tbuckley/cabot-search huggingface dataset:
Prospective cohort of real-world, curative-intent breast cancer treatment patterns in Malawi.
Authors: Jennifer Morgan, Takondwa Zuze, Shekinah Nefreteri Cluff Elmore, Matthew Painschab, Yolanda Gondwe, Richard Nyasosela, Chifundo Kajombo, Agness Manda, Katherine Elizabeth Reeder-Hayes, Tamiwe Tomoka
Journal: Journal of Clinical Oncology (2021)

e18736 Background: Despite increasing availability of curative-intent breast cancer treatment in concordance with the National Comprehensive Cancer Network (NCCN) Harmonized Guidelines for Sub-Saharan Africa (SSA), few descriptions of their application in SSA are available. Our aim was to describe patterns of curative-intent treatment including neoadjuvant (NAC) and/or adjuvant chemotherapy (AdC) and surgery (S) by stage and HIV status, and the association between guideline-concordant treatment completion and overall survival (OS). Methods: We enrolled newly diagnosed breast cancer patients in a prospective cohort study at Kamuzu Central Hospital in Malawi from Dec 2016 – Oct 2018. Unadjusted odds ratios (OR) with 95% CI were calculated to identify factors associated with completion of guideline-concordant treatment, defined as S and at least 4 cycles of NAC or AdC. A logistic regression model was performed using variables with p&lt;0.1. Survival analysis was performed with Kaplan Meier methods and log-rank test. Results: 67 non-metastatic patients were included. 12 (18%) were HIV+; 13 (19%) were Stage II and 54 (81%) Stage III. 46 (69%) began treatment with NAC, of which 39 (85%) were Stage III and 7 (15%) Stage II. 12 (18%) began treatment with S+AdC, of which 5 (42%) were Stage II and 7 (58%) were Stage III. 2 (3%) Stage III patients were treated with palliative chemotherapy (PC). 7 (10%) never received treatment. Overall, 41 (61%) underwent S. In bivariate analysis, factors associated with failure to complete treatment were HIV+ (OR 0.25 CI (0.06-0.99), Stage III (OR 0.10 CI (0.01-0.89) and ER/PR-/HER2+ (OR 0.07 CI (0.01-0.49). In adjusted analysis, ER/PR-/HER2+ (OR 0.12 (0.01-0.97) was associated with failure to complete treatment. HIV+ patients received less NAC than HIV- (2.5 vs 4 cycles; p=0.07) and similar AdC as HIV- (6 vs 6 cycles; p=0.7). Median OS for those who began treatment with NAC was shorter than with S+AdC (28.5 vs 40 months; p=0.01). Median OS for HIV+ vs HIV- who received NAC was 19.7 vs 32.7 months (p=0.10) and received S+AdC was unreached vs 37.1 months (p=0.27). Conclusions: When applying NCCN Harmonized Guidelines for SSA to Malawi, most patients received NAC for curative breast cancer treatment and had significantly shorter OS compared to those receiving upfront S+AdC. Stage III, HIV+, and ER/PR-/HER2+ patients were less likely to complete guideline-concordant treatment which may reflect advanced disease or poor treatment tolerability. Further study is needed to identify barriers to guideline-concordant treatment and inform interventions to improve breast cancer treatment outcomes in Malawi and SSA.[Table: see text]
Interferon γ Enhances the Anti-Myeloma Activity of the Fully Human Anti-HLA-DR Monoclonal Antibody 1D09C3.
Authors: Carmelo Carlo-Stella, Anna Guidetti, Massimo Di Nicola, Cristiana Lavazza, Loredana Cleris, Paolo Longoni, Marco Milanesi, Michele Magni, Zoltan Nagy, Paolo Corradini, Antonino Carbone, Franca Formelli, Alessandro M. Gianni
Journal: Blood (2006)
Anterior uveitis in patients with spondyloarthritis treated with secukinumab or tumour necrosis factor inhibitors in routine care: does the choice of biological therapy matter?
Authors: Ulf Lindström, Karin Bengtsson, Tor Olofsson, Daniela Di Giuseppe, Bente Glintborg, Helena Forsblad-d'Elia, Lennart T H Jacobsson, Johan Askling
Journal: Annals of the Rheumatic Diseases (2021)

