tbuckley/cabot-search huggingface dataset:
Comparison of outcomes following recurrence or metastasis in HPV+ and HPV- oropharyngeal carcinoma treated with definitive chemoradiation using IMRT.
Authors: Jonathan Eric Leeman, Jin-Gao Li, Praveen Venigalla, Zachary Stephan Zumsteg, Sean Matthew McBride, Jay Boyle, Benjamin R Roman, Eric Jeffrey Sherman, Nancy Y. Lee, Nadeem Riaz
Journal: Journal of Clinical Oncology (2016)

6063 Background: Outcomes following recurrence or metastasis of Human Papillomavirus (HPV)-related oropharyngeal carcinoma (OPC) have not been studied extensively. Herein, we report patterns of failure and the natural history following recurrence in a large cohort of locally advanced OPC patients treated with definitive loco-regional treatment using modern radiation techniques (IMRT). Methods: We reviewed outcomes from 734 consecutive locally advanced OPC patients treated with definitive chemoradiation using IMRT between July 2001 and December 2013 at a large cancer center. HPV/p16 status was available for 417 OPC patients (56.8%) with 302 HPV+ patients (72.4%) and 115 HPV- patients (27.6%). We compared patterns of failure between HPV+ and HPV- OPC cases as well as survival following locoregional recurrence (LRR) recurrence or distant metastasis (DM). Median follow-up was 63.8 months in surviving patients. Survival rates were estimated using the Kaplan-Meier method and compared with log-rank testing. Results: Five year rates of local control, regional control, distant control and overall survival in HPV+ vs HPV- OPC were 94.6% vs. 84.2% (p = 0.001), 93.2% vs 85.9% (p = 0.011), 92.2% vs 79.1% (p < 0.001) and 86% vs 69.2% (p < 0.001). Time to progression was not significantly different between HPV+ and HPV- OPC (10.3 vs 10.6 months, respectively). The proportion of patients with isolated LRR did not differ between the two groups: 78% of LRRs were isolated in HPV+ OPC vs. 77% in HPV- OPC. Time from DM to death was not significantly different between HPV+ and HPV- OPC (16.1 vs. 20.2 months, p = NS) but time from isolated LRF to death was significantly longer in HPV+ OPC compared to HPV- (median 36.5 vs 18.8 months, p = 0.04). Conclusions: HPV+ and HPV- OPC display similar proportions of local, regional and distant failures. Survival following DM is independent of HPV/p16 status but survival following LRR in HPV+ OPC is favorable compared to HPV- disease. HPV status is an important factor to consider in the design of clinical trials for recurrent OPC, particularly in the setting of isolated locoregional recurrence.
Baseline cognitive function to predict survival in patients with glioblastoma.
Authors: Katherine B. Peters, Sarah Woodring, Patrick Healy, James Emmett Herndon, Eric S Lipp, Janet Minchew, Ben Zalutsky, Mary Affronti, Dina Randazzo, Annick Desjardins, Gordana Vlahovic, Henry S. Friedman
Journal: Journal of Clinical Oncology (2016)

10125 Background: Overall survival of patients with glioblastoma (GBM) remains dismal with range from 12-14 months. In addition to the oncologic burden that these patients face during the disease trajectory, there are demonstrable neurologic and cognitive challenges. These cognitive challenges can occur at baseline and throughout the disease course. We sought to understand the contribution of baseline cognition on the overall survival of patients with newly diagnosed GBM. Methods: In this prospective single-center study, newly diagnosed GBM patients were evaluated with computerized neurocognitive testing including testing of domains of cognitive flexibility, complex attention, executive functioning, psychomotor speed, processing speed, verbal and visual memory. Demographic data and known prognostic factors (age, extent of resection, and KPS) were obtained. Associations of each cognitive test with survival were assessed using adjusted Cox proportional hazards models. Patients were dichotomized to cognitive function groups as performing poorly on 4 or less modalities or greater than 4 modalities and overall survival of each group was estimated using Kaplan Meier methods. Results: 61 newly diagnosed GBM patients were initially included with a mean age of 58.01 yrs (sd = 10.22 yrs) with KPS ≥ 90 for 45 patients (47.9%) and KPS 70-80 for 49 patients (52.1%). Overall survival of 61 GBM patients that had a baseline cognitive function showing poor performance on 4 modalities or less was 23.9 mos (95% CI 14.8 mos, 30.7 mos) whereas the overall survival of GBM patients that had a cognitive function showing poor performance on greater than 4 modalities was 14.1 mos (95% CI 11.8 mos, 20.3 mos). This difference neared significance with log-rank of p = 0.0273. Conclusions: These observations highlight the importance of baseline cognitive function as it pertains to survival in GBM patients. Understanding baseline cognition and continued measures of cognition in primary brain tumor patients remains important and should be taken into context in regards to prognostication and quality of life of patients and caregivers.
