSCLC) patients. Due to the limitation of the Blood-Brain Barrier (BBB), brain radiotherapy have become the standard treatment for brain metastases. Since the tumor microenvironment is in hypoxia, tumor cells are resistant to radiation. This study demonstrated that WBRT combined with Endostar could improve the efficacy of radiotherapy for NSCLC patients with BM. Methods: 23 advanced NSCLC patients with brain metastasis were randomly divided into two groups. The experimental group (n = 12) received WBRT (30Gy/10F) combined with Endostar (15mg/m2, 7days), and the control group (n = 11) only received WBRT (30Gy/10F). The changes in cognitive function and emotion were evaluated pre- and post- radiation against the MMSE, MoCA, SDS and SAS scales, physical, role function and overall healthy level. Moreover, cerebral hemodynamic changes of blood volume (CBV), blood flow (CBF) and mean perfusion time (MTT) were assessed by MR perfusion imaging pre- radiation and 3 months post-radiation. Tumor progression was established by certified oncologists based on whole brain CT scan or MRI. Progression of survival (PFS) was defined from prior treatment to tumor progression. Results: Two months after cranial radiation, compared with prior to radiation, the total scores of the experimental group on the MMSE, MoCA scales and cognitive function of the patients increased in two groups. In experimental group, the physical, role, social and emotional functions improved, and the scores of aforementioned functions declined in control group. Moreover, compared with the control group, CBF of the foci in the experimental group increased (368.89±226.88 vs. 30.67±37.21, P = 0.065), MTT decreased (282.5±254 vs. 936.8±160.4, P = 0.02), indicating that endostar could reverse hypoxia of tumors. The PFS has no significant difference between the two groups (control vs. experimental = 7.6 vs. 8.2 months), may for the limit of sample size. Conclusions: Our study showed that Endostar could improve cognitive and emotional functions after cranial radiation and inhibite intra-tumor neovascularization.
Difference in immune infiltration in MSI and MSS BRAF mutant colorectal cancer.
Authors: Elena Bolzacchini, Roberta Cerutti, Nunzio Digiacomo, Nora Sahnane, Graziella Pinotti, Marco Bregni, Salvatore Artale, Claudio Verusio, Filippo Crivelli, Carlo Capella, Fausto Sessa, Daniela Furlan
Journal: Journal of Clinical Oncology (2018)

e15624 Background: BRAFV600E mutation occurs in less than 10% of colorectal cancers (BmutCRCs) and is a strong predictor of poor prognosis not only in metastatic setting. Although BmutCRCs are usually considered a unique clinico-pathological entity, biological heterogeneity within this population has been recently described. Our aim was an extensive clinico-pathological study of a multicentric series of 74 BmutCRCs with a specific focus on the inflammatory profiles. Methods: Our cohort included 74 BmutCRCs. At diagnosis 2/74 were in stage I, 7/74 stage II, 27/74 stage III, 38/74 stage IV. We evaluated MSI status, intratumoral (ILI) and peritumoral lymphocytes (PLI), PDL1 (on tumor cells, on ILI and on PLI), CD3+ ILI, CD3+ PLI, CD8+ ILI, CD8+ PLI, p53, ki67, synaptophysin, CDX2, budding, lympho-angio-invasion, neuro-invasion, extent of active stroma, mytosis number. Analysis of mutational load by next generation sequencing is ongoing. Results: As expected, our series mainly included female (62%) and old patients (median age 67 years), right-sided CRCs (73%) with high frequency of MSI (44%). MSI CRCs showed higher number of ILI and PLI (p = 0.0001), and higher PDL1expression, both in tumor cells (p = 0.001) and in ILI/PLI (p = 0.01 and p = 0.0014, respectively). CD3+ ILI (p = 0.0015), CD3+ PLI (p < 0.0001), CD8+ ILI (p < 0.0001), CD8+ PLI (p < 0.0001) were prominent features of MSI CRCs. Synaptophysin expression, active stroma and neuro-invasion were less represented in MSI vs MSS CRCs (p < 0.0001, p = 0.03, p = 0.044, respectively). Twenty of 34 pts with early-stage CRCs relapsed. MSS CRCs relapsed more frequently than MSI CRCs (12/16 vs 8/20, p = 0.04) and DFS was shorter in MSS vs MSI patients (p = 0.007). Conclusions: BmutCRCs should not be considered as having a unique biology; BmutCRCs with MSI show a hot immunogenic phenotype. These observations may be helpful to identify BmutCRCs that might benefit from immunotherapy.
