tbuckley/cabot-search huggingface dataset:
Potential Benefits of Inhaled Nitric Oxide in Pulmonary Hypoplasia in Premature Neonates
Authors: Praveen Chandrasekharan, Veena Manja, Satyan Lakshminrusimha
Journal: JAMA Pediatrics (2018)

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Genomic mutation profiles of paired ovarian cancers (OC) across time.
Authors: Julia Fehniger, Amnon A Berger, Luke Juckett, Laurie M. Gay, Julia Andrea Elvin, Douglas A. Levine, Deborah A. Zajchowski
Journal: Journal of Clinical Oncology (2018)

5521 Background: Prior studies demonstrate the clonal heterogeneity of ovarian tumors but do not address the relationship between genomic alteration profiles and treatment selection. We analyzed comprehensive genomic profiling (CGP) results from paired recurrent OC tumor samples to identify changes in somatic mutations over time. Methods: DNA from two or more FFPE tumor samples collected serially during the course of clinical care from 49 OC patients in the Clearity Foundation Data Repository was analyzed for genomic mutations (Mut), microsatellite instability (MSI), tumor mutation burden (TMB), and loss of heterozygosity (LOH) by hybrid-capture, next-generation sequencing of up to 315 genes (Foundation Medicine, Cambridge, MA). Genomic profiles were compared between samples from the same patient excluding sub-clonal mutations and genes/biomarkers not assessed across assays. 5 pairs were excluded due to poor quality metrics. Results: 22 sample pairs compared primary tumor to recurrence (PR) and 22 pairs compared two or more recurrences (RR). The majority of patients had stage III/ IV (34/77%) and primary platinum-sensitive disease (30/68%). OC was diagnosed at a median age of 57.3 yrs (range 34.5-76.9 yrs). Most tumors demonstrated serous histology (31/70%). Between sample pairs the median number of treatments was 3 for the PR (range 1-13) and 2 for the RR (range 1-7) groups. There was a median of 2 Mut/per OC sample (range 0-5), with a minority (12/27%) of pairs with any discordant mutations (dMut; 9 gains; 5 losses). 36 (82%) OC had TP53 Mut and all were concordant. Four BRCA1 Mut were identified (9% of OC) and all four were conserved between sample pairs. dMut were identified in ARID1A for 4 (9%) patients and RB1 for 2 (5%). No dMut were targetable with FDA-approved therapies, but could impact enrollment in clinical trials. We found no significant clinical associations for patients with discordant alterations. Conclusions: The majority of targetable mutations from CGP of paired OC specimens are concordant over time, despite inter-current chemotherapy and associated clonal selection. For those genes with discordant findings, attention to specimen selection may be warranted in the clinical development of drugs targeting associated pathways.
Abstract 357: Treatment With Fibrinogen ?-chain Peptide-coated, Adenosine Diphosphate-encapsulated Liposomes as an Infusible Haemostatic Agent for Dilutional Coagulopathy
Authors: Kohsuke Hagisawa, Manabu Kinoshita
Journal: Circulation (2013)

Background: We developed a fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV, H12)-coated, adenosine-diphosphate (ADP)-encapsulated liposomes [H12-(ADP)-liposomes] that accumulate at bleeding site via interaction with activated platelets via GPIIb/IIIa and augment platelet aggregation by releasing ADP. Objective: To evaluate the haemostatic efficacy of H12-(ADP)-liposomes against active liver bleeding in dilutional thrombocytopenic rabbits following massive transfusion. Methods: Acute thrombocytopenia (platelets &lt; 50 х 10 3 /μL) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed red blood cells. In these thrombocytopenic rabbits, liver hemorrhage was made by penetrating liver injury. Subsequently, they received the astriction treatment against the liver hemorrhage for 5 min and were intravenously administered with H12-(ADP)-liposomes with platelet-poor plasma (PPP), platelet-rich plasma (PRP), PPP alone, H12-(PBS)-liposome/PPP or H12-(ADP)-liposomes/PPP + fibrinogen concentrate during the astriction. Results: Administration of H12-(ADP)-liposomes as well as PRP rescued 60% rabbits from the liver hemorrhage (PRP, 50%), although rabbits receiving PPP or H12-(PBS)-liposome/PPP showed 10 or 17% survival in the first 24 h, respectively. Administration of H12-(ADP)-liposomes as well as PRP potently reduced both bleeding volume and time from the liver injury site. H12-(ADP)-liposomes were observed at the bleeding site in the liver with thrombus formation, suggesting an induction of thrombi. Whereas, neither macro- nor micro-thrombi were detected in the lung, kidney or liver in rabbits treated with H12-(ADP)-liposomes. Supplementation of fibrinogen to H12-(ADP)-liposomes/PPP did not significantly improve rabbit survivals (40% survival). Conclusions: H12-(ADP)-liposomes may be a safe and effective therapeutic tool during damage control surgery for acute thrombocytopenic trauma patients with massive bleeding.
Efficacy of 2<sup>nd</sup>-line chemotherapy in patients with poorly differentiated, high grade extrapulmonary neuroendocrine carcinoma (PD NEC).
Authors: Patrick Walsh McGarrah, Konstantinos Leventakos, Timothy J. Hobday, Julian R. Molina, Heidi Diann Finnes, Thorvardur Ragnar Halfdanarson, Gustavo Figueiredo Marcondes Westin
Journal: Journal of Clinical Oncology (2018)