Olaparib in German routine clinical practice: Updated interim results of the non-interventional study C-PATROL.
Authors: Frederik Marme, Felix Hilpert, Manfred Welslau, Ahmed El-Balat, Eva-Maria Grischke, Timo Schinkothe, Regina Glowik, Jalid Sehouli
Journal: Journal of Clinical Oncology (2018)

e17549 Background: The PARP inhibitor olaparib is approved in the EU for maintenance therapy of BRCA-mutated (BRCAm+) platinum-sensitive relapsed ovarian cancer patients, who are in response to their most recent platinum-based chemotherapy. So far, only limited data on real-world olaparib treatment are available. Methods: The German prospective, non-interventional study C-PATROL (NCT02503436) collects real-world clinical and patient-reported outcome data in patients with BRCAm+ platinum-sensitive relapsed ovarian cancer treated with olaparib capsules according to EU label. Interim analyses generate data on patient characteristics, safety and dosing, thereby providing real word data on olaparib monotherapy as maintenance treatment within the first years after the German market access in JUN2015. Data are analyzed by descriptive statistics. Results: 75 patients with ≥3 mths of observation after start of olaparib therapy were analyzed in 1st interim analysis (cut-off: 06APR2017; median age: 61 [45 to 80] yrs; ECOG ≤ 1: 93.3%; ≥2 relapses: 49.3%; ≥ 3 prior platinum-based chemotherapeutic regimens: 46.7%). Data were stratified according to subgroups (age: < 70 [57 pts] vs. ≥70 yrs [18 pts]; comorbidities: yes [35 pts] vs. no [36 pts] vs. unknown [4 pts]). Patients started with a median daily dose of 800 [300 to 800] mg olaparib. 29.3% of patients had at least one dose reduction and at least one dose interruption (with a median duration of 10 [2 to 51] days). Olaparib was permanently stopped for 36% of patients mainly due to progression (81.5%), and for 3 patients (11%) due to an adverse event. 85.3% of patients had any adverse event. Anemia (34.7%), nausea (29.3%) and fatigue (26.7%) occurred most frequently, with anemia and nausea being more frequent in patients < 70 years and without comorbidities. Results will be updated according to the 2nd interim analysis (cut-off: 01FEB2018) including at least 150 patients. Conclusions: Current data from the ongoing non-interventional study C-PATROL indicate that olaparib is well tolerated under routine conditions. Adverse events are generally manageable and the toxicity profile is in line with results of the clinical trial program of olaparib. Funding: AstraZeneca Clinical trial information: NCT02503436.
Patient-clinician communication about nutrition, weight, fitness, and fatigue in cancer care.
