tbuckley/cabot-search huggingface dataset:
FOXO3a elicits a stress-specific cellular response involving the activation of distinct transcription programs
Authors: Oliver Mikse, Daniel Blake, Willard Freeman, Christopher Herzog
Journal: Cancer Research (2008)

3449  Lung cancer is the leading cause of cancer death worldwide, and patients diagnosed with lung cancer have a 5-year survival rate of only 15%. This makes lung cancer one of the deadliest diseases diagnosed today. Cellular pathways that transduce stress responses also regulate the effects of chemotherapy. We recently identified FOXO3a, a member of the forkhead transcription factor family, as a candidate tumor suppressor gene frequently deleted in mouse and human lung adenocarcinomas. Forkhead transcription factors operate as antagonists of the PI3K/Akt cell pro-survival pathway that is activated in response to various cellular stresses, including oxidative stress, DNA damage, and exposure to chemotherapeutic agents. Here we addressed the effect of FOXO3a, and its loss of function, on the response of lung adenocarcinoma cells to different cell stresses including lung carcinogens (BPDE, NNKOAc) and therapeutic agents. We observed the localization of FOXO3a to the nucleus in response to BPDE, NNKOAc, docetaxel, vinorelbine, CL387785 and LY294002 indicating its activation by various stresses. Microarray analysis of FOXO3a transfected cells showed that a FOXO3a-mediated transcriptional program elicited by docetaxel, a disrupter of microtubule dynamics, involved to a significant extent changes in the expression of genes encoding microtubule-related functions. This contrasted with the response to NNKOAc, a DNA damaging lung carcinogen, which resulted in a significant change in expression of DNA binding and DNA repair genes. Further examination of the response to docetaxel showed a FOXO3a-mediated increase in G1 fraction. A similar response to vinorelbine, an inhibitor of microtubule polymerization was observed, suggesting that FOXO3a protects against G2/M damage by arresting cells in G1 phase of the cell cycle. Excessive stress induced by these various agents ultimately caused FOXO3a-mediated increase in apoptosis involving caspase 9 and caspase 7 cleavage. Taken together, our data suggest that FOXO3a is activated by various types of cellular stress causing a rather stress-specific cellular response through FOXO3a transcriptional activity. However, when excessive, these various stress stimuli drive cell death down a common apoptotic pathway that is also enhanced by FOXO3a activation.
A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study first-stage.
Authors: Stefano Tamberi, Elisa Grassi, Jody Corbelli, Giorgio Papiani, Maria aurelia Barbera, Chiara Zingaretti, Chiara Carli Moretti, Isacco Montroni, Elisabetta Petracci, Dora Caruso, Sofia Nosseir, Oriana Nanni, Giovanni Luca Frassineti, Maria Di Bartolomeo, Marina Marzola, Andrea Bonetti, Fabio Gelsomino, Carmine Pinto, Davide Tassinari, Giampaolo Ugolini
Journal: Journal of Clinical Oncology (2021)