The effect of interleukin 17-inhibitors on anterior uveitis (AU) in spondyloarthritis (SpA) is poorly understood. This study aimed to compare the risk of AU during treatment with secukinumab versus tumour necrosis factor inhibitors (TNFi).Patients with SpA starting secukinumab or a TNFi 2015 through 2018 were identified in the Swedish Rheumatology Quality Register. Occurrence of AU was identified based on diagnosis codes in outpatient ophthalmology care in the National Patient Register. The main outcomes were crude rates of AU-diagnoses per 100 patient-years, and adjusted HRs for AU, during treatment, in patients without AU during the year before treatment start (in order to reduce confounding by indication). HRs were adjusted for age, sex, history of AU and patient global assessment of disease activity.Based on 4851 treatment starts (456 secukinumab; 4395 any TNFi), the rate of AU-diagnoses per 100 patient-years was 6.8 (95% CI 5.2 to 8.7) for secukinumab. Among the TNFi, the rate varied from 2.9 (95% CI 2.1 to 3.7) for infliximab and 4.0 (95% CI 3.3 to 4.9) for adalimumab to 7.5 (95% CI 6.7 to 8.4) for etanercept. The adjusted HRs for first AU (adalimumab as reference) were: secukinumab 2.32 (95% CI 1.16 to 4.63), infliximab 0.99 (95% CI 0.49 to 1.96), etanercept 1.82 (95% CI 1.13 to 2.93), golimumab 1.59 (95% CI 0.90 to 2.80) and certolizumab 1.12 (95% CI 0.44 to 2.83). Sensitivity analyses confirmed the pattern of higher AU rates with secukinumab and etanercept versus monoclonal TNFi.As used in clinical practice in SpA, secukinumab appears to be associated with a higher risk of AU, compared with the monoclonal TNFi and a similar risk compared with etanercept.
Incidence of venous thromboembolism in advanced lung cancer and efficacy and safety of direct oral anticoagulant: A multicenter, prospective, observational study (Rising-VTE/NEJ037 Study).
Authors: Yukari Tsubata, Takamasa Hotta, Kosuke Hamai, Naoki Furuya, Toshihide Yokoyama, Ryota Saito, Atsushi Nakamura, Takeshi Masuda, Megumi Hamaguchi, Shoichi Kuyama, Ryoichi Honda, Kikuo Nakano, Masamoto Nakanishi, Masahiro Yamasaki, Nobuhisa Ishikawa, Kazunori Fujitaka, Tetsuya Kubota, Hiroshi Ohtsu, Kunihiko Kobayashi, Takeshi Isobe
Journal: Journal of Clinical Oncology (2021)

12021 Background: Venous thromboembolism (VTE) is a well-known kind of cancer-associated thrombosis and a common complication of malignancy. However, little is known about the incidence of VTE and the effectiveness of direct oral anticoagulants (DOACs) associated with lung cancer chemotherapy. Methods: The Rising-VTE/NEJ037 study was a multicenter, prospective, observational study with 40 participating Japanese institutions. A total of 1,021 patients diagnosed with lung cancer that was unsuitable for radical resection or radiation were enrolled and followed up for two years. The diagnosis of VTE was confirmed through a central review by two radiologists. Patients with VTE at the time of lung cancer diagnosis started treatment with edoxaban. The primary endpoint of this trial was the rate of newly diagnosed VTE after enrollment or the recurrence rate 6 months after the start of treatment with edoxaban. Results: Of the 1,021 enrolled patients, data were available for 1,008 patients. The median age was 70 years (range: 30-94 years), and 70.8% were males. Eighty-six percent of patients had non-small cell lung cancer, and 13.6% had small cell lung cancer. Histological types included adenocarcinoma (N = 641, 63.6%), squamous cell carcinoma (N = 187, 18.6%), and others (N = 42, 4.2%). Sixty-two patients (6.2%) had VTE at the time of lung cancer diagnosis, and 42 patients (4.2%) developed VTE during two years follow-up, making a total of 104 patients (10.3%). No cases of VTE recurrence were found 6 months after the start of treatment with edoxaban. Major and minor bleeding occurred in 95 patients (9.4%) and increased to 23% in the edoxaban treatment group. The two-year survival probability was 0.43 in the non-VTE group and 0.48 in the VTE with edoxaban treatment group, showing no difference. Conclusions: This study shows a high cumulative incidence of VTE, suggesting that attention should be paid to VTE during treatment for lung cancer. Treatment with edoxaban was highly effective in preventing recurrence of VTE, and there was no difference in survival with or without VTE, but treatment should be considered more carefully because of the high bleeding rate associated with DOAC. Clinical trial information: jRCTs061180025.
Combining clinical, radiological and genetic approaches to pneumothorax management
Authors: Hannah L Grimes, Simon Holden, Judith Babar, Sumit Karia, Maria TA Wetscherek, Allanah Barker, Jurgen Herre, Martin D Knolle, Eamonn R Maher, Stefan John Marciniak
Journal: Thorax (2021)

