tbuckley/cabot-search huggingface dataset:
Cytokines performance during nivolumab treatment: A subgroup analysis of NIVACTOR study.
Authors: Nerina Denaro, Matteo Paccagnella, Danilo Galizia, Antonella Falletta, Andrea Abbona, Loretta Gammaitoni, Erika Fiorino, Lorena De Zarlo, Paolo Bossi, Dario Sangiolo, Lisa F. Licitra, Massimo Aglietta, Marco Carlo Merlano
Journal: Journal of Clinical Oncology (2021)

e18008 Background: Nivolumab is approved for 2 nd line R/M SCCHN, but only ̃20% of patients will benefit. Therefore, there is an unmet need for predictive markers. Nivactor is a prospective real-life study of nivolumab in SCC-HN. We report an ancillary study on circulating cytokines in a subgroup of patients from Nivactor. Methods: We analysed changes of circulating cytokines (IL-2/4/5/6/8/10/12/13/15, CCL-2/4/22, CXCL-10, IFN-γ, TGF-β, TNF-α, VEGF) during nivolumab therapy at baseline (T0), cycle 3 (T1), cycle 7 (T2) and at disease progression (TPD). ROC analysis identifies cytokines that correlate best with PFS and OS and calculate cut-off points. Cox analysis was performed to assess HR. Hierarchical Clustering on Principal Components (HCPC) was performed to cluster pts and then compared clusters for good or poor PFS and OS. Correction for multiplicity was applied. Results: 19 pts were analysed. Using ROC analysis, we were able to identify cut-off values correlated with PFS at T0 only for IL-6 and IL-10. Similarly, we identified IL-6, IL-10, TGF-β and VEGF cut-off for OS. Then we performed Cox analysis dividing the population based on the identified cut-offs and we found that pts with IL-6 or IL-10 lower than cut off had a significant better PFS and OS (p = 0.049 and p = 0.003 for PFS, respectively; p = 0.029 and p = 0.006 for OS, respectively). TGF-β lower than cut-off correlates with better OS (p = 0.02). Interestingly, pts with all the 3 cytokines below the cut-off show the best OS. Finally, we performed a multivariate analysis using HCPC to identify 4 clusters of pts. Cluster 2 has the best PFS and OS than all other cluster considered together (p = 0.001 and p = 0.004 respectively). Patients in cluster 2 show at T0 lower IL-6/10/15 and at T1 lower IL-5/10 and higher IFN-γ compared to the others. Longitudinal analysis among the 3 time points shows that the increase of IFN-γ, IL-5 and IL-10 between T0 and T1 correlates with better PFS (p = 0.01, p = 0.03, p = 0.02, respectively); only IFN-γ and IL-5 correlates with better OS (p = 0.04; p = 0.02, respectively). Conclusions: ROC analysis can identify cytokines whose basal level may predict patients that could benefit from nivolumab treatment: low IL-6 and IL-10 positively influence both PFS and OS. Low TGF-β does not correlate with PFS but only with better OS and can be considered a pure prognostic marker. Longitudinal analysis offers information on the effect of treatment on circulating cytokines, and show that the subgroup of pts with better PFS exhibits an increase of inflammatory cytokines values.
Phase 2 Study of Adjuvant Radiotherapy Following Narrow‐Margin Hepatectomy in Patients With HCC
Authors: Bo Chen, Jian‐Xiong Wu, Shu‐Hui Cheng, Li‐Ming Wang, Wei‐Qi Rong, Fan Wu, Shu‐Lian Wang, Jing Jin, Yue‐Ping Liu, Yong‐Wen Song, Hua Ren, Hui Fang, Yuan Tang, Ning Li, Ye‐Xiong Li, Wei‐Hu Wang
Journal: Hepatology (2021)

