tbuckley/cabot-search huggingface dataset:
Abstract 18255: Gastric Mucosal Devitalization Reduces Blood Pressure, Cardiac Lipotoxicity and Endothelial Function in Diet Induced Obese Rats
Authors: Andreas Oberbach, Nadine Schlichting, Stefanie Lehmann, Yvonne Kullnick, Marco Heinrich, Ulf Retschlag, Stefan Feder, Mouen A Khashab, Anthony Nicholas Kalloo, Vivek Kumbhari
Journal: Circulation (2015)

Background: Metabolic surgery induces a substantial reduction in cardiovascular mortality and comorbidities such as blood pressure (BP), cardiac lipotoxicity and endothelial function. Metabolic surgery, such as vertical sleeve gastrectomy (VSG), reduces gastric volume and excludes the gastric mucosa. The gastric mucosa is recognized as an endocrine organ and is involved in the regulation of neurohormonal pathways effecting cardiovascular status. Our study aims to investigate the independent effects of altering gastric mucosa on blood pressure, cardiac lipotoxicity and vascular function in a diet induced obese rat model. Methods: Four-week old male Sprague-Dawley rats were fed a high fat diet for 11 weeks. At week 15, HFD rats (n=64) were randomized to undergo either gastric mucosal devitalization GMD, VSG or Sham (SH) surgery with HFD being continued in all cohorts. GMD of 80% of the stomach was achieved by argon plasma coagulation and compared to VSG and SH. At 8 weeks follow-up (week 23), we quantified blood pressure, cardiac lipid content (ELISA) and related metabolic active proteins adipophilin and periphilin (western blott analysis). Additionally we measured acetylcholine-induced relaxation response of aortic rings. Results: GMD and VSG resulted in a significant reduction of arterial blood pressure (MABP) compared to sham. Cardiac lipid content was significantly reduced in GMD (41%) and VSG (53) compared with SH. Adipophilin was significantly increased in GMD and VSG compared to SH, whereas periphilin was significantly opposite regulated in both intervention groups compared to SH. Area under the curve (AUC) for aortic ring relaxation was statistically relevant lower both in GMD and VSG compared to SH. Conclusions: Devitalization of the gastric mucosa (independent of altering gastric volume) reduces blood pressure, cardiac lipid content and regulate metabolic active proteins involved in cardiac muscle lipid storage as well as vascular function. Therefore, GMD deserves further attention as a promising method to treat obesity related cardiovascular comorbidities.
Baseline cell-free DNA (cfDNA) and metabolic tumor volume (MTV) independently predict outcome in metastatic chemorefractory colorectal cancer (mCRC).
Authors: Erwin Woff, Pashalina Kehagias, Caroline Vandeputte, Tarek Kamoun, Thomas Guiot, Lieveke Ameye, Karen Paula Geboes, Thierry Delaunoit, Gauthier Demolin, Marc Peeters, Lionel A. D'Hondt, Jos Janssens, Javier Carrasco, Stephane Holbrechts, Jean-Charles Goeminne, Jean-Luc Van Laethem, Philippe Vergauwe, Marianne Paesmans, Patrick Flamen, Alain Hendlisz
Journal: Journal of Clinical Oncology (2017)

11569 Background: No validated prognostic biomarker is currently available for mCRC. This trial assessed cfDNA and MTV before treatment with regorafenib as prognostic biomarkers for progression-free survival (PFS) and overall survival (OS) in mCRC. Methods: After signed informed consent, mCRC patients were enrolled in a prospective non-randomized trial aiming to define unlikelihood to benefit from regorafenib (EudraCT number: 2012-005655-16) and assessed for cfDNA and FDG PET/CT MTV at baseline. cfDNA was extracted from 3mL of plasma and quantified using the Qubit 2.0 fluorometer. All target lesions were delineated on FDG PET/CT using a PERCIST-based threshold and their volumes were summed to obtain total MTV. MTV and cfDNA optimal cutoffs for OS and PFS prediction were determined by the Contal and O’Quigley’s