Familial spontaneous pneumothorax (FSP) accounts for 10% of primary spontaneous pneumothoraces. Appropriate investigation of FSP enables early diagnosis of serious monogenic diseases and the practice of precision medicine. Here, we show that a pneumothorax genetics multidisciplinary team (MDT) can efficiently diagnose a range of syndromic causes of FSP. A sizeable group (73.6%) of clinically unclassifiable FSPs remains. Using whole genome sequencing we demonstrate that most of these cases are not known monogenic disorders. Therefore, clinico-radiological assessment by an MDT has high sensitivity for currently known clinically important monogenic causes of FSP, which has relevance for the design of efficient pneumothorax services.
Anti-inflammatory activity of curcumin-loaded tetrahedral framework nucleic acids on acute gouty arthritis
Authors: Mei Zhang, Xiaolin Zhang, Taoran Tian, Qi Zhang, Yuting Wen, Junyao Zhu, Dexuan Xiao, Weitong Cui, Yunfeng Lin
Journal: Bioactive Materials (2021)

Gouty arthritis is a very familiar inflammatory arthritis. Controlling inflammation is the key to preventing gouty arthritis. However, colchicine, the most highly represented drug used in clinical practice, has strict contraindications owing to some severe side effects. Curcumin (Cur), a natural anti-inflammatory drug, has demonstrated good safety and efficacy. However, the rapid degradation, poor aqueous solubility, and low bioavailability of Cur limit its therapeutic effect. To strengthen the effectiveness and bioavailability of Cur. Cur loaded tetrahedral framework nucleic acids (Cur-TFNAs) were synthesized to deliver Cur. Compared with free Cur, Cur-TFNAs exhibit a preferable drug stability, good biocompatibility (CCK-8 assay), ease of uptake (immunofluorescence), and higher tissue utilization (in vivo biodistribution). Most importantly, Cur-TFNAs present better anti-inflammatory effect than free Cur both in vivo and in vitro experiments through the determination of inflammation-related cytokines expression. Therefore, we believe that Cur-TFNAs have great prospects for the prevention of gout and similar inflammatory diseases.
Real-world outcomes of patients with advanced non-small cell lung cancer and driver mutations treated with frontline immunotherapy and/or chemotherapy.
Authors: Bharathi Muthusamy, Nathan A. Pennell, Andrew J. Belli, Eric Hansen, Victoria Devincenzo, Shubha Shankaranarayana, Ming He, Ching-Kun Wang
Journal: Journal of Clinical Oncology (2021)

e21156 Background: The identification of driver mutations and development of targeted therapies have significantly improved outcomes of patients with advanced non-small cell lung cancer (aNSCLC). It has been shown in clinical trials that immunotherapy (IO) has limited effectiveness in patients with aNSCLC and driver mutations, but as there is a lag in the widespread use of targeted agents for newer driver oncogenes it is important to define the efficacy of non-targeted treatments. We sought to explore the real-world treatment patterns and outcomes of patients with aNSCLC and driver mutations treated with first-line (1L) chemotherapy (chemo) as compared to chemo +/- IO. Methods: This retrospective study utilized the COTA real-world database, a de-identified database derived from the electronic health records of healthcare providers in the United States. Patients included in the study had diagnosed aNSCLC and at least one positive test result for BRAF v600, HER2 mutation, EGFR, MET, RET or ROS1 prior to the initiation of 1L therapy. Additionally, patients must have received frontline chemotherapy, IO monotherapy, or IO+chemo combination in the advanced setting. Outcomes to first-line treatment (real-world progression-free survival (rwPFS) and real-world time to next treatment (rwTTNT)) were calculated using the Kaplan-Meier method. Results: A total of 170 qualified patients were identified as having at least one positive mutation and having received frontline chemotherapy (n=119), IO monotherapy (n=28), or chemo+IO combination (n=23). Mean age was 65 yrs and patients were predominantly white (71.2%), treated in the academic setting (74.1%), and denovo metastatic (67.1%). Outcomes to 1L treatment are reported in Table. Patients treated with 1L chemo+IO combination had longer rwPFS and rwTTNT as compared to patients treated with chemo alone or IO monotherapy, though outcomes did not reach statistical significance. Conclusions: Our study showed that in a real-world population of patients with aNSCLC and driver mutations, patients treated with chemo+IO combination had longer rwPFS and rwTTNT as compared to those treated with chemo alone or IO monotherapy. The overall short duration of benefit supports the model of using targeted treatment as optimal first line therapy, and the overall lack of benefit from IO. [Table: see text]
EMBR-13. NOVEL SYNERGISTIC APPROACHES FOR TARGETED THERAPY OF MYC-DRIVEN MEDULLOBLASTOMA USING CRISPR/CAS9 GENE EDITING
Authors: Nan Qin, Daniel Picard, Daniel Rickert, Frauke-Dorothee Meyer, Lena Blümel, Sarah Göbbels, Jasmin Bartl, David Pauck, Ute Fischer, Arndt Borkhardt, Guido Reifenberger, Marc Remke
Journal: Neuro-Oncology (2021)