3607 Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. Pathologic Complete remission (pCR) can be considered as surrogate end point of efficacy of treatment in terms of disease free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multi-centre study, conducted with support from AstraZeneca, in patient with locally advanced rectal cancer who receive concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is pCR rate after at least 1 cycle of durvalumab. The sample size has been estimated by using the optimal Simon’s two-stage design. If more than 4 complete responses are observed in the first 19 enrolled patients, 36 additional patients will be accrued for a total of 55 evaluable patients. Results: Between November 2019 and July 2020, 20 patients were accrued and 19 were evaluable for study objectives, concluding the first stage of the trial. Baseline characteristics of the first 19 evaluable patients enrolled are listed in the table. All patients received 3 infusions of durvalumab; 18 patients underwent surgery after a median of 13 weeks from CHT/RT end. Five complete pathological responses (ypT0N0) were observed, allowing to proceed to the second stage. About toxicity, four patients had Grade 3-4 adverse events (AE); the most frequent G3-4 AE related to the neoadjuvant therapy were anemia (n=1), diarrhea (n=2) and neuthropenia (n=2). No grade 3 and 4 adverse events related to Durvalumab treatment were observed. Eight patients had G1-2 AE related to durvalumab, the most common being asthenia (n=2) and nausea (n=2). Conclusions: At the end of study’s first stage the preoperative treatment with radiotherapy plus capecitabine followed by durvalumab showed a safe toxicity profile and promising activity in terms of pCR rate. The second part of the trial is ongoing, and the accrual is under completion (44 patients enrolled as of 10 February 2021). Clinical trial information: NCT04083365. [Table: see text]
Comparison of therapy benefit from standard anti-HER2 directed approaches in metastatic breast cancer (MBC) between initially HER2-positive patients and patients initially HER2-negative with switch to HER2-positive.
Authors: Hans-Christian Kolberg, Özlem Yüksel, Peter A. Fasching, Sara Brucker, Hans Tesch, Diethelm Wallwiener, Lothar Haeberle, Markus Wallwiener, Peyman Hadji, Tanja N. Fehm, Wolfgang Janni, Diana Lüftner, Michael P Lux, Johannes Ettl, Andreas D. Hartkopf, Volkmar Müller, Florin-Andrei Taran, Erik Belleville, Alexander Hein, Andreas Schneeweiss
Journal: Journal of Clinical Oncology (2021)

1040 Background: Metaanalyses have demonstrated that 5% of initially HER2 negative breast cancer patients switch to HER2 positive during the course of the disease. Whether there is a difference in benefit from standard HER2 targeted therapies between patients initially HER2 positive and patients switching from negative to positive is unclear. We used data from the PRAEGNANT registry to compare the outcome of those patients. Methods: PRAEGNANT is a prospective advanced breast cancer registry (NCT02338167) focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis compared progression-free survival (PFS) with standard HER2 targeted therapies between patients with tumors initially HER2 negative and switched to HER2 positive and patients with tumors that were initially HER2 positive adjusted for age and hormone receptor status. Results: At the time of this analysis 4061 patients with MBC were included in the PRAEGNANT registry, 49 of which met the requirements for this analysis. Median age was 56 (IQR 48-64) years and 87.8% of the patients were hormone receptor positive. At first diagnosis 15 patients were HER2 negative and 34 patients were HER2 positive. Within a median observation time of 9 months (95%CI: 3.8, 23.7) 35 PFS events occurred. Median observation time was 9 months (95% CI: 3.8, 23.7). Initially HER2 positive patients had a longer progression-free survival (HR = 0.49, 95% CI (0.24, 1.03), p = 0.07) as compared to initially HER2 negative patients switched to HER2 positive. The 1- and 2-year-PFS rates were also higher for patients initially HER2 positive: 1-year-PFS: 52% (95% CI: 36%, 73%) versus 26 % (95% CI: 12%, 52%); 2-year-PFS: 44% (95% CI: 29%, 67%) versus 19% (95% CI: 7%, 50%). Conclusions: Median PFS and 1- and 2-year PFS rate seem to be better in patients HER2 positive at initial diagnosis receiving standard HER2 directed therapies. Although our result has to be interpreted with caution because of the small cohort and the retrospective nature of our analysis, it justifies prospective research including the group of initially HER2 negative patients switched to HER2 positive as a distinct entity. Clinical trial information: NCT02338167 .
A phase II study of anlotinib combined with STUPP regimen in the treatment of patients with newly diagnosed glioblastoma (GBM).
Authors: Peijing Li, Yuan yuan Yuan Chen, Shuzhen Lai, Fagui Jiang, Xiaohui Liu, Changjuan Tao, Lei Wang, Guihong Liu, Jing Huang, Yiqiang Tang, Zhigang Liu, Guoping Shen, Chaoming Li, Tieming Xie, Fangxiao Lu
Journal: Journal of Clinical Oncology (2021)

