tbuckley/cabot-search huggingface dataset:
Lung transplantation for sarcoidosis: outcome and prognostic factors
Authors: Jérôme Le Pavec, Dominique Valeyre, Pierre Gazengel, Are M. Holm, Hans Henrik Schultz, Michael Perch, Aurélie Le Borgne, Martine Reynaud-Gaubert, Christiane Knoop, Laurent Godinas, Sandrine Hirschi, Vincent Bunel, Rosalia Laporta, Sergio Harari, Elodie Blanchard, Jesper M. Magnusson, Adrien Tissot, Jean-François Mornex, Clément Picard, Laurent Savale, Jean-François Bernaudin, Pierre-Yves Brillet, Hilario Nunes, Marc Humbert, Elie Fadel, Jens Gottlieb
Journal: European Respiratory Journal (2021)

Study question In patients with sarcoidosis, past and ongoing immunosuppressive regimens, recurrent disease in the transplant and extrapulmonary involvement may affect outcomes of lung transplantation. We asked whether sarcoidosis lung phenotypes can be differentiated and, if so, how they relate to outcomes in patients with pulmonary sarcoidosis treated by lung transplantation. Patients and methods We retrospectively reviewed data from 112 patients who met international diagnostic criteria for sarcoidosis and underwent lung or heart–lung transplantation between 2006 and 2019 at 16 European centres. Results Patient survival was the main outcome measure. At transplantation, median (interaquartile range (IQR)) age was 52 (46–59) years; 71 (64%) were male. Lung phenotypes were individualised as follows: 1) extended fibrosis only; 2) airflow obstruction; 3) severe pulmonary hypertension (sPH) and airflow obstruction; 4) sPH, airflow obstruction and fibrosis; 5) sPH and fibrosis; 6) airflow obstruction and fibrosis; 7) sPH; and 8) none of these criteria, in 17%, 16%, 17%, 14%, 11%, 9%, 5% and 11% of patients, respectively. Post-transplant survival rates after 1, 3, and 5 years were 86%, 76% and 69%, respectively. During follow-up (median (IQR) 46 (16–89) months), 31% of patients developed chronic lung allograft dysfunction. Age and extended lung fibrosis were associated with increased mortality. Pulmonary fibrosis predominating peripherally was associated with short-term complications. Answer to the study question Post-transplant survival in patients with pulmonary sarcoidosis was similar to that in patients with other indications for lung transplantation. The main factors associated with worse survival were older age and extensive pre-operative lung fibrosis.
Alliance/CALGB 80802: Impact of hepatitis C (HCV) on doxorubicin (DO) + sorafenib (S) versus S in patients (pts) with advanced hepatocellular carcinoma (aHCC).
Authors: Imane H. El Dika, Susan Michelle Geyer, Andrew B. Nixon, Federico Innocenti, Qian Shi, Sawyer B. Jacobson, Amin Yaqubie, Juan C. Lopez, Binhui Huang, Yi-Wei Tang, Yujia Wen, Lawrence Howard Schwartz, Monica M. Bertagnolli, Jeffrey A. Meyerhardt, Eileen Mary O'Reilly, Alan P. Venook, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2021)