Abstract Introduction Resistance to chemotherapy is a common cause of treatment failure in cancer patients and a major problem facing current cancer research. Targeted modulation of oncogenic signaling pathways may be used to systematically characterize drug resistance mechanisms across tumor entities and may help to identify new therapeutic strategies. Since the transcription factor MYC is aberrantly activated in many cancers including pediatric malignant brain tumors, like medulloblastoma (MB), our study focused on MYC-related drug resistance. Methods and Results We performed high-throughput drug screening using our in-house semi-automated platform and identified the HDAC inhibitor Entinostat as a drug that shows promising effects in MYC-driven MB. Investigating genome-wide dCas9-based transcriptional activation screening, potential drug response modulators, mainly TGFB1/Erk/MKNK1 signaling including neural EGFL like 2 (NELL2), were discovered. For further validation, we stably overexpressed NELL2 in MYC-driven MB cells and treated overexpressing cells and the corresponding control cells with Entinostat. Using PI staining, cell cycle status was tracked. Entinostat treatment led to modest induction of cell death in MYC-driven MB control cells but only slightly increased cell death rate in MYC-driven MB cells with NELL2-overexpression. Conclusion We report that the combination of genetic and pharmacological approaches is a powerful approach to study drug resistance. Our data suggest that activation of the TGFB1/Erk/MKNK1 signaling pathway desensitizes MYC-driven MB cells to Entinostat. Synergistic targeting of TGFB1/Erk/MKNK1 signaling and MYC could therefore provide a novel therapeutic option in this aggressive MB subtype.
Tissue-specific therapy in immune-mediated kidney diseases: new ARGuments for targeting the IL-23/IL-17 axis
Authors: Christian F. Krebs, Jan-Eric Turner, Jan-Hendrik Riedel, Ulf Panzer
Journal: Journal of Clinical Investigation (2021)

Immune-mediated kidney diseases are a leading cause of end-stage renal disease. Despite recent discoveries, the immunopathogenesis of this heterogeneous disease group remains incompletely understood, which is a major reason for the lack of specific therapies and targeted interventions. Accumulating evidence suggests that cytokines related to the T cell response play an important role in renal autoimmunity. In this issue of the JCI, Li et al. demonstrate that IL-23 directly regulates the metabolism of parenchymal kidney cells, thereby generating a proinflammatory microenvironment that exacerbates T cell-driven renal tissue damage. These findings identify the IL-23/IL-17 axis as a key mediator of renal tissue injury and open new avenues for the development of pathogenesis-based treatment strategies in renal inflammatory diseases.
Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation from HLA-Identical Siblings Versus Unmanipulated Haploidentical Donors in Relapsing or Refractory Acute Myeloid Leukemia: A Retrospective Study from the ALWP of the EBMT
Authors: Giorgia Battipaglia, Ariane Boumendil, Myriam Labopin, Annalisa Ruggeri, Fabio Ciceri, Johanna Tischer, Matthias Stelljes, Gerhard Ehninger, Dietrich W Beelen, Jürgen Finke, Maria Teresa van Lint, Arnold Ganser, Boris Afanasiev, Renato Fanin, Mohamad Mohty, Arnon Nagler
Journal: Blood (2017)
Association of basophil to lymphocyte ratio (BLR) with clinical outcomes in metastatic hormone sensitive prostate cancer.
Authors: Katherine Emilie Rhoades Smith, Limeng Wan, Yuan Liu, Jacqueline T Brown, Greta Russler, Lauren Beth Yantorni, Sarah Caulfield, Bradley Curtis Carthon, Omer Kucuk, Bassel Nazha, Viraj A. Master, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2021)