2039 Background: STUPP regimen is now the standard treatment for newly diagnosed GBM, while the effectiveness is limited. This study assessed the efficacy and safety of anlotinib, a multitarget tyrosine kinase inhibitor, combined with the STUPP regimen in treating these patients. Methods: This is a phase II, multicenter, open-label, single-arm trial (NCT04119674). Thirty-three patients (17 males and 16 females) were enrolled from 8 hospitals in China between January 2019 and February 2021. Inclusion criterion included 1) newly diagnosed histologically confirmed glioblastoma (WHO grade IV), 2) 2-6 weeks (wks) after surgery with healed incision, 3) 18-70 years old, 4) KPS≥60, 5) at least one measurable lesion according to RANO criteria, 6) radiotherapy (RT), chemotherapy, immunotherapy or biotherapy naïve. All patients received 54-60 Gy radiation (1.8-2.0 Gy per fraction, five days per week) concurrently with temozolomide (TMZ, 75mg/m 2 , orally, QD) and anlotinib (8mg, orally, QD, d1-14/3wks). Adjuvant therapy started four weeks after RT completion, including six cycles of TMZ (150-200mg/m², orally, d1-5/4wks) and eight cycles of anlotinib (8mg, orally, QD, d1-14/3wks). Patients who completed adjuvant therapy were administrated anlotinib continuously until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Safety assessment was done in patients who received at least one dose of study agent. Results: The median age is 52 (range 32-69) years. Analyses included data collected through February 6, 2021. The median treatment duration was 6.5 months. The median PFS was not reached, and the median overall survival (OS) was 17.4 months [95%CI 11.6-23.2]. The 1-year PFS and OS rate was 84.0% and 100.0%, respectively. Tumor response occurred in 21 patients, 63.6% (21/33) objective response (CR/PR), and 24.2% (8/33) patients had stable disease (SD).The clinical benefit rate (CBR), defined as the proportion of patients who achieved durable disease control (CR/PR/SD) more than six months, was 57.6% (19/33). Hypertension (6.1%) was the most common ≥grade 3 adverse event. No treatment related death occurred in this study through the last follow-up. Overall, toxicities are mild and manageable. Conclusions: Anlotinib combined with the STUPP regimen is efficacious and well-tolerated in newly diagnosed GBM patients. Clinical trial information: NCT04119674.
Performance of Xpert MTB/RIF Ultra for tuberculosis diagnosis in the context of passive and active case finding
Authors: Belén Saavedra, Edson Mambuque, Dinis Nguenha, Neide Gomes, Shilzia Munguambe, Juan Ignacio García, Santiago Izco, Sozinho Acacio, Adrià Murias-Closas, Marta Cossa, Irene Losada, Hadrián Pernas-Pardavila, Laura Oliveras, Grant Theron, Alberto L. García-Basteiro
Journal: European Respiratory Journal (2021)

Aims We present a field evaluation of the diagnostic accuracy of Xpert MTB/RIF (“Xpert”) and Xpert MTB/RIF Ultra (“Ultra”) using two cohorts in a high tuberculosis/HIV burden setting in Southern Mozambique. Methods Single respiratory specimens from symptomatic adults accessing healthcare services (passive case finding (PCF) cohort) and from household and community close contacts (active case finding (ACF) cohort) were tested by smear microscopy, culture, Xpert and Ultra. Liquid and solid culture served as a composite reference standard. We explored the impact of trace results on specificity via their recategorisation to negative (in all and just among those previously treated individuals). Results 1419 and 252 participants were enrolled in the PCF and ACF cohorts, respectively. For the PCF cohort, Ultra showed higher sensitivity than Xpert overall (0.95 (95% CI 0.90–0.98) versus 0.88 (96% CI 0.82–0.93); p&lt;0.001) and among smear-negative patients (0.84 (96% CI 0.71–0.93) versus 0.63 (96% CI 0.48–0.76)). Ultra's specificity was lower than Xpert's (0.96 (96% CI 0.95–0.97) versus 0.98 (96% CI 0.97–0.99); p=0.008). For ACF, sensitivities were the same (0.67 (95% CI 0.22–0.96) for both tests), although Ultra detected a higher number of microbiologically confirmed samples than Xpert (4.7% (12 out of 252) versus 2.7% (seven out of 252)). Conditional recategorisation of trace results among previously treated participants maintained differences in specificity in the PCF cohort. Conclusion These results add evidence on the improved sensitivity of Ultra and support its use in different case finding scenarios.
Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome
Authors: Mickaël Canouil, Amna Khamis, Elina Keikkala, Sandra Hummel, Stephane Lobbens, Amélie Bonnefond, Fabien Delahaye, Evangelia Tzala, Sanna Mustaniemi, Marja Vääräsmäki, Marjo-Riitta Jarvelin, Sylvain Sebert, Eero Kajantie, Philippe Froguel, Toby Andrew
Journal: Diabetes Care (2021)