325 Background: Alliance/CALGB 80802 randomized phase III trial evaluated DO+S vs. S in pts with aHCC, and showed no improvement in median OS. Multi-drug resistant pathway mitigation by the Ras/Raf/MEK/ERK pathway and bFGF-mediated activation of Raf-1 promotes the formation of antiapoptotic Raf-1 and ASK1 complex, induced by anthracyclines. S efficiently blocks NS5A-recruited c-Raf mediated HCV replication and viral gene expression. Once inhibited by S, VEGF expression of HepG2 may limit HCV cellular entry. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via S putatively differ in the presence or absence of DO. We hypothesize treatment with S reduces HCV titer levels (TL) and influence pts’ outcome. Methods: In 80802 HCV pts, TL were evaluated in both arms at baseline and post-baseline at Day 1 of Cycles 2, 3, and every 2 cycles and at progression or discontinuation of therapy. HCV undetectable (HCV-UN) levels were defined as &lt; 50 copies/mL. TL were evaluated in relation to OS and PFS. HCV RNA levels were measured by TaqMan PCR and by genotype. Results: Of 356 pts, 83 were HCV+ with more Black/African American (25/50 = 50%) vs. White (54/239 = 23%) or other race groups (4/67 = 6%) (p &lt; 0.0001). HCV titer data were available on 54 pts (S: 28, DO+S: 26). At baseline, 12 pts (S: 7, DO+S: 5) were HCV-UN, and post-baseline HCV TL did not significantly differ between treatment arms; one patient in each arm went from detectable (HCV-D) to HCV-UN. Post-baseline, 40 pts were HCV-D vs. 14 who were HCV-UN (S+DO: 8, S: 6 pts). Except for the two pts who became HCV-UN, baseline HCV-D vs. HCV-UN titers was similar to that status post-baseline. PFS and OS between HCV-D and HCV-UN both at baseline and post-baseline are delineated in the table. Conclusions: We observed that S did not influence HCV TL. Pts treated with DO+S vs. S had worse PFS if they had HCV-UN, and further that higher levels of HCV titers at baseline were associated with significantly improved PFS. Given the small sample size, these findings warrant further prospective evaluation. Support: U10CA180821, U10CA180882, U24CA196171; Bayer, Bristol-Myers-Squibb, and Sanofi. https://acknowledgments.alliancefound.org . Clinical trial information: NCT01015833. [Table: see text]
Evaluation of neratinib (N), pembrolizumab (P), everolimus (E), and nivolumab (V) in patients (pts) with fibrolamellar carcinoma (FLC).
Authors: Ghassan K. Abou-Alfa, Tim Meyer, Jie Zhang, Scott Sherrin, Amin Yaqubie, Alison Clemens O’Neill, Feng Xu, Lisa D Eli, James J. Harding, Eileen Mary O'Reilly, Alshad S. Lalani, Richard Bryce, John Dozier Gordan
Journal: Journal of Clinical Oncology (2021)

310 Background: FLC, a rare liver cancer of young adults, has no effective systemic therapies. Surgical resection is used extensively with non-curative intent. FLC is associated with a DNAJB1- PRKACA chimeric transcript that produces a fusion protein with retained kinase activity and increased expression of several oncogenic signaling pathways including, but not limited to, HER2 ( ERBB2). Methods: N (240 mg oral daily) was studied in FLC pts in the SUMMIT study (NCT01953926); and later under compassionate use for N-based combinations (combo): P (2 mg/kg q3w), E (7.5 mg daily), and V (240 mg q2w) in doublet or triplet regimens. Eligible pts: ≥12y; histologically confirmed FLC; adequate organ function; any number of prior therapies. Primary endpoint: objective response rate (ORR; RECIST v1.1). Secondary endpoints: duration of response; clinical benefit rate (CBR); safety (CTCAE v4.0); somatic and germline sequencing (MSK IMPACT). Results: As of 03-Sep-2020, 15 pretreated pts received N in SUMMIT (confirmed ORR 0%; CBR 13%). Efficacy data for 5 pts from SUMMIT and 2 more pts receiving combo under compassionate use (4 male, 3 female, median age 26 years, median 0 [range 0–4] prior systemic therapies) are in shown in the table. The most common adverse events (AE) with single-agent N (n = 5) were diarrhea (grade 1 80%; grade 2 20%) and nausea (grade 1 60%); other AEs were grade ≤1 in ≤20% of pts. Conclusions: N monotherapy had limited benefit as a single agent in FLC pts. Several case studies evaluating N-based combo with checkpoint inhibitors administered under compassionate use demonstrated that NP led to 1 PR, and the triplet of NPE to prolonged SD. These are case-limited observations but are critical and worth evaluating further in upcoming clinical trials given the continued lack of a standard of care therapy for pts with FLC. Clinical trial information: NCT01953926. [Table: see text]
Population-based analysis of National Comprehensive Cancer Network (NCCN) guideline adherence for patients with anal squamous cell carcinoma in California.
Authors: Priyanka Kumar, Michael Del Rosario, Jenny Chang, Argyrios Ziogas, Mehraneh D. Jafari, Robert E. Bristow, Sora Park Tanjasiri, Jason A. Zell
Journal: Journal of Clinical Oncology (2021)