e16162 Background: Platinum/etoposide doublet is considered standard 1st-line therapy for PD NEC, however evidence to guide treatment beyond 1st-line regimens is lacking. Second-line small cell lung cancer (SCLC) regimens are commonly used, but despite morphological similarities, extrapulmonary PD NEC is genetically distinct from SCLC. The aim of this study was to evaluate the efficacy of 2nd- line regimens for pts with PD NEC. Methods: We performed a retrospective analysis of pts at Mayo Clinic treated with 2nd-line chemotherapy for extrapulmonary PD NEC. Inclusion criteria were previous 1st-line therapy with platinum/etoposide, extrapulmonary PD NEC, and follow-up data. The primary end points were overall survival (OS) and progression-free survival (PFS) from the start of 2nd-line therapy. Secondary end-points included OS and PFS from the start of 1st-line therapy. Results: A total of 64 patients were included. The median OS from initiation of 2nd-line therapy for all regimens was 6.2 months [95% CI 4.9–8.9]. The median PFS was 2.3 months [95% CI 2.0–3.2]. No 2nd-line regimen showed a statistically significant difference in OS or PFS, though irinotecan-containing regimens had the longest OS (7.8 months [3.3–14.8]) and paclitaxel-containing regimens (without topotecan) had the longest PFS (2.7 months [1.3–6.4]). Multiple-agent regimens showed a nonsignificant increase in both OS (6.2 months [3.7–10.8]) and PFS (2.3 months [1.8–4.6]) compared to singlets (OS 5.8 months [4.9–11.3]; PFS 2.2 months [1.4–4.1]). Tumors of unknown primary site had the longest PFS from 2nd- line, but this was nonsignificant. There was a significant increase in OS for cisplatin 1st-line regimens compared to carboplatin (17.0 months [12.5–22.6] vs 11.7 months [8.0–14.0]). These patients were younger (median age 54 vs 63), but the effect persisted when controlling for age. Conclusions: The efficacy of current 2nd-line therapy in PD NEC is poor. No 2nd-line regimen showed statistically significant superiority. Cisplatin was associated with a longer OS regardless of 2nd-line regimen or age. However, unmeasured confounders such as performance status or comorbidities may explain some of this effect.
A phase Ia/Ib trial of the DNA-PK inhibitor M3814 in combination with radiotherapy (RT) in patients (pts) with advanced solid tumors: Dose-escalation results.
Authors: Baukelien Van Triest, Lars Damstrup, Johan Falkenius, Volker Budach, Esther Troost, Michael Samuels, Juergen Debus, Morten Mau Sørensen, Karin Berghoff, Rainer Strotman, Mark van Bussel, Sanjay Goel, Poul F. Geertsen
Journal: Journal of Clinical Oncology (2018)