Authors: Alexandra Katherine Zaleta, Shauna McManus, Julie S. Olson, Thomas William LeBlanc, Kathryn Hamilton, Nicole Koesel, Melissa F Miller, Joanne S. Buzaglo
Journal: Journal of Clinical Oncology (2018)

e22131 Background: Many cancer patients have concerns about nutrition, weight, fatigue, or fitness, but may have difficulty discussing these topics with their health care team (HCT). We examined associations between 1) patients’ physical and psychosocial well-being and 2) comfort and confidence in talking to their HCT about nutrition and weight, changes in muscle tone and fitness, and fatigue (NWMTF). Methods: 294 cancer survivors completed an online survey including demographics, clinical history, functional well-being (FACT-G subscale), depressive symptoms (CES-D), body image views (BIS), and rated (0 =not at all; 4 =very much) 9 statements about HCT communication confidence and comfort. We examined bivariate associations between demographics, treatment history, weight change, FACT-G, CES-D, BIS, and HCT communication. Variables associated with communication (FACT-G, CES-D, BIS) were entered into hierarchical multiple regression analyses, with level of comfort and confidence in HCT communication as dependent variables. Results: Participants were 85% White; 78% female; mean age = 58.7 (SD= 11) years; 40% breast cancer, 24% blood cancer, mean time since diagnosis = 5.9 (SD= 5) years; 22% metastatic. 70% of participants reported speaking with their HCT about NWMTF concerns. 52% indicated they would discuss NWMTF concerns when fatigue and energy levels prevented usual activities, 47% when first noticing NWMTF, 17% when clothes did not fit. Greater functional well-being, lower depression, and better body image were associated with more comfort in discussing NWMTF concerns with the HCT (rs = -.22 to .16, ps < .01) and more confidence that the HCT understands and can help with NWFMT concerns (rs = -.32 to .25, ps < .01). Regression models confirmed that better body image—but not functional well-being or depression—was associated with greater comfort and confidence in HCT communication (semipartial rs = -.12, -.20; ps < .05, < .001 respectively). Conclusions: Our findings suggest that patients’ body image perception is related to comfort with talking to their HCT about weight and nutrition, changes in muscle tone and fitness, and fatigue, as well as confidence that their HCT understands and can help with these concerns.
Defining orphan conditions in the context of the European orphan regulation: challenges and evolution
Authors: Daniel J. O’Connor, Maria E. Sheean, Matthias P. Hofer, Stelios Tsigkos, Segundo Mariz, Laura Fregonese, Kristina Larsson, Virginie Hivert, Kerstin Westermark, Frauke Naumann-Winter, Violeta Stoyanova-Beninska, Ingeborg Barišić, Giuseppe Capovilla, Armando Magrelli, Bruno Sepodes
Journal: Nature Reviews Drug Discovery (2018)
Phase I study of the anti-HGF monoclonal antibody (mAb), ficlatuzumab, and cetuximab in cetuximab-resistant, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Julie E. Bauman, Umamaheswar Duvvuri, Robert L. Ferris, James Ohr, William E. Gooding, Seungwon Kim, Jonas Talmadge Johnson, Jennifer R. Grandis, Laura P. Stabile
Journal: Journal of Clinical Oncology (2017)

6038 Background: Cetuximab, an anti-EGFR mAb, is approved for R/M HNSCC but only a minority benefits. Activation of cMet, the receptor for hepatocyte growth factor (HGF), overcomes EGFR inhibition in preclinical models and high serum HGF is associated with resistance in patients (pts). We conducted a phase I trial evaluating the combination of cetuximab and ficlatuzumab, an IgG1 anti-HGF mAb, in pts with cetuximab-resistant, R/M HNSCC. Methods: In this Narayana k-in-a-row phase I design, cetuximab 500 mg/m 2 was administered every 2 weeks. Ficlatuzumab dose tiers were 10 mg/kg (tier 1) or 20 mg/kg IV every 2 weeks (tier 2), with inter-patient escalation or de-escalation based on cumulative dose-limiting toxicities (DLT). The recommended phase II