A multicentre, phase II study with cabazitaxel in previously treated patients with advanced or metastatic adenocarcinoma of the oesophagogastric junction and stomach (CABAGAST).
Authors: Harald Schmalenberg, Claudia Pauligk, Thomas Zander, Alexander Reichart, Udo Lindig, Mathias Kleiss, Lothar Müller, Claus Bolling, Thomas Seufferlein, Peter Reichardt, Frank Kullmann, Henning Eschenburg, Alexander Schmittel, Matthias Egger, Andreas Block, Salah-Eddin Al-Batran, Thorsten Oliver Goetze
Journal: Journal of Clinical Oncology (2017)

4054 Background: This is a single-arm study to determine prolonged ( &gt; = 4 months) disease control rate with cabazitaxel administered in second- (or later) setting for patients with advanced or metastatic adenocarcinoma of the esophagogastric junction (EGJ) and stomach. Methods: 65 patients with advanced EGJ and stomach cancer were treated with 20mg/m 2 Cabazitaxel every 3 weeks for a maximum of 6 cycles. Main objective of the study was a prolonged Disease Control Rate (pDCR: CR, PR or SD lasting at least 4 months). Secondary Outcome Measures were overall survival (OS), progression-free survival (PFS), response rate by subgroup (with vs without previous treatment with a taxane) and toxicity. Patients were assessed for tumor response every 6 weeks during therapy and during follow-up (up to 12 months). Results: 65 patients (median age: 63, range 31-86 years) were assigned. Median no. of prior therapies was 2. 80% had received prior taxane therapy. Patients received a median of 2 cycles of cabazitaxel. Efficacy results are shown for the per protocol (PP) population. pDCR rate was 12.7%, (95%CI: 5,3%- 24.5%). pDCR was 20.0% in 2 nd line patients (95%CI: 6.8%-40.7%) and 30.0% (95%CI: 6.7%-65.2%) in all lines in patients without prior taxane use. Response Rate was 5.5% (95%CI: 1.1%-15.1%) in total PP and 20.0% in the population without prior taxane use. Median OS was 4.6 months (7.4 months without prior taxane vs 3.8 months with prior taxane). Median PFS was 1.38 months (95%CI: 1.28- 1.87) with and 2.01 months (95%CI: 0.20- 4.67) without prior taxane use. Most common grade 3/4 toxicities were neutropenia in 13% of the patients, pain (12%), leucopenia (10%), anemia (10%), fatigue (10%) and nausea (10%). Conclusions: Cabazitaxel is active in heavily pretreated patients with metastatic and advanced esophagogastric junction and gastric adenocarcinoma. Toxicity is moderate. Patients without prior taxane use derived more benefit from Cabazitaxel. Clinical trial information: NCT01956149.
Expression profiles in the histological subtypes of lung adenocarcinoma based on the classification of the IASLC/ERS/ATC.