1 Background: Oncology-specific evidence-based treatment guidelines aim to improve cancer care. Our study analyzed adherence to the National Comprehensive Cancer Network (NCCN) treatment guidelines for anal squamous cell carcinoma in California and the associated impacts on survival. Methods: Patients aged 18 to 79 years diagnosed with anal squamous cell carcinoma (SCC) between January 1, 2004 and December 31, 2017 with follow-up through November 30, 2018 were identified in the California Cancer Registry. Patient demographics, socioeconomic status (SES) and tumor stage were identified. We determined whether patients received NCCN guideline-adherent care (AdC) by pre-defined criteria. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression for receiving AdC. Overall survival (OS) and disease specific-survival (DSS) were calculated using Cox regression models. Results: Of 4,740 patients with a diagnosis of anal SCC in California, 926 (19.5%) did not receive AdC (non-AdC). Non-AdC had worse DSS (HR 1.96, 95% CI = 1.56, 2.46, p &lt; 0.0001) and worse OS (HR 1.87, 95% CI = 1.66, 2.12, p &lt; 0.0001). Females were more likely to receive AdC (OR 1.38, 95% CI = 1.18, 1.62, p &lt; 0.0001). Medicaid patients were less likely to receive AdC (OR 0.75, 95% CI = 0.57, 1.00, p = 0.0476). Patients with the lowest SES were less likely to receive AdC (OR 0.65, 95% CI = 0.50, 0.83, p = 0.0007). Characteristics associated with DSS and OS included female gender, black race, Medicare/Medicaid, and SES (particularly, lower-middle SES). Conclusions: NCCN guideline-adherent care was associated with improved disease-specific and overall survival in anal SCC patients in California.
Treatment patterns and survival in patients with late-stage hepatocellular carcinoma in France: A retrospective database analysis.
Authors: Jean-frederic Blanc, Caroline Laurendeau, Nadia Kelkouli, Philippe Mathurin
Journal: Journal of Clinical Oncology (2021)

288 Background: The prognosis for patients with late-stage hepatocellular carcinoma (HCC) is poor, with only one systemic treatment option available for patients until 2017. Aim: To describe treatment patterns and survival of French patients following diagnosis of late-stage HCC (Barcelona Clinic Liver Cancer classification B, C or D), using a comprehensive nationwide claims database, SNDS. Methods: The SNDS database was searched from 1 January 2015 to 31 December 2017 for patients with a diagnosis of HCC (ICD-10: C220) and late-stage disease, defined by the identification of transcatheter arterial chemoembolization (TACE) or radioembolization (TARE), HCC systemic therapy and/or best supportive care (BSC). Patients were followed up for a maximum of 2 years. Results: 17,298 patients (mean age: 68.7 years (SD: 11.3), 82.6% male) were identified, with 72.4% diagnosed at late stage. During follow-up, 29.6% of patients were treated with TACE or TARE, and 27.1% received systematic therapy (sorafenib in 99.5% of cases). The median duration of systemic treatment was 7.9 (95% CI: 7.4-8.5) months. In 62.5% of cases, this treatment was discontinued at 12 months; this proportion fell to 40.3% when using mortality as a competitive risk. Survival since diagnosis of late stage HCC differed according to the type of first treatment received. Median overall survival was 23.7, 11.9, 7.4 and 1 month in patients initially receiving TACE, TARE, systemic therapy or no treatment, respectively. Conclusions: These results confirm the high clinical burden of late-stage HCC over this period and the need for second-line systemic treatments to improve patient outcomes.
Abstract 19429: Trx1 Regulates Nitroso-redox Balance to Stimulate Autophagy and Cell Survival in Cardiomyocytes
Authors: Narayani Nagarajan, Sebastiano Sciarretta, Junichi Sadoshima
Journal: Circulation (2015)