dose (RP2D) was set at tier 2 if no DLTs were observed after 8 enrolled pts; expansion continued to n = 12. Key eligibility criteria: R/M HNSCC; recurrence within 6 months of cetuximab-radiation or progression during/within 6 months of palliative cetuximab; ECOG PS 0-1. Candidate biomarkers included serum Veristrat, a proteomic classifier in lung cancer where “good” predicts benefit from anti-EGFR therapy and “poor” indicates resistance and poor prognosis. Results: From Sept 2015–June 2016, 12 pts were enrolled and treated. Primary site: 1 oral cavity; 3 oropharynx (1 p16+); 2 hypopharynx; 5 larynx; 1 external auditory canal. Platinum-refractory: 11/12. Veristrat: 8 poor; 4 good. Three pts were treated at tier 1 and 9 at tier 2. No DLTs were observed. Grade 3 adverse events included: edema (1), hypoalbuminemia (1), infection (2), thromboembolic event (2). Median PFS and OS at RP2D were 6.0 mos (90% CI = 2.0 mos–not reached) and 8.2 mos (90% CI = 2.7 mos–not reached), respectively. Response rate was 17% (90% CI = 0–28%): 2/12 partial response (PR); 1/3 at 10 mg/kg; 1/9 at 20mg/kg. Clinical benefit rate (PR + stable disease) was 67%. Veristrat was not associated with PFS. Conclusions: The RP2D is cetuximab 500 mg/m 2 and ficlatuzumab 20 mg/kg every 2 weeks. This well-tolerated combination demonstrated promising activity in pts with poor prognosis, cetuximab-resistant R/M HNSCC. Phase II testing is justified. Clinical trial information: NCT02277197.
Prognostic significance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in untreated and treated stage IV non-small cell lung cancer (NSCLC): An Australian cancer centre experience.
Authors: Hiren A. Mandaliya, Mark Jones, Christopher Oldmeadow, Ina Nordman
Journal: Journal of Clinical Oncology (2017)

e20630 Background: Baseline high NLR predicts poorer outcome in stage IV NSCLC; post-treatment variation in NLR and potential impact on overall survival (OS) is not clear in this group. Prognostic implications of PLR and LMR are not well studied for stage IV NSCLC. We aimed to assess the prognostic role of NLR, LMR and PLR in stage IV NSCLC at diagnosis and post-treatment. Methods: A retrospective descriptive study of 279 patients with Stage IV NSCLC treated at our centre over five year period (2010 to 2015). NLR, PLR and LMR calculated at diagnosis and post first cycle chemotherapy/targeted treatment. Demographic variables summarized. Estimates of Kaplan-Meier survival distributions for OS were generated. Cox regression used to derive OS hazard ratios of predictive variables. Approval from ethics committee obtained. Results: Baseline NLR, PLR and LMR showed strong association with OS. A five-unit increase at baseline (treatment start date) in NLR was associated with an 11% increase in the hazard of death (HR = 1.115, 95% CI: 1.077-1.148) while the same increase in PLR was associated with 0.5% increase in the hazard of death (HR = 1.005, 95% CI:1-1.005). A five-unit increase in LMR at baseline was associated with a 50% reduction in the hazard of death (HR = 0.50, 95% CI:0.260-0.956). Post-treatment NLR, PLR and LMR were examined in 221 patients. Fitted models incorporating adjustment for baseline values demonstrated that increasing NLR correlated with a shorter OS (HR = 1.574, 95% CI:1.295-1.917) but no statistically significant relationship could be demonstrated for PLR nor LMR. Conclusions: While NLR, PLR and LMR showed significant associations with OS prior to treatment, only NLR showed an association with OS after treatment. OS was shorter for high NLR and high PLR at baseline compared to low NLR and low PLR at baseline. OS was longer for high LMR at baseline compared to low at baseline. An increase in NLR post-treatment correlated with a shorter OS. This is the first study examining the prognostic significance of all three ratios in patients with untreated and treated stage IV NSCLC.
Circulating exosomal microRNA profiling to depict mechanisms of chemotherapy resistance among triple negative breast cancer.