method. MTV, cfDNA, age, gender, Body Mass Index (low, normal, high, obese), ECOG PS, number of chemotherapy lines (NCL), previous use of bevacizumab and presence of a KRAS mutation were included in a multivariate analysis. Results: MTV and cfDNA of 132 evaluable/141 eligible patients were well correlated (Spearman’s correlation coefficient = 0.70; p &lt; 0.001) and risk groups for both PFS and OS were identified on the basis of cfDNA (cfDNA &lt; 1 µg/mL; cfDNA≥1 µg/mL) and MTV (MTV &lt; 100 cm³; 100-300 cm³; &gt; 300 cm³). The multivariate analysis retained cfDNA, MTV, NCL, and obesity as independent parameters for PFS prediction, and cfDNA, MTV, NCL, BMI, and previous use of bevacizumab as independent parameters for OS prediction. Prognostic scores for PFS and OS were developed based on regression coefficients from the final Cox proportional hazards models. Prognostic scores for PFS (1.8 vs 5.3 months, HR: 3.15 for score ≥-3 vs &lt; -3, (95% CI, 2.08-4.76); p &lt; 0.001) and for OS (4.2 vs 13.9 months, HR: 4.59 for score ≥-6 vs &lt; -6: (95% CI, 2.92-7.21); p &lt; 0.001) both identified patients with much contrasted outcomes. Conclusions: Baseline cfDNA and MTV along with BMI parameters predict outcome in patients with mCRC before regorafenib onset. These parameters not related to treatment should be considered, if validated in further studies, as stratification factors in future clinical trials. Clinical trial information: 2012-005655-16.
Chemoradiotherapy (CRT) for locally-advanced (LA) lung cancer patients with interstitial lung abnormalities (ILA).
Authors: Toshio Kubo, Hisao Higo, Takashi Ninomiya, Eiki Ichihara, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Satoko Makimoto, Hiroki Ihara, Yoshihisa Masaoka, Kuniaki Katsui, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2017)

e20057 Background: Interstitial lung disease (ILD) is an independent risk factor for lung cancer. The incidence of ILD in lung cancer patients is 5–10%. Although CRT is the standard treatment for LA lung cancer and has potential for long-term disease-free survival or cure, the treatment is avoided in patients with ILD because of the risk of severe radiation pneumonitis or acute ILD exacerbation. ILA has recently been evaluated using high-resolution computed tomography (HRCT) to assess interstitial changes. The aim of this study was to determine the feasibility and efficacy of CRT for LA lung cancer patients with ILA. Methods: Patients who underwent CRT for LA lung cancer at Okayama University Hospital between 2012 and 2015 were reviewed retrospectively. HRCT prior to treatment was evaluated by one pulmonologist and two radiologists using sequential reading. Results: Of 74 patients, ILA was present in 25 (33.8%) and indeterminate ILA was present in 23 (31.1%); 26 patients (35.1%) did not have ILA. Patient characteristics are shown below. Desaturation at rest (SpO 2 &lt; 95%) and honeycombing on HRCT were not observed in patients with ILA. Only one patient with ILA had a low vital capacity (VC% of predicted, &lt; 80%). Severe radiation pneumonitis (≥ grade 2) occurred in 32.0% of patients with ILA and 19.2% of patients without ILA (P=0.35). All radiation pneumonitis was controllable and grade 4 or 5 was not observed. Using multivariate analyses, treatment &gt; 20 Gy involving &gt; 25% of the lung volume was a predictive factor for severe radiation pneumonitis, but not ILA. The 2-year survival percentages of patients with and without ILA were 56.8% and 72.5%, respectively (hazard ratio, 1.21; 95% confidence interval, 0.76–1.90; P=0.42). Conclusions: Although severe radiation pneumonitis tended to increase, CRT was appropriate for patients with ILA without desaturation, low VC, and honeycombing on HRCT. [Table: see text]
Anti-PD-1 tolerance after severe toxicity with ipilimumab therapy in metastatic melanoma patients.