OBJECTIVE Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure. RESEARCH DESIGN AND METHODS We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring. RESULTS We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10−2) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. CONCLUSIONS Our study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.
Prevalence of hyperprogressive disease (HPD) mutations and correlations to immune-related biomarkers in a large pan-cancer Chinese cohort.
Authors: Shengli Yang, Xinyi Liu, Ting Bei, Mengli Huang
Journal: Journal of Clinical Oncology (2021)

2649 Background: Immune checkpoint blockade (ICI) therapies have demonstrated inspiring clinical efficacy in multiple types of cancer. However, a subset of patients suffered rapid tumor growth after ICI treatment, which is known as hyperprogressive disease (HPD). Although the mechanism of HPD has not been fully elucidated, some genomic alterations, such as CDKN2A/CDKN2B loss and MDM2/MDM4 amplification were reported to occur in tumors with ICI-related HPD. We analyzed the prevalence of these four “HPD mutations” and their association with PD-L1 expression, TMB, and occurrence of driver gene mutations in a large pan-cancer Chinese cohort. Methods: Patients whose tumor tissues were subjected to molecular profiling using targeted next-generation sequencing from January 2017 – November 2020 were included. Single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels) and fusions were called. PD-L1 expression was stratified by CPS 5. Fisher’s exact test were conducted to compare the frequencies of biomarkers and Mann-Whitney U test was used to compare the TMB level between the “HPD mutations” group and their wild-type counterpart. Results: 45,785 patients of 22 types of cancer were queried. Across all 22 cancers, CDKN2A loss and CDKN2B loss were most commonly seen in ESCA (23.3%, 19.8%), while with the lowest frequency in PRAD (0.18%, 0.18%). MDM2 gain and MDM4 gain occurred most frequently in SARC (14.6%) and BRCA (3.3%), respectively, with the lowest frequency in COAD (0.05%, 0.07%). PD-L1 positive (CPS≥5) rates were similar in CDKN2A/B loss, MDM2/4 amp and wild-type groups in the whole cohort (26.1%, 25%, 27.7%). Enrichment of PD-L1 positivity was not observed in HPD-mutant groups in a specific cancer type. Compared with wild-type group, CDKN2A/B loss significantly correlated with higher TMB levels in NSCLC and SARC (p &lt; 0.05) while MDM2/4 amp correlated with lower TMB levels in NSCLC, BTC, and STAD (p &lt; 0.05). In NSCLC, SNV in EGFR, TP53, KEAP1, NFE2L2, STK11, PIK3CA, and SMARCA4 genes were significantly enriched in the CDKN2A/B loss group, while SNV in EGFR, RBM10, AR, KDR genes, and fusion in RET were significantly enriched in MDM2/4 amp group. Conclusions: HPD mutations were significantly associated with TMB level and occurrence of some driver genes, but were not correlated with PD-L1 expression. Our results revealed the immune-related molecular characteristics in tumors with HPD mutations, providing more insights into the exploration for mechanism of HPD.
Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
Authors: Paul G. Richardson, Shaji K. Kumar, Tamás Masszi, Norbert Grzasko, Nizar J. Bahlis, Markus Hansson, Luděk Pour, Irwindeep Sandhu, Peter Ganly, Bartrum W. Baker, Sharon R. Jackson, Anne-Marie Stoppa, Peter Gimsing, Laurent Garderet, Cyrille Touzeau, Francis K. Buadi, Jacob P. Laubach, Michele Cavo, Mohamed Darif, Richard Labotka, Deborah Berg, Philippe Moreau
Journal: Journal of Clinical Oncology (2021)