Thioredoxin-1 (Trx1) is cardioprotective during oxidative stress. In addition to acting as an oxidoreductase, Trx1 also trans-nitrosylates other proteins. However, the role of Trx1-dependent S-nitrosylation in cardiomyocytes (CMs) is unknown. We investigated how Trx1 affects protein S-nitrosylation (SNO) and the nitroso-redox balance to regulate CM survival during glucose deprivation (GD). Mass spectrometry (MS/MS) analysis showed that Trx1 is S-nitrosylated at Cys73. Protein SNO levels were increased after 4 hrs of GD (1.64 fold, p&lt;0.05; biotin switch assay). Overexpression of Trx1WT increased (3.94 fold), whereas knockdown of Trx1 (0.66 fold, p&lt;0.01) or overexpression of Trx1C73S (0.77 fold, p&lt;0.01) decreased, total protein SNO in response to GD, suggesting that Trx1 Cys73 regulates protein SNO in CMs during GD. Overexpression of Trx1 increased CM survival 24 hrs after GD (1.42 fold vs LacZ, p&lt;0.05). Conversely, shTrx1 (2.13 fold vs control, p&lt;0.01) or Trx1C73S (1.73 fold vs LacZ, p&lt;0.01) increased cell death during GD. Either knockdown of Trx1 (LC3-II/Tubulin, 0.55 fold vs control) or overexpression of Trx1C73S (vs LacZ: LC3-II/Tubulin, 0.60 fold; autophagosomes, 0.83 fold, p&lt;0.005; autolysosomes, 0.62 fold, p&lt;0.005) significantly decreased autophagosome formation during GD. Increased interaction between Trx1 and a key autophagy protein, Atg7, was observed during GD and oxidative stress, as evaluated with the Trx1C35S trapping mutant. However, addition of DTT abolished this interaction, suggesting that Trx1 and Atg7 interact with one another via a disulfide linkage. By biotin switch assay and MS/MS analyses, we found that SNO-Trx1 can trans-nitrosylate Atg7 in vitro and that Atg7 is S-nitrosylated during GD in CMs. By labeling reduced and oxidized Cys residues in Atg7 with iodoacetamide and MMTS respectively, we determined that the level of Atg7 oxidation did not increase during oxidative stress in CMs, suggesting that Trx1 trans-nitrosylates Atg7 to prevent irreversible oxidative damage in Atg7. Taken all together, our results indicate that Trx1 promotes trans-nitrosylation of cellular proteins such as Atg7 to regulate the nitroso-redox balance and thus promote cell survival by stimulating autophagy during energy stress in CMs.
AB0204 A NEW INFLAMMATORY MARKER ASSOCIATED WITH DISEASE ACTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS: PLATELET TO ALBUMIN RATIO
Authors: M. Liu, Y. Huang, Z. Huang, Q. Huang, T. Li
Journal: Annals of the Rheumatic Diseases (2020)

Background: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by disordered immunity and dysregulated cytokine. Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have been defined as inflammatory markers to evaluate disease activity of RA. Recently, platelet to albumin ratio (PAR) was reported as a new prognostic index in patients with cancer. However, similar studies have not been displayed in RA. Objectives: This study was to explore the role of PAR in RA and its association with disease activity. Methods: This retrospective study enrolled 136 RA patients and 87 age- and gender-matched healthy controls. Neutrophil, lymphocyte, monocyte, platelet, hemoglobin, albumin, NLR, neutrophil to hemoglobin ratio (NHR), neutrophil to albumin ratio (NAR), monocyte to lymphocyte ratio (MLR), monocyte to hemoglobin ratio(MHR), monocyte to albumin ratio(MAR), PLR, platelet to hemoglobin ratio (PHR), PAR, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and Disease Activity Score of 28 joints - ESR (DAS28-ESR) were detected. Receiver operation characteristic (ROC) curve was used to discriminate RA patients from healthy individuals. Relationships between PAR and DAS28-ESR as well as other laboratory data were measured by the Spearman’s correlations analysis. Results: RA patients showed higher levels of NLR, NHR, NAR, MLR, MHR, MAR, PLR, PHR PAR and lower levels of albumin than healthy controls. PAR and other inflammatory parameters were also raised along with increased disease activity in RA patients (P &lt; 0.05) except NHR (P = 0.098). Similarly, albumin was decreased in RA patients as the disease activity increased (P = 0.001). ROC showed that area under curve (AUC) of PAR (0.887, 95%CI: 0.843-0.931) was higher than NLR (0.818, 95%CI: 0.762-0.874), NHR(0.839, 95%CI: 0.787-0.890), NAR(0.829, 95%CI: 0.776-0.882), MLR (0.794, 95%CI: 0.734-0.854), MHR(0.817, 95%CI: 0.760-0.874), MAR(0.814, 95%CI: 0.757-0.872), PLR (0.832, 95%CI: 0.779-0.886), PHR(0.884, 95%CI: 0.838-0.930) and albumin(0.860, 95%CI: 0.813-0.908). Besides, PAR was positively correlated with DAS28-ESR (r = 0.429, P &lt; 0.001), CRP (r = 0.540, P &lt; 0.001) and ESR (r = 0.492, P &lt; 0.001), yielding a highest relevance than other inflammatory indexes. Conclusion: This study demonstrated that PAR was elevated in RA patients and increased with the disease activity. PAR may be a novel marker to assess the disease activity of RA patients. References: [1]Li C, Peng W, Zhang X Y, et al. The preoperative platelet to albumin ratio predicts the prognosis of hepatocellular carcinoma patients without portal hypertension after liver resection[J]. Medicine, 2019, 98:e17920. Acknowledgments: Science and Technology Project of Haizhu District (No.Hai ke gong shang xin ji 2018-89), Youth Foundation of Guangdong Second Provincial General Hospital (No. YQ2017-009). Disclosure of Interests: None declared
Phase Ib Clinical Trial of IGV-001 for Patients with Newly Diagnosed Glioblastoma
Authors: David W. Andrews, Kevin D. Judy, Charles B. Scott, Samantha Garcia, Larry A. Harshyne, Lawrence Kenyon, Kiran Talekar, Adam Flanders, Kofi-Buaku Atsina, Lyndon Kim, Nina Martinez, Wenyin Shi, Maria Werner-Wasik, Haisong Liu, Mikhail Prosniak, Mark Curtis, Rhonda Kean, Donald Y. Ye, Emily Bongiorno, Sami Sauma, Mark A. Exley, Kara Pigott, D. Craig Hooper
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma. Patients and Methods: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4–6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies. Results: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001–treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine–DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted. Conclusions: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).
Deploying an AI-based online search tool to increase patients’ access to and understanding of solid tumor GI clinical trials.
Authors: Pashtoon Murtaza Kasi, Emily Jordan, Luca Jahreiss
Journal: Journal of Clinical Oncology (2021)