Authors: Jianhua Zhao, Jinhai Tang
Journal: Journal of Clinical Oncology (2018)

e13124 Background: Chemotherapeutic resistance leads to high mortality among triple negative breast cancer (TNBC) and underlying mechanisms are poorly understood. Exosomes have been new member of liquid biophsy. MicroRNAs (miRNAs), as the most important inclusions in exosomes, making them ideal candidate biomarkers and therapeutical targets. Methods: We isolated exosomes and analyzed exosome-carried miRNAs signatures in several TNBC cells lines sensitive or resistant to adariamycin, docetaxel or cisplatin. The resistance transfer capacity was determined by flow cytometry after sensitive cells incubated 48 hours with exosomes from drug resistant cells. Locked nucleic acid probes and enzyme-labeled fluorescence (LNA-ELF-FISH) was performed to detect exosomal miRNA molecules transfer. Animal mode was constructed to evaluate treatment feasibility using miRNA modified exosomes. Serum exosomes from 40 TNBC stage IV patients underwent chemotherapy before or after progress disease (PD) status were isolated to analyze miRNA profiling for potential biomarkers identification. Results: We successfully isolated and identified exosomes from several drug sensitive and resistant TNBC cell lines and patients. Exosomal miR-222, miR-4443, miR-100, miR-17, miR-210 were found significantly upregulated from chemotherapy resistance cells. Incubation of exosomes from the resistant cells with the sensitive cells resulted in increasing resistant capacity among sensitive cells. Exosomal miRNA molecules transfer were detected using LNA-ELF-FISH. Transfection of synthesized miRNAs competitors into exosomes increased drug sensitivity in vivo. Exosomal miR-222, miR-4443, miR-100, miR-17, miR-210 were also found upregulated significantly from serums of patients after PD status. These five miRNA were able to differentiate patients with PD status from those with CR or PR status with at least 89% accuracy. Conclusions: Exosomes from chemotherapy resistant TNBC cells could transfer drug resistance to sensitive cells via exosomal miRNAs. A circulating exosomal microRNA profiling was estabilished for potential biomarkers and therapeutical targets identification.
Correlation between a new growth modulation index (GMI)-based Geistra score and efficacy outcomes in patients (PTS) with advanced soft tissue sarcomas (ASTS) treated with trabectedin (T): A Spanish group for research on sarcomas (GEIS-38 study).
Authors: Javier Martinez-Trufero, Nadia Hindi, Josefina Cruz, Rosa Maria Alvarez Alvarez, Roberto Pedro Diaz Beveridge, Claudia Maria Valverde Morales, Antonio Gutierrez, Isabel Pajares Bernad, Antonio Lopez-Pousa, María Ángeles Vaz Salgado, Javier Lavernia, Juana Maria Cano, Isabel Sevilla, Jordi Rubió-Casadevall, Ana De Juan, Juan Antonio Carrasco, Nieves Hernandez Leon, Carolina Agra Pujol, Lucia Ferrando Lamana, Javier Martin Broto
Journal: Journal of Clinical Oncology (2017)

11070 Background: The GMI is a marker of drug activity and represents an intra-patient comparison of successive time to progression (TTP), defined as the TTP ratio between the second (or later) line (TTPn) of therapy divided by the prior line (TTPn−1). Defining a clinical profile of pts with GMI &gt;1.33 could help to identify pts who can gain greater benefit from T. Methods: We retrospectively evaluated the concordance between the GMI and the efficacy outcomes and clinical profiles of 198 pts with ASTS treated with trabectedin 1.5 mg/m² (24-h infusion q3w) as a 2 nd or further-line treatment from Jan 2007 to Jun 2016. Results: After a median follow-up of 58 months (m; range: 18-172) median overall survival from ASTS diagnosis (MOS) and from T (MT-OS) were 27.5 m (23-32.1) and 10.8 m (8.9-12.7), respectively, while median TTP from T (MT-TTP) and T-1 were 3.4 m (2.8-4) and 3.5 m (2.8-4.2). Overall, 106 pts (53%) had a GMI &lt;1; 22 (11%) a GMI=1-1.33 and 70 pts (35%) a GMI &gt;1.33. A high GMI (&lt;1.33 vs &gt;1.33) correlated with favorable efficacy outcomes: MT-OS: 23 vs 36 m (p&lt;0.001), MT-TTP 2.3 vs 8.2 m (p&lt;0.001) and clinical benefit (objective response + stable disease) 23% vs 68% (p=0.001). The multivariate analysis identified L-type sarcoma (Odds ratio: 1.99, 95% CI 1.06-3.71), metastatic free interval (MFI) from initial diagnosis &gt; 8.1 m (2.24, 95%CI 1.19-4.18) and Karnofsky &gt;80 (2.3, 95%CI 1.00-5.28) as factors independently associated to GMI&gt; 1.33. Based on these 3 variables we defined a new GEISTRA score assigning 1 point for each adversely affected variable: non L-Sarcoma, MFI&lt;8.1m or Karnofsky &lt;80. This score showed a strong correlation with MT-TTP (p&lt;0.001) and MT-OS (p&lt;0.001). Conclusions: Based on the high GMI we defined a new GEISTRA score, which is strongly associated with favorable efficacy outcomes in pts with ASTS treated with T. Thus, GEISTRA score could be a potentially useful predictable clinical tool for T benefit. [Table: see text]
Biomarkers of pembrolizumab (P) activity in mesothelioma (MM): Results from a phase II trial.