2518 Background: DNA-dependent protein kinase (DNA-PK), regulates one of the major pathways responsible for repair of DNA double-strand breaks. The combination of RT and DNA-PK inhibition (DNA-PKi) has been shown to be synergistic in preclinical studies. The purpose of this phase I trial is to explore the safety, tolerability, pharmacokinetic (PK) profile, and clinical activity of M3814 administered together with RT (Arm A) and chemo-RT (CRT; Arm B). Results for Arm A are reported. Methods: Pts with tumors or metastases in the head and neck region or thorax in need of palliative RT (30 Gy in 10 factions) are enrolled in the dose escalation part Ia of Arm A to receive M3814, starting dose 100 mg. Dose escalation is aided by a Bayesian logistic regression model. Dose-limiting toxicity (DLT) is evaluated up to 3 weeks after RT. Rich PK sampling is taken during treatment. Tumor evaluation is performed every 6 weeks up to 6 months and every third month thereafter. Results: 16 pts had been enrolled, 100 mg (N = 7), 200 mg (3) and 400 mg (6). The most frequent adverse events (AEs) were fatigue (n = 12), nausea (8), constipation, decreased appetite, dysphagia, mucosal inflammation/stomatitis (6), vomiting (5), back pain, chest pain, diarrhea, radiation skin injury, and weight decreased (4). All pts completed treatment ( > 80% of specified dose) and no pts discontinued due to DLTs. Four DLTs were reported: grade 3 mucositis lasting > 7 days in 3 pts (100 and 400 mg) and odynophagia in one pt (400 mg). All pts with DLTs recovered without sequelae. One fatal suspected unexpected serious AE considered as radiation pneumonitis occurred. Preliminary efficacy: in field response: one pt had pCR, 4 PR, 7 SD, and 3 have not yet been evaluated one pt was not evaluable. PK was like an earlier first-in-man study, including high inter-subject variability. Conclusions: M3814 is well tolerated at doses of 100 and 200 mg QD as part of a palliative treatment combination with RT. Since 2 DLTs were seen at 400 mg QD, the therapeutic window will be further evaluated based on toxicity profile and PD data. Currently, M3814 300 mg QD is being explored. Updated safety and efficacy data will be presented Clinical trial information: NCT02516813.
Study of non-small cell lung cancer using ultra-high-performance liquid chromatography-mass spectrometry.
Authors: Kai Zhang, Rubo Cao, Yue Hu, Yangyang Liu, Qifan Yang, Yulan Zeng, Jinyan Liang, Li Liu
Journal: Journal of Clinical Oncology (2018)

e24085 Background: This study is to explore changes of serum metabolites in non-small cell lung cancer (NSCLC) patients and healthy controls, so as to provide new diagnostic strategies for NSCLC. Methods: A total of 77 samples were obtained, including 45 NSCLC patients and 32 healthy controls. After serum was extracted, metabolic assays based on a wide range of targeted metabolome technologies and the ultra-high-performance liquid chromatography-mass spectrometry/ mass spectrometry (UPLC-MS / MS) detection platform were explored to detect metabolites in it. Self-built database and multivariate statistical analysis were utilized to study the difference of metabolome between different arms. Results: A total of 296 metabolites were detected in all samples. Eighty-one genes were found differentially expressed, of which 48 were down-regulated and 33 were up-regulated in NSCLC patients. There were no significant differences in the serum metabolite between denocarcinoma and squamous cell carcinoma. KEGG functional annotation analysis was made on the 81 metabolites to elucidate the biological functions, and signaling pathways which might cause changes in metabolites were summarized. Conclusions: Based on our novel UPLC-MS / MS platform, more metabolites can be detected, which might provide new potential tumor biomarkers. Our study can accelerate development of new diagnostic stragies in NSCLC.
Outcomes of febrile neutropenia following hematopoietic stem cell transplantation.
Authors: Tanmay Sahai, Naomi Hauser, Shiva Kumar Reddy Mukkamalla, Alvaro G. Menendez, Todd F. Roberts, Richa Tandon
Journal: Journal of Clinical Oncology (2016)