Background and Aims Surgical resection is the primary treatment for HCC; however, it is associated with a high rate of recurrence and death. We conducted this phase 2 study to investigate the efficacy and safety of postoperative intensity‐modulated radiotherapy (IMRT) for HCC after narrow‐margin hepatectomy. Approach and Results We designed a single‐arm, prospective phase 2 trial to evaluate overall survival (OS), disease‐free survival (DFS), recurrence patterns, and toxicity in patients receiving adjuvant radiotherapy. The eligibility criteria included the following: pathological diagnosis of HCC after hepatectomy, with narrow pathological margins (&lt; 1 cm); age &gt; 18 years; and Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients received IMRT within 4‐6 weeks after surgical resection. This trial was registered at ClinicalTrials.gov (NCT01456156). Between 2008 and 2016, a total of 76 eligible patients who underwent narrow‐margin resection were enrolled. The median follow‐up duration was 70 months; the 3‐year OS and DFS rates were 88.2% and 68.1%, respectively; and the 5‐year OS and DFS rates were 72.2% and 51.6%, respectively. Intrahepatic recurrence was the primary recurrence pattern. No marginal recurrence was found. Intrahepatic, extrahepatic, and combined recurrences at the first relapse were found in 33, 5, and 1 patient, respectively. The most common radiation‐related grade‐3 toxicities were leukopenia (7.9%), elevated alanine aminotransferase (3.9%) and aspartate aminotransferase (2.6%) levels, and thrombocytopenia (1.3%). Classical or nonclassical radiation‐induced liver disease was not noted. Conclusions Adjuvant radiotherapy is an effective, well‐tolerated, and promising adjuvant regimen in patients with HCC who have undergone narrow‐margin hepatectomy. Our trial provides evidence and a rationale for planning a future phase 3 trial.
Gene Fusions Create Partner and Collateral Dependencies Essential to Cancer Cell Survival
Authors: Riaz Gillani, Bo Kyung A. Seong, Jett Crowdis, Jake R. Conway, Neekesh V. Dharia, Saif Alimohamed, Brian J. Haas, Kyuho Han, Jihye Park, Felix Dietlein, Meng Xiao He, Alma Imamovic, Clement Ma, Michael C. Bassik, Jesse S. Boehm, Francisca Vazquez, Alexander Gusev, David Liu, Katherine A. Janeway, James M. McFarland, Kimberly Stegmaier, Eliezer M. Van Allen
Journal: Cancer Research (2021)

Abstract Gene fusions frequently result from rearrangements in cancer genomes. In many instances, gene fusions play an important role in oncogenesis; in other instances, they are thought to be passenger events. Although regulatory element rearrangements and copy number alterations resulting from these structural variants are known to lead to transcriptional dysregulation across cancers, the extent to which these events result in functional dependencies with an impact on cancer cell survival is variable. Here we used CRISPR-Cas9 dependency screens to evaluate the fitness impact of 3,277 fusions across 645 cell lines from the Cancer Dependency Map. We found that 35% of cell lines harbored either a fusion partner dependency or a collateral dependency on a gene within the same topologically associating domain as a fusion partner. Fusion-associated dependencies revealed numerous novel oncogenic drivers and clinically translatable alterations. Broadly, fusions can result in partner and collateral dependencies that have biological and clinical relevance across cancer types. Significance: This study provides insights into how fusions contribute to fitness in different cancer contexts beyond partner-gene activation events, identifying partner and collateral dependencies that may have direct implications for clinical care.
Outcomes of active cancer patients with COVID-19 infection treated with COVID-19 neutralizing monoclonal antibodies.
Authors: Justin Shaya, Aaron Lee, Angelo Cabal, Rana R. McKay
Journal: Journal of Clinical Oncology (2021)

3137 Background: Treatment with COVID-19 (C19) neutralizing monoclonal antibodies (mAbs), including bamlanivimab and casirivimab/imdevimab, has been associated with decreased rates of C19-related hospitalizations in high-risk patients. Patients with active cancer are at high-risk for C19 complications and currently are candidates for C19-mAbs. Little is known about C19-related outcomes with mAb therapy in cancer patients. Here, we examine the outcomes of a cohort of active cancer patients infected with C19 who were treated with C19-neutralizing mAbs. Methods: Retrospective, single center cohort of patients with active cancer and mild-moderate C19 infection not requiring hospitalization who were treated with either bamlanivimab or casirivimab/imdevimab. Active cancer was defined as a solid or hematologic malignancy diagnosed within 90 days of C19 diagnosis or recurrent/metastatic disease. The primary endpoint was the rate of C19-related hospitalization. Secondary endpoints included the rate of C19-related mortality and adverse events associated with mAb therapy. Results: We identified 38 active cancer patients with C19 who were treated with mAbs. Median age was 65 years (range 20-89) and 47.4% (N = 18) had a hematologic malignancy. Among the cohort, 73.7% (N = 28) were on an anti-cancer therapy at the time of C19 diagnosis: targeted therapy (n = 18), cytotoxic chemotherapy (N = 5), immunotherapy (n = 3), or hormonal therapy (n = 2). 42.1% (N = 16) received bamlanivimab and 57.9% (N = 22) received casirivimab/imdevimab. Median time from C19 diagnosis to mAb infusion was 2 days (range 0-6 days). With a median follow-up of 21 days (range 7-71), 7.9% (N = 3) required hospitalization for C19-related complications. Median time from mAb infusion to hospitalization was 25 days (range 5-29). C19-related deaths occurred in 5.3% (N = 2) of the cohort. No significant adverse events were reported with either mAb formulation. Conclusions: Among a cohort of high-risk cancer patients treated with mAbs, rates of hospitalization and mortality due to C19 were low compared to previously described rates among active cancer patients. Key limitations of this analysis include the lack of a control group for comparison and a small sample size given the recent emergency use authorization of these agents. Given the high mortality rate of active cancer patients with C19, these data support the use of mAbs in cancer patients with C19.
Human papillomavirus seroprevalence in pregnant women following gender-neutral and girls-only vaccination programs in Finland: A cross-sectional cohort analysis following a cluster randomized trial
Authors: Penelope Gray, Hanna Kann, Ville N. Pimenoff, Tiina Eriksson, Tapio Luostarinen, Simopekka Vänskä, Heljä-Marja Surcel, Helena Faust, Joakim Dillner, Matti Lehtinen
Journal: PLoS Medicine (2021)