Authors: Hedy L. Kindler, Theodore G. Karrison, Buerkley Rose, Y-H Carol Tan, Arun Khattri, Rajesh Acharya, Christopher M. Straus, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2017)

8557 Background: PD-L1 expression and the Interferon-Gamma gene expression profile (IFN-G GEP) are predictive of response to checkpoint blockade in several solid tumors. Relevant biomarkers in mm pts treated with these agents have not been determined; these were evaluated in a phase 2 trial of P in mm (NCT02399371). Methods: Eligible pts had histologically confirmed MM, PS 0-1, disease progression on 1-2 prior regimens. P 200 mg was given Q21 days. Part A (N = 35) determined the response rate (RR) of P in PD-L1 unselected mm pts and assessed an optimal PD-L1 threshold (22C3 IHC assay). If ≥3 responses, the study proceeded to Part B (N = 30), using a biomarker enrichment strategy if a threshold was found. Nanostring nCounter was used to assess IFN-G GEP (6 gene). Results: 35 pts enrolled in Part A 5/15-2/16; 1 withdrew. Median age 66 (range 26-85); PS 0: 62%; male: 82%; epithelial/sarcomatoid/biphasic/NOS: 74%/21%/3%/3%; pleural/peritoneal: 85%/15%; 2 nd -line: 59%. Partial response (PR): 7 (21%), stable disease (SD): 20 (59%). Median response duration: not reached. Median progression-free survival (PFS): 6.2 months (95% CI: 3.2, 8.2). Median overall survival: 11.9 months (95% CI: 6.4, --). Toxicity ≥ grade 3: adrenal insufficiency, fatigue, pneumonitis 6%; colitis, confusion, hepatitis, hyponatremia, neutropenia, rash 3%. PD-L1 expression by tumor proportion score (N = 32): none (53%); 1-49%: (22%); ≥50%: (25%). PD-L1 IHC (ROC area 0.63; 95% CI: 0.37, 0.89), CD274 mRNA expression, and IFN-G GEP did not correlate statistically with response. Responses occurred in GEP low, non-inflamed tumors, and in PD-L1- tumors. RR was numerically higher in PD-L1+ (27%) than in PD-L1- pts (12%); there was a trend towards longer PFS and OS in PD-L1+ pts. Conclusions: P has clinically meaningful single-agent activity in PD-L1 unselected, previously treated mm pts, achieving a 21% RR and a disease control rate of 80%. Biomarkers established in other cancers, such as PD-L1 IHC and IFN-G GEP, may not be as useful in MM. Novel biomarkers including MM-specific gene signatures may be necessary and are being evaluated. Part B of the study is ongoing with no PD-L1 pre-selection (19/30 pts enrolled), and will be used as a biomarker validation cohort. Funded by a MARF grant. Clinical trial information: NCT02399371.