e18562 Background: Hematopoietic stem cell transplant (HSCT) patients are at increased risk of fever and infection. This study aims to investigate outcomes in this population during their hospitalization. Methods: A total of 108 HSCT recipients from 2002-2014 were included in this retrospective single-center study. Patients were included if they had a febrile episode defined by IDSA as a temperature > 100.4°F while being neutropenic with ANC < 1500 cells/mm3. Gender was equally distributed with 53 females and 55 males. Patients were then stratified into allogeneic (n = 42) and autologous (n =66) HSCT recipients. Data was analyzed with Student’s t-test and Chi-Square. Results: Allogeneic HSCT patients had longer hospitalization (29.4 vs. 21.9 days, P < 0.001) and duration of neutropenia (15.6 vs. 9.2 days, P < 0.001) than autologous patients. 32 patients (29%) had documented infections with an identifiable source. 65 patients (60 %) had an unexplained fever with no clinical or microbial evidence. Allogeneic HSCT had higher treatment related mortality (TRM) in comparison to autologous (19% vs. 4.5 %, P ≈ 0.0151). Relative frequencies of infections were: C. Diff (2%), ESBL (1%), fungus (1%), Gram negative rods (3%), Gram positive cocci (13%), VRE (2%), virus (1%), and >1 class of organism (7%). They did not statistically alter length of stay as most episodes were linked to unexplained fever. Other variables analyzed in the table below. Conclusions: Our study shows a difference in hospital course and outcome in febrile neutropenic HSCT patients receiving allogeneic vs. autologous transplants. These findings suggest a potential indication for treatment of febrile episodes post-transplant. Empirical regimens, aggressiveness of treatment, and TRM should be further explored in patients with and without febrile neutropenia in both groups. ALLO AUTO P value Length of Hospitalization 29.4±15.9 21.9 ± 9.8 P <0.001 Age 55.2 ±13.6 55.1 ±12.8 P < 0.001 Duration of Neutropenia 15.6 ±9.7 9.2 ±4.5 P < 0.001 Profound Neutropenia 71% 73% P = 0.203 Unexplained Fever 22 (52%) 43 (65%) P = 0.132 Microbiology identified 17 (41%) 15 (23%) P = 0.132 Clinical infection 3 (7%) 8 (12%) P = 0.132 Mortality 8 (19%) 3 (4.5%) P = 0.015 30 Day Readmission 9 (21%) 7 (11%) P = 0.122
Supportive care and symptom burden in patients with myeloproliferative neoplasms.
Authors: Krisstina L. Gowin, Denise Millstine, Heidi E. Kosiorek, Blake Langlais, Jennifer Huberty, Ryan Eckert, Ruben A. Mesa
Journal: Journal of Clinical Oncology (2017)

e21684 Background: Pharmacologic therapy stabilizes hematologic counts and splenomegaly in myeloproliferative neoplasms (MPN), however only partial symptom improvement typically occurs. Evidenced-based supportive care interventions are needed, however data is limited in patients with MPNs. Methods: Patients were recruited internationally via social media. Informed consent and online self-report surveys (Qualtrics) were completed capturing patient demographics, disease specific data, supportive care utilization, and symptom burden via MPN-SAF TSS. ANOVA, chi square tests, and Wilcoxon rank sum tests methods were applied. Results: Patients:1087 patient surveys were consented. Of these, 858 had 10 or more responses. There were 338 essential thrombocytosis (ET), 188 myelofibrosis (MF), 315 polycythemia vera (PV), and 17 other. In MF: DIPSS risk categories included low (8%), Int-1 (19%), Int-2 (29%), high (12%), and unknown (32%). Supportive care:The most frequently utilized therapies were aerobic activity in 442 patients (51.5%), massage in 244 (28.4%), yoga in 220(25.6%), nutrition in 216 (25.1%), and strength training in 204 (23.7%). Symptom association: Among all respondents, aerobic activity (p=&lt;0.001), massage (p=&lt;0.001), yoga (p=0.02), and strength training (p=&lt;0.001) was associated with lower symptom burden by the MPN-SAF TSS however, nutrition was not (p=0.10). In ET and PV subgroups, yoga intervention was no longer statistically significant (p=0.35, p=0.14). In the MF subgroup, no intervention was found to be significant in any risk category. Conclusions: Supportive care with aerobic activity, massage, yoga, and strength training is associated with improved symptom burden in patients with MPN. Further studies are needed to understand the benefits of such therapies. [Table: see text]
Cancer-related distress screening in a radiation oncology clinic: A snapshot view of a Veterans Administration (VA) institution screening program.
Authors: Timothy A. Lomauro, George Anthony Dawson, Lori Magda, Kristen Tobias, Maria D. Kelly
Journal: Journal of Clinical Oncology (2017)