Cervical cancer elimination through human papillomavirus (HPV) vaccination programs requires the attainment of herd effect. Due to its uniquely high basic reproduction number, the vaccination coverage required to achieve herd effect against HPV type 16 exceeds what is attainable in most populations. We have compared how gender-neutral and girls-only vaccination strategies create herd effect against HPV16 under moderate vaccination coverage achieved in a population-based, community-randomized trial.
A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors
Authors: Jia Zhou, Camille Gelot, Constantia Pantelidou, Adam Li, Hatice Yücel, Rachel E. Davis, Anniina Färkkilä, Bose Kochupurakkal, Aleem Syed, Geoffrey I. Shapiro, John A. Tainer, Brian S. J. Blagg, Raphael Ceccaldi, Alan D. D’Andrea
Journal: Nature Cancer (2021)
CVTree: A Parallel Alignment-Free Phylogeny and Taxonomy Tool Based on Composition Vectors of Genomes
Authors: Guanghong Zuo
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Composition Vector Tree (CVTree) is an alignment-free algorithm to infer phylogenetic relationships from genome sequences. It has been successfully applied to study phylogeny and taxonomy of viruses, prokaryotes, and fungi based on the whole genomes, as well as chloroplast genomes, mitochondrial genomes, and metagenomes. Here we presented the standalone software for the CVTree algorithm. In the software, an extensible parallel workflow for the CVTree algorithm was designed. Based on the workflow, new alignment-free methods were also implemented. And by examining the phylogeny and taxonomy of 13,903 prokaryotes based on 16S rRNA sequences, we showed that CVTree software is an efficient and effective tool for studying phylogeny and taxonomy based on genome sequences. The code of CVTree software can be available at https://github.com/ghzuo/cvtree.
The effect of body mass index on efficacy and safety of bosutinib or imatinib in patients with newly diagnosed chronic myeloid leukemia.
Authors: Tim H. Brümmendorf, Jorge E. Cortes, Lambert Busque, Carlo Gambacorti-Passerini, Leif Stenke, Andrea Viqueira, Eric Leip, Simon Purcell, Michael W Deininger
Journal: Journal of Clinical Oncology (2021)