PURPOSE The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS). PATIENTS AND METHODS Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point. RESULTS With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age &gt; 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns. CONCLUSION Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.
A phase Ib study of a PI3K<b>δ</b> inhibitor Linperlisib in patients with relapsed or refractory peripheral T-cell lymphoma.
Authors: Jie Jin, Hong Cen, Keshu Zhou, Xiaohong Xu, Fei Li, Tao Wu, Haiyan Yang, Zheng Wang, Zhiming Li, Lugui Qiu, Hanying Bao, Zusheng Xu, Yang Shu
Journal: Journal of Clinical Oncology (2021)

7531 Background: PI3Kδ inhibitors have been shown to have important roles in blocking mitogenic and survival signaling within the tumor cell and the tumor microenvironment and activate antilymphoma immune responses. Linperlisib is an oral highly selective small molecule inhibitor of PI3Kδ and has been demonstrated to be well-tolerated with a favorable PK profile in patients with lymphomas at the RP2D. This phase Ib study is evaluating the efficacy and safety of Linperlisib in relapsed or refractory peripheral T-cell lymphoma (PTCL), a highly aggressive malignancy with few treatment options for patients. Methods: Eligible PTCL patients who must have received at least 1 prior systemic conventional therapy were administrated Linperlisib 80mg orally once daily (RP2D) in 28 days cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Tumor response was assessed by IWG 2007 criteria with CT performed every 2 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoint was toxicity assessed by NCI-CTCAE5.0. Results: As of February 2, 2021, 36 PTCL patients were enrolled in this exploratory trial. Most patients were stage III (38.2%) or IV (50%). Of the 27 evaluable patients to date, the PTCL histologies were PTCL-NOS (n=12), AITL (n=10), ALCL (n=3), NKTCL (n=1) and MEITL (n=1). 19 of the 27 evaluable patients had Investigator confirmed responses for a 70.4% ORR including 25.9% CR (7pt) and 44.4% PR (12pt). In the major subtypes, ORR was 50% (6/12) PTCL-NOS and 80% (8/10) AITL, respectively. A disease control rate of 100% was observed, and most responses occurred by first assessment at C2D28. One subject who had a CR at C2D28 is currently in cycle 9 and continuing on Linperlisib. 36 patients experienced at least 1 AE in the trial, with 95% of AEs ≤ grade 2. Consistent with previously treated lymphoma patients, no unexpected toxicities were observed. The most common TRAEs (≥10%) were neutrophil count decreased (55.6%), leukocyte count decreased (33.3%), hypertriglyceridemia (22.2%), aspartate aminotransferase increased (16.7%), hypercholesterolemia (16.7%), alanine aminotransferase increased (11.1%), creatinine increased (11.1%), rash (11.1%), thrombocyte count decreased (11.1%) and electrocardiogram T wave abnormal (11.1%). No AE grade 4 was observed. 6 patients (16.7%) experienced at least one SAE, in which 4 (11.1%) SAEs were considered to be drug-related, including neutrophil count and leukocyte count decreased (2.8%), gastritis (2.8%), and pneumonia (5.6%). Conclusions: The oral PI3Kd inhibitor Linperlisib had significant activity in patients with relapsed or refractory PTCL. Toxicities with Linperlisib therapy were generally tolerable and manageable. Further efficacy and safety is being evaluated. Clinical trial information: NCT04108325.