Authors: Oscar Arrieta, Camilo Molina-Romero, Claudia Rangel, Maria Alejandra Castillo-Zamora, Alette Ortega, Eleazar Omar Macedo-Perez, Alejandro Aviles-Salas
Journal: Journal of Clinical Oncology (2016)

e23226 Background: The 2015 WHO/IARC classification of lung adenocarcinoma now classifies lepidic adenocarcinomas as low, acinar and papillary tumors as intermediate, whereas solid and micropapillary tumors as high grade. Tumor molecular heterogeneity partly explains why NSCLC patients who exhibit similar clinical stages and tumor histology can have dramatically different responses to treatment and clinical outcome. However, the different prognosis could be associated with the gene expression of each subtype. We studied the genetic expression profile according to the WHO/IARC classification. Methods: A cohort of 29 NSCLC patients treated at the Instituto Nacional de Cancerología from 2008 to 2011, were biopsied and classified according to the 2015 WHO/IARC. Tissue samples were analyzed by microarrays to distinguish different gene expression profiles. Clinical-pathological characteristics, mutations (EGFR, KRAS or ALK), and prognosis were also evaluated. Statistical analysis was done using R and Bioconductor data. Classification for differential expression was performed using LIMMA (Smyth), and genes were selected as significant according to p-value and fold-change. The biological networks and functional analyses were performed by IPA. Results: Mean age of patients was 62.4 years, 75.9% were females. The histological subtypes were acinar (58.6%), solid (27.6%), papillary (6.9%) and lepidic (6.9%). Median follow-up was 12.2 months [95% CI 0-26.9]. Median overall survival (OS) was 34.6 months. Papilar vs Lepidic (4227 up- and 3815 down-represented genes) and Solid vs Lepidic (6 up- and 23 down-represented genes) were the only comparisons that showed differential gene expression profiles (p < 0.01) and IPA analysis revealed 3 networks with 7 function-pathways and 2 networks with 5 function-pathways, respectively. Conclusions: Our data provide new networks between the genes for understanding the biological properties of different histological subtypes of adenocarcinoma and useful common pathway maps for the understanding of the clinical, mutational and prognostic differences of the disease.
Polypharmacy and potentially inappropriate medication use in older patients with aggressive non-Hodgkin lymphoma (NHL) leads to inferior survival and increased treatment-related toxicities.
Authors: Richard Jirui Lin, Helen Ma, Robin Guo, Michael L. Grossbard, Andrea B. Troxel, Catherine S. Magid Diefenbach
Journal: Journal of Clinical Oncology (2017)

10039 Background: Survival outcomes for older patients with aggressive NHL are disproportionally inferior to those of younger patients. While differences in tumor biology may play a role, older patients are often frail with comorbidities, polypharmacy, and use potentially inappropriate medications (PIM) such as anticholinergics and benzodiazepines. Methods: Using Cox proportional hazard and logistic regression models, we analyzed all aggressive NHL patients age ≥60 treated at our two affiliated hospitals from 2009-2014 to examine the association of polypharmacy and PIM use with progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Results: In this updated and final analysis, we included 171 patients with complete records from these two hospitals. They share similar demographic, clinical, and laboratory characteristics except for higher International Prognostic Index (IPI) in patients from one hospital. The median age was 70 years (range 65-77). At the time of diagnosis, 46% of patients used more than 4 medications (polypharmacy) and 47% used at least one PIM. Only 43% of patients received first-line chemotherapy of adequate relative dose intensity (&gt;85% dosage), and 65% experienced ≥grade 3 toxicities. Polypharmacy and PIM use were associated with shortened PFS and OS by log-rank test. Most importantly, PIM use remained an independent predictor of PFS, OS, and ≥ grade 3 toxicities in multivariable analyses (Table). Conclusions: This is the first report of significantly adverse survival impacts of polypharmacy and PIM use in older patients with aggressive NHL, presumably from drug-drug interactions that increase toxicities and impair the delivery of adequate chemotherapy dosage. Our findings support the use of evidence-based geriatric principles to guide meticulous medication management to improve outcome disparity for these patients. [Table: see text]
TCT-517 Outcome of Transcatheter Aortic Valve Replacement Versus Surgical Aortic Valve Replacement in Patients with Peripheral Arterial Disease
Authors: Amr Idris, Yasser Al-khadra, Amjad Kabach, Mohammad Altujjar, Anwar Zaitoun, Zaher Fanari, Fahed Darmoch, Ziad SayedAhmad, Mohamad Soud, Homam Moussa Pacha, Amir Kaki, M Chadi Alraies
Journal: Journal of the American College of Cardiology (2018)
The utility of genomics and functional imaging to predict Sunitinib PK and PD: The Predict SU study.