7037 Background: Bosutinib (BOS) is approved for the treatment (Tx) of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Body mass index (BMI) was shown to influence Tx response with front-line dasatinib vs imatinib (IMA). We report the efficacy and safety of BOS and IMA by BMI in patients (pts) with newly diagnosed CP CML. Methods: In the open-label BFORE trial, pts were randomized to receive 400 mg once daily BOS or IMA. Outcomes were assessed according to baseline BMI ≥25 or = 25 kg/m 2 . This post hoc analysis was based on the final 5-y analysis (database lock: June 12, 2020). Results: In the BOS and IMA arms, respectively, 149 (56.4%) vs 115 (43.6%) pts and 145 (54.3%) vs 122 (45.7%) pts had BMI ≥25 vs = 25. In both the BOS and IMA arms, median Tx duration and time on study was 55 mo for pts with BMI ≥25 or = 25; respective median dose intensity was 394 vs 393 mg/d and 400 vs 400 mg/d. Molecular response (MR) rates are shown in the table. Cumulative incidence of major MR was similar in pts with ≥25 vs = 25 receiving BOS (HR 0.99; 95% CI 0.74−1.31) or IMA (HR 1.09; 95% CI 0.81−1.47). Event-free survival (EFS) and overall survival (OS) rates at 60 mo are shown in the table. Most common reasons for Tx discontinuation were adverse events (AEs) (BOS 28.2 vs 20.0%; IMA 13.3 vs 10.7%) and lack of efficacy (BOS 5.4 vs 5.2%; IMA 16.1 vs 19.8%). In pts with BMI ≥25 vs = 25, dose reductions and interruptions due to Tx-emergent AEs (TEAEs) occurred in 43.6 % vs 46.2% and 66.4% vs 69.7% of pts with BOS and 24.5% vs 24.6% and 40.6% vs 50.8% with IMA. Any grade TEAEs in ≥30% of pts with BMI ≥25 vs = 25 were diarrhea (73.8 vs 73.1%), nausea (40.9 vs 31.9%), thrombocytopenia (30.9 vs 41.2%), increased alanine (37.6 vs 28.6%) and aspartate aminotransferase (30.2 vs 20.2%) with BOS and diarrhea (49.0 vs 29.5%), nausea (46.2 vs 37.7%), muscle spasms (33.6 vs 26.2%), neutropenia (14.7 vs 32.0%) and thrombocytopenia (10.5% vs 30.3%) with IMA. Conclusions: Efficacy of BOS was consistent in pts with BMI ≥25 or = 25; however, with IMA a low (vs high) BMI appeared to be associated with worse survival outcomes. Differences in certain TEAEs were observed between BMI subgroups in both treatment arms. Clinical trial information: NCT02130557. [Table: see text]
Inhibition of histone lysine demethylases with TACH101, a first-in-class pan-inhibitor of KDM4.
Authors: Chandtip Chandhasin, Sanghee Yoo, Joselyn Del Rosario, Young K Chen, Jeffrey Stafford, Frank Perabo, Michael F. Clarke
Journal: Journal of Clinical Oncology (2021)

3105 Background: The KDM4 family of histone lysine demethylases consists of four main isoforms (KDM4A, B, C, D), all of which have been identified as key oncogenic drivers. They function as epigenetic regulators and control transitions between transcriptionally silent and active chromatin states via removal of methyl marks on histone H3K9 and histone H3K36. KDM4 isoforms play an important role in the epigenetic dysregulation in various cancers and is linked to more aggressive disease and poorer clinical outcomes. Functional redundancy and cross-activity have been observed across KDM4 family members, thus, selective inhibition of one isoform appears to not be effective. TACH101 is a novel, first-in-class pan inhibitor of KDM4 that simultaneously targets multiple isoforms of KDM4. Here we present data that show TACH101 has promising pre-clinical and pharmacologic properties as a cancer therapeutic. Methods: TACH101 was evaluated in in vitro and in vivo studies including cell-proliferation assays in multiple cancer cell lines, apoptotic and cell cycle analyses, and efficacy studies in various xenograft tumor models and patient-derived organoid models. Results: In vitro, TACH101 was broadly effective in killing 67% (200 out of 300) of cancer cell lines screened. TACH101 demonstrated potent increase of H3K36me3 levels (EC50 &lt; 0.001 mM, HTRF) in KYSE-150 cell line engineered to overexpress KDM4C and potent anti-proliferative activity in multiple cell lines in OncoPanel. TACH101 treatment increased cancer cell population in S-phase in multiple cancer cell lines indicating cell-cycle arrest. TACH101 induced apoptosis in human colorectal (HT-29), esophageal (KYSE-150), and triple negative breast cancer (MDA-MB-231) cell lines with EC50s ranging from 0.033-0.092 µM. In vivo, TACH101 triggered effective tumor control in xenograft models including colorectal, esophageal, gastric, breast, and lymphoma with tumor growth inhibition of up to 100%. Further evaluation using a panel of patient-derived colorectal models and patient-derived organoids showed a strong correlation of TACH101 sensitivity with MSI-H status (IC50 ranges 1-150 nM). TACH101 also reduced tumorigenic potential by 4.4-fold as determined by FACS analysis using sorted CD44High EpCAM+ population in Limiting Dilution Assays in vivo, suggesting that reduction of cancer stem cells by TACH101 may be effective in therapy-resistant settings. Pharmacologic studies showed TACH101 demonstrated favorable cell permeability, good oral bioavailability, and high metabolic stability. Conclusions: Extensive preclinical work on TACH101 KDM4 inhibitor shows compelling data and broad applicability as a potential anti-cancer agent. Further evaluation is ongoing to advance the molecule into clinical trials.
A NIR fluorescent probe for Vanin-1 and its applications in imaging, kidney injury diagnosis, and the development of inhibitor
Authors: Zhenhao Tian, Fei Yan, Xiangge Tian, Lei Feng, Jingnan Cui, Sa Deng, Baojing Zhang, Tian Xie, Shanshan Huang, Xiaochi Ma
Journal: Acta Pharmaceutica Sinica B (2021)