Authors: Angelique Brunot, Geraldine Jeudy, Mathieu Tas, Bernard Guillot, Nora Kramkimel, Laurent Mortier, Sandrine Mansard, Celeste Lebbe, Astrid Blom, Yannick Le Corre, Henri Montaudie, Sorilla Prey, Boris Campillo-Gimenez, Thierry Lesimple
Journal: Journal of Clinical Oncology (2016)

9551 Background: Anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) antibody ipilimumab has been proved efficacy in treatment of metastatic melanoma, but with immune-related adverse events (irAE). Anti-Programed cell Death-1 (PD-1) antibodies, such as nivolumab or pembrolizumab, improve overall survival with a better safety profile, but their use is theoretically not allowed in case of previous severe (grade 3 or 4) ipilimumab irAE. We hypothesized that the occurrence of severe ipilimumab irAE is not predictive of anti-PD-1 irAE. Methods: We retrospectively collected safety outcomes of patients with metastatic melanoma treated with at least one cycle of nivolumab or pembrolizumab, who previously experienced severe ipilimumab irAE. Patients alive signed a non-opposition form to study their data, and we obtained the authorization of the ethic committee of the University Hospital of Rennes. Results: Data of 37 patients were collected in 17 French centers members of the French Society of Dermatology. Twelve (32.5%) patients with previous severe ipilimumab irAE suffered from one or more irAE with pembrolizumab (n=6) or nivolumab (n=6), regardless of the grade. Five patients (13.5%) experienced grade 3 or 4 immune toxicity and among them, 3 (8%) presented the same irAE than with ipilimumab treatment. Severe irAE were resolved with use of steroid (n=3) and/or anti-TNF therapy (n=1). No grade 5 toxicity has been reported. Organ-related toxicity was summarized in the following table. Most frequent severe anti-PD-1 irAE were gastrointestinal and endocrine. Conclusions: This study permitted to collect the safety profile of anti-PD-1 treatment after severe ipilimumab irAE. Comparing with reported data, there is no clear evidence for an increased risk in this population of patients during therapy with anti-PD-1, which seems to be safety used. Occurrence of severe immune related adverse events (irAE) in patients treated with antiPD-1 after grade 3 or 4 ipilimumab irAE. ipilimumab irAE (Grade≥3) anti-PD-1 irAE (Grade≥3) N=37 N=37 irAE (organ category) n (n/N %) n (n/N %) Gastrointestinal 22 (59,4 %) 2 (5,4 %) Hepatobiliary 5 (13,5 %) 0 (0 %) Dermatology 1 (2,7 %) 1 (2,7 %) Endocrine 11 (29,7 %) 3 (8,1 %) Others 7 (18,9 %) 0 (0 %)
Medical scribes in a community oncology clinic.