e17049 Background: There is limited biomarker data available for metastatic hormone sensitive prostate cancer (mHSPC). Inflammatory markers found on routine clinical lab data, including leukocyte to lymphocyte ratios calculated from complete blood counts (CBC), is associated with clinical outcomes (CO) in different malignancies. We investigated the association between basophil-to-lymphocyte ratio (BLR) and CO in a racially diverse patient population with mHSPC. Methods: We performed a retrospective multicenter review from Winship Cancer Institute at Emory University and Georgia Cancer Center for Excellence at Grady Memorial Hospital (2014 – 2020). Demographics, disease characteristics, and laboratory data were collected at the start of upfront therapy with either docetaxel (DOC) or abiraterone (ABI). Overall survival (OS) and progression-free survival (PFS) were used to measure CO. Results: Included were 165 patients with mHSPC with a median follow-up time of 22.6 months. 89 (53.9%) were Black and 76 (46.1%) were Non-Black (White, Asian, or Hispanic). 106 (63%) had Gleason scores of 8-10 and 105 (63.6%) were classified as high-volume disease (per CHAARTED trial criteria). 92 (55.8%) received DOC and 73 (44.2%) received ABI. Worse CO were associated with high BLR at an optimal cut of 0.0265 (range 0 – 0.81 , mean of 0.03, standard deviation 0.09). Elevated BLR is associated with decreased OS (HR 3.51, 1.79 – 6.91, p &lt;0.001) and PFS (HR 1.85, 1.14 – 3.00, p 0.013) in multivariable analyses (MVA). High BLR and low BLR groups were similar except for age as a continuous variable, which was associated with high BLR. Otherwise, there were no significant difference for all reported clinical characteristics, including drug (DOC vs ABI), race (Black vs Non-Black), Gleason, disease volume (per CHARRTED criteria), ECOG, or BMI. Conclusions: In mHSPC, high baseline BLR is associated with worse OS and PFS. Our results are the first to identify that BLR is associated with CO in mHSPC. Further study is needed to validate BLR as a potential biomarker.[Table: see text]
A phase 1 study of an off-the shelf, multi-neoantigen vector (ADXS-503) in subjects with metastatic non-small cell lung cancer (NSCLC) progressing on pembrolizumab as last therapy.
Authors: Missak Haigentz, Suresh S. Ramalingam, Gregory James Gerstner, Balazs Halmos, Neil Morganstein, Surya Vangala, Megan Parsi, Victor Kabala, Dinesh Simkhada, Cristiane Metran, ANDRES A. GUTIERREZ, Jonathan Wade Goldman
Journal: Journal of Clinical Oncology (2021)

2616 Background: ADXS-503 (A503) is an off-the-shelf, attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit potent T cell responses against 22 tumor antigens commonly found in NSCLC (i.e., 11 hotspot mutations and 11 tumor-associated antigens, TAAs). Pembrolizumab (Pembro) is a programmed death receptor-1 (PD-1)- blocking antibody approved for the treatment of advanced lung cancer. A503 and Pembro have complementary mechanisms of immune activation and reversal of immune tolerance. Methods: A phase 1 study of A503 ± Pembro has been conducted in patients (pts) with metastatic squamous or non-squamous NSCLC. In dose-escalation part B, A503 was added-on to Pembro within 12 weeks of the first scan showing disease progression per RECIST criteria v1.1. Both, A503 (1 x10 8 CFU) and Pembro (200 mg) were infused by IV every 3 weeks until disease progression or limiting toxicity. The dose-escalation cohort has established safety, tolerability and immunogenicity of the combination therapy and it has been further expanded to evaluate efficacy (Goldman JW et.al., SITC 2020). Results: Nine pts have been treated and evaluated in Part B. Pembro + A503 combo has been well tolerated and without immune related AEs. Of the nine evaluable pts, one has achieved partial response (PR) and 3 stable disease (SD), yielding an overall response rate (ORR) of 11% and disease control rate (DCR) of 44%. Two patients have had clinical benefit for over 12 months (i.e., one PR and one SD) and both of them had been on Pembro therapy for 2 years before enrollment. The two other pts with SD have sustained it for almost 6 months thus far. Seven pts have been evaluated for immunogenicity. In all pts there was a transient release of pro-inflammatory cytokines and proliferation of cytotoxic- and memory-CD8+ T cells. Seven evaluable pts had antigen-specific T cells within 1-2 weeks after starting therapy and 4/7 showed antigen spreading. Conclusions: ADXS-503 as an add-on therapy to Pembro at disease progression has been well tolerated and it has induced antigen specific-T cell responses and durable disease control in 44% of pts. Part B cohort is currently enrolling additional pts to further explore the potential reversal of Pembro resistance with ADXS-503. Clinical trial information: NCT03847519.