Vanin-1 is an amidohydrolase that catalyses the conversion of pantetheine into the amino-thiol cysteamine and pantothenic acid (coenzyme A precursor), which plays a vital role in multiple physiological and pathological processes. In this study, an enzyme-activated near-infrared (NIR) fluorescent probe (DDAV) has been constructed for sensitively detecting Vanin-1 activity in complicated biosamples on the basis of its catalytic characteristics. DDAV exhibited a high selectivity and sensitivity toward Vanin-1 and was successfully applied to the early diagnosis of kidney injury in cisplatin-induced kidney injury model. In addition, DDAV could serve as a visual tool for in situ imaging endogenous Vanin-1 in vivo. More importantly, Enterococcus faecalis 20247 which possessed high expression of Vanin-1 was screened out from intestinal bacteria using DDAV, provided useful guidance for the rational use of NSAIDs in clinic. Finally, oleuropein as a potent natural inhibitor for Vanin-1 was discovered from herbal medicines library using a high-throughput screening method using DDAV, which held great promise for clinical therapy of inflammatory bowel disease.
COVID-19 related outcomes for hospitalized patients (pts) with solid malignancies (SM).
Authors: Jeffrey Chi, David Chitty, Nina Kohn, Janice Shen, Carlos Alberto Lopez, Adam Hines, Vernon Wu, Jung-In Yang, Bradley Harris Goldberg, Wasif M. Saif
Journal: Journal of Clinical Oncology (2021)

e18626 Background: Pts with malignancies are at risk for developing severe complications of COVID-19 with high mortality rate. We retrospectively analyzed COVID-19 related outcomes for hospitalized pts with SMs. Methods: We collected data on hospitalized pts with SMs and COVID-19 from 3/1/20 to Jan 1/1/21. Diagnosis COVID-19 was confirmed by RT-PCR of nasopharyngeal swabs. We assessed the association between the 30-day mortality and potential prognostic variables such as tumor types, cancer status, timing of treatment, types of anticancer therapy using logistic regression analyses. Results: A total of 246 hospitalized pts with SMs had COVID-19. Median age was 70 years, 87 (35%) were ≥75 years, 151 (61%) were female. The most common SMs were breast (56 [23%]), non-small cell lung (44 [18%]) and colon (31 [13%]). 154 (63%) pts were on active anticancer therapies. Of those 88 (35.5%) received treatment within 2 weeks, 16 (16.5%) within 4-12 weeks, 99 (39.9%) &gt;3 months prior to COVID-19 diagnosis. 101 (65%) pts received cytotoxic chemotherapies, 26 (16.8%) received immune check point inhibitors (ICIs), 17 (11%) received targeted agents such as anti-EGFR therapy and 11 (7.1%) received monoclonal antibodies. Overall 30-day mortality was 42%, however, all pts with melanoma (7/7) died. The 30-day mortalities for pts who received anticancer treatments within 4 weeks, 4-12 weeks and &gt;12 weeks of COVID-19 diagnosis were 47%, 50%, and 37%. For pts who never received treatment, 30-day mortality was 31%. For pts were in remission, stable disease and progressive disease, the 30-day mortalities were 32%, 35% and 62%. The 30-day mortalities for pts who received cytotoxic therapy, monoclonal antibodies, targeted therapies and ICIs, were 38%, 46%, 41% and 69%. Logistic regression analysis showed that pts who were &gt;80 years of age (OR 3.6, 95% CI 1.6-8.1), had progressive disease (OR 3.4, 95% CI 1.8-6.5) or treated with ICIs (OR 3.6, 95% CI 1.5-8.7) were associated with higher 30-day mortality. Conclusions: COVID-19 associated 30-day mortality is high for hospitalized pts with SMs. Early surveillance of clinical deterioration could be helpful for hospitalized SMs pts with risk factors identified here. Further studies are needed to discern the observed association between ICIs use and worse COVID-19 outcome.[Table: see text]