Authors: Rachel E. Lerner, Alice C. Shapiro, Sara Richter, Cheryl Craft, Mark R. Menge, Dylan M. Zylla, Lori Fewer, Mary Ehresman, Alexander Max Barnett, Laura Holasek
Journal: Journal of Clinical Oncology (2016)

6585 Background: Recent reports have suggested that scribes may improve clinician satisfaction, productivity, and clinic-related efficiencies, while maintaining patient satisfaction; however, there is limited data on the use of scribes in the oncology setting. Methods: This quality improvement project assessed the practical and financial feasibility of using medical scribes in a community cancer center. Three oncologists utilized scribes for a six-month period. Physician productivity, timeliness and quality of physician electronic health-record (EHR) documentation, patient and physician satisfaction, and overall costs were measured and compared to the same time period for the previous year. Data were extracted and summarized from the EHR data warehouse. Patient and provider satisfaction were surveyed by questionnaire; quality of clinical documentation was evaluated by independent blinded reviewers for best-practices. Results: Physician average work RVU’s per clinic day did not change, but average number of new patient visits/day/physician increased by 29% (from 1.4 to 1.8). After scribe implementation, nearly all encounters were closed within 30 days of the visit (83% pre to 99.8% post). Participating oncologists showed marked improvements in satisfaction with the amount of time spent with patients, ability to complete documentation, and in their work-life balance compared to non-participating colleagues. Patient satisfaction was high at scribe implementation, and remained so through the study period. For patients that had a scribe, 90% were comfortable having a scribe present. Based on scored elements from institutional note optimization guidelines, EHR note quality improved from 76% to 98%. Conclusions: The use of medical scribes in a cancer clinic was well accepted by patients and physicians. Physicians maintained productivity, increased access and improved their workplace quality of life. Timeliness and quality of documentation improved. These outcomes can provide financial and patient safety benefits for the broader health-care organization. However, the use of scribes might be more costly than dictation or voice recognition software, and models for cost sharing should be explored.
A phase II study of BKM120 (buparlisib) in relapsed or refractory thymomas.
Authors: Mohammad Issam Abu Zaid, Milan Radovich, Sandra K. Althouse, Hai Liu, Aaron John Spittler, Jeffrey Peter Solzak, Bradley Allen Hancock, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (2018)

e20580 Background: For residual or metastatic thymomas, the majority of patients require second-line therapy after platinum-combination chemotherapy with response rates ranging from 0 to 20%. Prior genomic analyses of thymoma demonstrated an activated PI3K pathway in a subset of tumors. We investigated the efficacy of buparlisib, an oral pan-PI3K inhibitor, in relapsed or refractory thymomas. Methods: This was a single center, single arm, open label phase II trial of buparlisib in patients with recurrent thymoma who have progressed after at least one prior line of treatment. Subjects were treated until disease progression or unacceptable toxicity. Thymic carcinomas were excluded. The primary endpoint was objective response rate (ORR) (complete response [CR] + partial response [PR]) using the RECIST 1.1 criteria. Secondary endpoints included toxicity assessments; progression free survival (PFS); overall survival (OS); disease control rate (DCR), i.e. percentage of patients who achieve either PR or CR or stable disease [SD] for at least 4 months. Results: Between 10/13/2014 and 1/18/2017, 14 patients were enrolled. Median age was 58 y (23 – 74). 71% were females and 71% white. All patients had WHO B2 (29%) or B3 (71%) thymoma. 12 patients had stage IV disease. Patients received buparlisib for a median of 4.5 m (2 – 33). At a median follow up of 16.6 m (2.4 – 31.3), 1 patient (7%) achieved a PR that lasted 9.7 m. DCR was 50%. Median PFS was 11.1 m (95% CI 2.9 – 18.8). Median OS was 22.5 m (10.7 – 31.3). Most common grade 3-4 adverse events related to buparlisib were dyspnea (21%), rash (14%), pneumonitis (7%), anxiety (7%), fatigue (7%) and hyperglycemia (7%). Reasons for treatment discontinuation were rash (43%), pneumonitis (29%), transaminits (21%) and autoimmune cholangitis (7%). As of 1/5/2018, 5 patients have died, 4 due to disease progression and 1 due to central nervous system toxoplasmosis and autoimmune cholangitis. Conclusions: Buparlisib showed modest activity in patients with relapsed or refractory thymomas. Further investigation of PI3K pathway targeted therapy is warranted. Clinical trial information: NCT02220855.
Closure of Medicare Part D coverage gap by the Affordable Care Act (ACA) and use of oral anti-myeloma agents.