456 Background: The number and complexity of clinical trials has been growing, making finding and accessing trials increasingly challenging. Additionally, the goal of representative trial populations remains elusive with sometimes devastating medical consequences. A key barrier to increasing recruitment efficiency is patients’ low awareness of clinical trials as an option. They rarely hear about trials from their oncologists, unless they are based at a research center, which introduces trial population biases by including only patients with good healthcare access. And even if patients decide to search for information on trials themselves, the information is difficult to understand. There are existing trial search tools, but they have multiple shortcomings: complex navigation, limited search functionality, clinical trial data is too complex for non-specialists to understand, and lack of clarity on next steps. Methods: Access to trials via a novel trial search tool (www.ancora.ai) which uses AI to restructure trial information was the main focus of this study. For increased GI cancer specificity, 6 key GI cancers were included into the AI model and information was restructured based on key eligibility differentiators identified (see data structure table). Research participants (xx GI oncology patients) were recruited with the support of patient associations (e.g. The Colon Club) leveraging social media. They were asked to complete a 20 minute survey evaluating both an established tool (clinicaltrials.gov) and the novel tool to find trials relevant for them. They had to assess different aspects of the tools’ usability on a 5-level Likert scale. Survey results were analyzed in MS Excel, using built-in statistical functions (mean, standard deviation, student’s t-test). Results: Please note the survey is ongoing and results will be updated. Current survey respondents had a base level of awareness of clinical trials (3.1±1.2), with patient associations and the internet as leading information sources. The novel tool seemed to make it easier to find trials (3.7±0.9 vs. 2.7±1.3), showed an improvement in ease of understanding information presented (3.8±1.1 vs. 2.6±1.3) and directionally provided more clarity on what next steps towards trial enrollment would be (4.2±0.8 vs. 3.7±1.4). Overall, this led to higher patient satisfaction (3.4±1.1 vs. 2.3±0.5). Conclusions: Novel patient-focused, AI-driven clinical trial support tools can unlock trial access for all patients. Democratizing trial information will not only increase trial accrual, but also patient satisfaction while reducing disparities. [Table: see text]
Forecasting adverse surgical events using self-supervised transfer learning for physiological signals
Authors: Hugh Chen, Scott M. Lundberg, Gabriel Erion, Jerry H. Kim, Su-In Lee
Journal: npj Digital Medicine (2021)

Hundreds of millions of surgical procedures take place annually across the world, which generate a prevalent type of electronic health record (EHR) data comprising time series physiological signals. Here, we present a transferable embedding method (i.e., a method to transform time series signals into input features for predictive machine learning models) named PHASE (PHysiologicAl Signal Embeddings) that enables us to more accurately forecast adverse surgical outcomes based on physiological signals. We evaluate PHASE on minute-by-minute EHR data of more than 50,000 surgeries from two operating room (OR) datasets and patient stays in an intensive care unit (ICU) dataset. PHASE outperforms other state-of-the-art approaches, such as long-short term memory networks trained on raw data and gradient boosted trees trained on handcrafted features, in predicting six distinct outcomes: hypoxemia, hypocapnia, hypotension, hypertension, phenylephrine, and epinephrine. In a transfer learning setting where we train embedding models in one dataset then embed signals and predict adverse events in unseen data, PHASE achieves significantly higher prediction accuracy at lower computational cost compared to conventional approaches. Finally, given the importance of understanding models in clinical applications we demonstrate that PHASE is explainable and validate our predictive models using local feature attribution methods.