Authors: Michael Michael, David William Pook, Vinod Ganju, Emma Link, Guy C. Toner, Rodney J Hicks, Anetta Matera, Mick Thompson, Carleen Cullinane, Ian Campbell, Matthew Burge, Christos Stelios Karapetis
Journal: Journal of Clinical Oncology (2018)

2563 Background: Current dosing of Sunitinib (Su) is associated with marked variability in pharmacokinetics (PK) & pharmacodynamics (PD). Despite its hepatic metabolism, genotyping & phenotyping of ABCB1 & CYP3A4 have inconsistently accounted for this variability. This study has evaluated the utility of extensive excretory/metabolic/PD pharmacogenomics (PG) combined with 99mTc-MIBI hepatic nuclear imaging (HNI, to phenotype ABCB1 biliary excretory function), to predict Su PK/PD. Methods: Patients (pts) had advanced renal cell carcinoma (RCC) or GIST, treated with Su, 50mg daily for 4 weeks, q6 weekly. Pts had blood analyzed by Affymetrix DMET™ Plus Array and additional PD SNPs were genotyped. For HNI, pts were given IV 800MBq 99mTc-MIBI, the imaging data was analysed for hepatic extraction/excretion parameters (Clearance [CL], Deconvolutional excretion half-life [DeT1/2], hepatic extraction fraction [HEF]). Pts were restaged after 2 cycles (12 weeks). Blood were taken for Su parent (SuP) and metabolite (SU12662- SuM) analysis in cycles 1 & 2, days 1, 14 and 28. PK parameters derived by non-compartmental analysis. Statistical associations were evaluated between (i) HNI parameters and (2) PGs, with Su PK, toxicity, response and progression-free survival (PFS). Results: 15 pts analysed (10 RCC, 5 GIST). (1) PK predictors: HEF with SuP and SuM cycle 1 logAUC0-14days (P < 0.05) and DeT1/2 with SuP cycle 1 logAUC0-28days (P < 0.02) (2) Diarrhea ≥Grade 1 (N = 4): HEF (P = 0.03), and gene variants VEGFR3 (P < 0.0004) and SCL7A8, ABCC3 (P < 0.05), (3) ≥Grade 3 Adverse events (N = 2): variants in ABCC4, SLC7A7 (P < 0.05). (4) Disease control rate: N = 7 (54%): HNF1A (79A > C) (P = 0.4), variants in SCLO5A1, SLC7A5, ABCG1, ABCC4, ABCB4, (P < 0.05). (4) PFS: SuP cycle 1 logAUC0-14days (P < 0.03), HNF1A (79A > C) (P < 0.03), PDGFRα (-1171C > G) (P < 0.04), ABCC4, ABCC1, SULT1C2, SLC01A2, CYP2D6, (P < 0.02). Multiparameter models were generated for the prediction of (i) SuP logAUC0-14days incorporating HEF + TNFα (-857C > T) (P = 0.02) and (ii) SuM AUC0-14days with VEGFR3 (150A > G) + DeT1/2 (P = 0.009). Conclusions: Hepatic functional imaging with extensive pharmacogenomics were associated with Su PK and PD, potentially enabling individualized dosing Clinical trial information: ACTRN12610000897066.
Atezolizumab (A) + cobimetinib (C) in metastatic melanoma (mel): Updated safety and clinical activity.