Authors: Adam J. Olszewski, Stacie Dusetzina, Amy J. Davidoff, Amal N Trivedi
Journal: Journal of Clinical Oncology (2017)

6522 Background: Medicare Part D pays for oral anti-myeloma immunomodulatory drugs (IMiDs, lenalidomide and thalidomide), but has a coverage gap resulting in an out-of-pocket (OOP) expense of &gt; $ 3000 for the 1st prescription (Rx). Patients (pts) eligible for Low Income Subsidies (LIS) are exempt from cost sharing, and LIS is associated with IMiD receipt ( Olszewski, ASH 2016). In 2011, the ACA partly closed the coverage gap with a 50% manufacturer discount on the price of brand-name drugs within the gap. We examined effects of this policy on IMiD use. Methods: From the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we selected Part D enrollees who started anti-myeloma chemotherapy in 2008-2012. We identified IMiD use in periods pre-ACA (2008-10) and post-ACA (2011-12), among pts with or without LIS. After confirming parallel trends in IMiD use before the ACA, we examined the effect of ACA discount on IMiD use in a difference-in-differences (DiD) model, using LIS recipients as controls whose OOP costs were not influenced by the ACA. Results: Among 3,313 Part D enrollees (of whom 31% received LIS), 41% received IMiDs as part of their anti-myeloma regimen. Compared with the pre-ACA period, in the post-ACA period the median gross IMiD cost of the 1st Rx increased for all pts (Table). OOP costs for the 1st Rx, and for the 1st year of IMiD therapy, decreased for LIS non-recipients. Proportion of pts entering catastrophic coverage with their 1st IMiD Rx decreased from 71% to 49%. However, there was no statistically significant effect of the ACA discount on the proportion of pts treated with IMiDs (DiD estimator, 3% [95%CI, -4 to 10]; P=.40), or on the time from diagnosis to 1st Rx (median 1.5 mo. in all groups). Conclusions: The ACA-mandated partial closure of coverage gap lowered the OOP costs for Part D enrollees treated with IMiDs. As the median OOP cost remains &gt; $2400 for the 1st Rx, and &gt; $4900 for the 1st year of therapy, the policy may be insufficient to overcome the financial barrier for beneficiaries who do not receive the LIS. [Table: see text]
Immunotherapy Targeting HPV16/18 Generates Potent Immune Responses in HPV-Associated Head and Neck Cancer
Authors: Charu Aggarwal, Roger B. Cohen, Matthew P. Morrow, Kimberly A. Kraynyak, Albert J. Sylvester, Dawson M. Knoblock, Joshua M. Bauml, Gregory S. Weinstein, Alexander Lin, Jean Boyer, Lindsay Sakata, Sophie Tan, Aubrey Anton, Kelsie Dickerson, Drishty Mangrolia, Russell Vang, Michael Dallas, Sandra Oyola, Susan Duff, Mark Esser, Rakesh Kumar, David Weiner, Ildiko Csiki, Mark L. Bagarazzi
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Clinical responses with programmed death (PD-1) receptor–directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition. Patients and Methods: We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16+ HNSCCa received MEDI0457. Results: MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3–5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/106 peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti–PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1+ CD8+ T cells that were not found prior to MEDI0547 (0% vs. 1.8%). Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.
A phase Ib study to assess the efficacy and safety of vismodegib in combination with ruxolitinib in patients with intermediate- or high-risk myelofibrosis
Authors: Stephen Couban, Giulia Benevolo, William Donnellan, Jennifer Cultrera, Steffen Koschmieder, Srdan Verstovsek, Gregory Hooper, Christian Hertig, Maneesh Tandon, Natalie Dimier, Vikram Malhi, Francesco Passamonti
Journal: Journal of Hematology & Oncology (2018)

The JAK inhibitor (JAKi) ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining ruxolitinib with vismodegib in ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting.In this phase Ib study, ten patients with intermediate- or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (≥ 35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (≥ 50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria).As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and ruxolitinib; two discontinued treatment early. At week 24 (± 1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events.The combination of vismodegib and ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued.ClinicalTrials.gov, NCT02593760 . Registered November 2, 2015.