e21562 Background: The emotional and psychosocial stress experienced by cancer patients are significant factors impacting cancer treatment outcomes and quality of life. Increased emphasis upon programmatic approaches to identifying distress has evolved to current evidenced-based treatment guidelines as reflected by American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have identified distress screening standards of care. This report is a snapshot of the results of a distress screening program in a VAMC Radiation Oncology clinic. Methods: Calendar year 2016 data was chosen for this quality improvement review. We wanted to assess the effectiveness of psychosocial distress screening process now routinely done in Radiation Oncology. Distress screening was completed utilizing the NCCN Distress Thermometer. The program’s goal was to administer distress screening to all patients at the time of their initial consultation and to follow up screening as appropriate. Results: The mean age of the patients was 68.6 years; 98% were male. The treatment population was 58% Caucasian, 38% African-American, 2% Hispanic, and 2% other. The most prevalent cancer diagnoses were: Prostate, 52%; Lung, 13.9%; Head &amp; Neck Cancer, 7.2%, Skin, 4.6%; Esophageal or Gastric Cancer, 3.1%; Brain, 2.0%; and Breast, 2.0% Screenings were completed on 161 of 193 (83%) new consults in Radiation Oncology; 47.6% of patients screened scored at or above the established cut score of 4. Referrals to Oncology Psychology were initiated for 29.5% of total sample. Significant mental health co-morbidities were identified in the treatment population studied; 58.5% of patients had at least one mental disorder diagnosis. Examples: PTSD, Major Depressive Disorder, Substance Use Disorder, and Adjustment Disorder. Conclusions: Results reflect the usefulness of the distress screening process in identifying adjustment issues specific to cancer patients' experience, as well as exacerbations of existing mental health conditions. The screening process facilitated referral to specialty (Oncology Psychology) and general (Mental Health Clinic) services.
WT1 heteroclitic epitope immunization following autologous stem cell transplantation in patients with high-risk multiple myeloma (MM).
Authors: Guenther Koehne, Sean Devlin, David J. Chung, Heather Jolie Landau, Neha Korde, Sham Mailankody, Hani Hassoun, Alexander M. Lesokhin, Nikoletta Lendvai, Sergio Giralt, Carl Ola Landgren
Journal: Journal of Clinical Oncology (2017)

8016 Background: Host T-cells mount immune responses (IR’s) against Wilms tumor 1 (WT1) in A*0201 + MM pts through formation of WT1 peptide fragment (RMFPNAPYL)/HLA-A*0201 complex. We report initial results from MM pts immunized with the WT1 heteroclitic peptide mixture galinpepimut-S (GPS) after autoSCT. Methods: 16 MM pts underwent autoSCT with melphalan conditioning followed by (f/b) lenalidomide maintenance starting 3 months (mos) post-SCT. 13/16 pts presented with high-risk (HR) cytogenetics [t(4;14), t(14;16), del17p, 1q21/25 gain and/or del13q]. GPS was administered with montanide s.c. starting 2 wks post-SCT and q.2 wks thereafter x 6 initial doses f/b boosters q.4 wks x 6 additional doses. GM-CSF was given on days -2 and 0 of each cycle. GPS consisted of 4 peptides: WT1-A1: Y*MFPNAPYL; 427-L (long): RSDELVRHHNMHQRNMTKL; 331-L: PGCNKRYFKLSHLQMHSRKHTG, and 122A1-L: SGQAY*MFPNAPYLPSCLES. 2 of the 4 peptides were mutated at a single residue (*) to induce stronger HLA-binding/reduce tolerance. WT1-specific IR’s were assessed by intracellular IFN-g analyses post-challenge with PBMC’s pulsed with a ‘total pool’ of overlapping 15mers along the entire WT1 protein; or each of the 4 WT1 peptides in GPS; or the non-mutated (native) WT1 peptides corresponding to the 2 heteroclitic sequences. Results: 16 pts; median follow-up: 18 mos (range: 5-31 mos) for survivors; median age: 61.6 y. Overall survival (OS) and progression-free survival (PFS) (95% CI) at 18 mos: 0.88 (0.73-0.99) and 0.62 (0.42-0.97) respectively. Current median PFS: 23.6 mos (15.2 - not reached). No &gt;G2 systemic side effects were observed, however, all pts developed local nodularity at the site of injections which resolved over 2 – 6 wks. Both CD8+ and CD4+ IR’s could be detected at various levels and were induced not only against the heteroclitic peptides (within GPS), but also against the corresponding native WT1 peptide sequences as well as the ‘total pool’ of WT1-derived overlapping peptides. Conclusions: Administration of the novel WT1 heteroclitic peptide immunizer GPS post auto SCT demonstrates favorable safety profile along with encouraging mPFS of currently 23.6 mos in this high-risk MM population. Clinical trial information: NCT01827137.