Authors: Wilson H. Miller, Tae Min Kim, Carrie B. Lee, Keith T. Flaherty, Sunil Reddy, Rahima Jamal, Laura Q. Chow, Isabelle Anne Rooney, Bethany Pitcher, Edward Cha, Jeffrey R. Infante
Journal: Journal of Clinical Oncology (2017)

3057 Background: A, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, inhibits PD-L1/programmed death-1 (PD-1) and PD-L1/B7.1 binding and shows promising clinical activity in patients (pts) with cutaneous mel (objective response rate [ORR] 33%; median progression-free survival [mPFS] 5.5 months; Hodi et al SMR 2014). C promotes intratumoral T-cell infiltration, major histocompatibility complex 1 upregulation, and PD-L1 expression via targeted MEK inhibition in preclinical models (Ebert et al Immunity 2016) and tumor biopsy specimens (Bendell et al ASCO 2016). Therefore, clinical benefits may be enhanced by combining A + C vs A. This Phase Ib dose-escalation and -expansion study (NCT01988896) suggested higher ORR/disease control rate (DCR, ORR + stable disease) and longer PFS may be achieved with A + C vs A or C alone in mel. We present updated safety and efficacy data. Methods: Oral C, escalated 20 mg→40 mg→60 mg, was given qd for 21 days followed by 7 days off. Intravenous (IV) A was given at 800 mg q2w. Tumor-specific expansion cohorts were enrolled at maximum tolerated doses (C 60 mg/d 21/7; A 800 mg IV q2w). No prior anti–PD-L1 or –PD-1 therapy was allowed. Results: Data cut-off was Oct 12, 2016; 22 patients were safety-evaluable (two ocular, 20 non-ocular [ten each BRAF-mutant and -wild-type]). Median safety follow-up was 14.4 months (range 2.1–23.2). Adverse events (AEs) were experienced in all pts (diarrhea [20 pts, 90.9%] and rash [15 pts, 68.2%] were most common); related grade (G)3–4 AEs in 54.5% (diarrhea [three pts, 13.6%] and dermatitis acneiform [two pts, 9.1%] were most common; no related G5 AEs); related serious AEs in 13.6%. All were manageable. One pt discontinued A + C due to an AE. RECIST v1.1-confirmed ORR was 45.0% in pts with non-ocular mel (median duration of response was not reached); DCR was 75.0%; mPFS was 12.0 months (95% CI 2.8–not evaluable). ORR was similar for pts with BRAF-mutant and wild-type mel. Conclusions: Updated results confirm previous findings that suggest higher ORR/DCR and longer PFS may be achieved with A + C vs A or C monotherapy for mel. Together with biomarker data from other cohorts, our data suggest that the immune contexture may be altered by C, enhancing A activity. Clinical trial information: NCT01988896.
Phase 1b/2 study of nivolumab in combination with an anti–IL-8 monoclonal antibody, BMS-986253, in a biomarker-enriched population of patients with advanced cancer.
Authors: Ignacio Melero Bermejo, Elizabeth M. Jaffee, Diwakar Davar, Josephine Cardarelli, Daphne Williams, Penny Phillips, Michael Carleton, Ming Zhou, Olivier De Henau, Manish Monga, Charles G. Drake
Journal: Journal of Clinical Oncology (2018)

TPS3109 Background: Interleukin 8 (IL-8) is a chemokine that has been suggested to play a predominant role in tumor immune escape by promoting an immunosuppressive tumor microenvironment (TME). High levels of serum IL-8 are associated with a poor prognosis in various tumors (Sanmamed, MF, et al. Clin Cancer Res. 2014;20:5697-5707), such as melanoma, non-squamous small cell lung cancer (NSCLC), and renal cell carcinoma, and decreases in serum IL-8 levels have been suggested to be associated with response to anti–PD-(L)1 therapy with nivolumab in a small cohort of pts with melanoma and NSCLC (Sanmamed, MF et al. Ann Oncol. 2017;28:1988-1995). Preclinical studies showed synergetic antitumor activity by combining anti-CXCR2 with anti–PD-1 vs either agent alone in mouse. BMS-986253 is a fully human-sequence IgG1κ anti–IL-8 monoclonal antibody that abrogates signaling through both IL-8 receptors (CXCR1 and CXCR2), resulting in a complete blocking of IL-8 mediated pathway, and as such, can be used to assess the mechanistic role of this pathway in IO resistance. Here we describe a phase 1b/2 study of the combination of BMS-986253 plus nivolumab in a biomarker-enriched population of pts with advanced cancers (NCT03400332). Methods: This is a 2-part study with an enrollment of ≈ 260 target selected pts, aged ≥ 18 y with advanced solid tumors. Pts must have ≥ 1 measurable lesion at baseline per RECIST v1.1. Outcomes include safety, tolerability, efficacy, pharmacokinetics, immunogenicity of BMS-986253 plus nivolumab, and measurement of serum IL-8 levels at baseline and during treatment. This study will also explore various peripheral and intra-tumor pharmacodynamic effects of blocking IL-8 in a target selected pt population. Clinical trial information: NCT03400332.
Predictors of sorafenib efficacy in treated patients with hepatocellular carcinoma: A tertiary cancer center experience.
Authors: Kanaan Alshammari, Ashwaq Al Olayan, Yara Alkhodair, Ahmed Hashim Mohammad, Rehan Ul-Hassan, Osama Al Najeely, Abdul Rahman Jazieh
Journal: Journal of Clinical Oncology (2016)

e15604 Background: Hepatocellular carcinoma (HCC) is the fourth commonest solid cancer in males in Saudi Arabia. Sorafenib is the only FDA approved drug for advanced unresectable HCC. In this study, we evaluated the efficacy and survival predictors of sorafenib in HCC patients at KAMC, Riyadh, KSA. Methods: A retrospective review of all sorafenib-treated HCC patients from October 2007 till January 2016 was performed to determine efficacy, safety, and outcome. Results: 212 patients were included with a median age of 68 years (29-98). Hepatitis C and B were present in 44% and 30%, respectively. Most had advanced HCC with 31% having stage III and 41% with stage IV (AJCC staging). Child A and B patients were 63% and 37%, respectively. Sorafenib dose was reduced in 46% and the commonest reason was poor performance status (39%). Grade 3 and 4 adverse events includeaspartate aminotransferase elevation (44%), hyperbilirubinema (34%), fatigue (19%), rash (18%), anorexia (15%), and diarrhea (10%). Out of the 130 evaluable patients, four achieved complete response, 26 had partial response, and 28 had stable disease. Median overall survival (OS) was 9.5 months (6.9 – 11.9). It was 11.1 months for Child A patients and 7 months for Child B patients (p = 0.047). Multivariate analysis results are summarized in the table. Conclusions: Although we had to reduce the dose in almost half of the patients, sorafenib use in our population compared favorably to other studies in terms of safety and outcomes including survival. P value Hazard Ratio 95% Confidence Interval Hepatitis B vs C 0.001 0.101 0.034 – 0.34 Dose reduced yes vs no 0.001 6.886 2.6 – 18.2 Child A vs B 0.003 0.248 0.09 – 0.62 Male vs female 0.003 0.135 0.04 – 0.5 Rash yes vs no 0.028 3.78 1.2 – 12.2
Feasibility of continuing crizotinib therapy after RECIST-PD in advanced non-small cell lung cancer patients with ALK/ROS-1 mutations.
Authors: Jun Liu, Shaohua Cui, Liyan Jiang
Journal: Journal of Clinical Oncology (2018)

e21132 Background: To study whether ongoing clinical benefits of continuing anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) inhibition are achieved by crizotinib treatment post progressive disease (PD) in advanced non-small cell lung cancer (NSCLC) patients harboring ALK/ROS1 mutations. Methods: Demographic and clinicopathologic parameters were collected from 38 patients who continued crizotinib therapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined PD and analyzed. After adjusting for potential confounding factors, factors influencing the time from RECIST-PD to crizotinib discontinuation (progress-free survival 2, PFS2) were analyzed. Results: The median time from first dose treatment to RECIST-PD (PFS1) was 9.6 months (95% CI 5.6-13.6 months). The estimated median PFS2 was 5.9 months (95% CI 0.1–11.7 months). Six- and twelve-month crizotinib treatment probabilities after initial PD were 42.1% (95% CI 25.7–58.6%) and 21.1% (95% CI 7.5–34.6%), respectively. Patients who demonstrated RECIST-PD due to new lesions had a longer median PFS2 compared to patients who were attested to enlargement of original lesions (10.0 versus 2.4 months, p = 0.009). The median PFS2 was numerically longer among patients who received local therapy compared to those who did not receive local therapy, however the difference was not significant (9.9 versus 4.2 months, p = 0.094). Multivariable Cox regression analysis showed that only the progression pattern [new lesions versus enlargement of original lesions, HR = 0.329 (95% CI 0.138–0.782), p = 0.012] remained an independent prognostic factor of PFS2. Conclusions: Continuation of crizotinib therapy after RECIST-PD in Chinese NSCLC patients with positive ALK/ROS1 mutations is feasible in clinical practice.