tbuckley/cabot-search huggingface dataset:
LGG-16. TO BE PRECISE - KNOW YOUR TARGETS: INSTITUTIONAL EXPERIENCE WITH TUMOR TARGETED THERAPY FOR RECURRENT/PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA AND PLEXIFORM NEUROFIBROMA
Authors: Mackenzie Silverman, Joseph Piatt, Andrew Walter, Rahul Nikam, Gurcharanjeet Kaur
Journal: Neuro-Oncology (2021)

Abstract Introduction The oncogenic drivers of pediatric CNS tumors are rapidly being identified with the implementation of high throughput genetic screening. Precision medicine approaches to treatment have shown promising results, but data remains limited in the community oncology setting. We aim to describe our institutional experience using targeted therapies for plexiform neurofibroma and recurrent/progressive pediatric low-grade glioma (pLGG). Methods We performed a retrospective chart review of all patients treated with tumor targeted therapies for recurrent/progressive pLGG and plexiform neurofibroma over the past 5 years. Results Ten patients treated with tumor targeted therapies were identified. Regimens included combination Dabrafenib and Trametinib (n=3), Trametinib monotherapy (n=2), Selumetinib (n=3), Vemurafenib (n=1), and Larotrectinib (n=1). Median age at therapy initiation was 11.5 years (range 1.1 - 18 years). Tumor molecular status included BRAFV600E mutation (n=4), NF1 mutation (n=2), KIAA1549-BRAF fusion (n=1), NACC-NTRK fusion (n=1), and FGFR1 mutation (n=1). Patients trialed an average of 2 treatment regimens prior to targeted therapy initiation (range 0–5). Mean duration of therapy was 14.5 months (range .5–33 months) with 8 patients remaining on treatment. Based on modified RANO criteria, responses included partial (n=1), stable disease (n=8), and progressive disease (n=1). Progressive disease was noted after 4 months of treatment with Dabrafenib and Trametinib combination therapy, but rate of tumor growth was decreased. Subjective functional improvement was seen in 50% of patients. The most common toxicities included rash (n=5) and pyrexia (n=2). Trametinib was discontinued in one patient due to intra-tumoral hemorrhage of unclear etiology. Conclusion Treatment of pediatric CNS tumors with targeted agents appears to be feasible and efficacious in the community oncology setting. Multi-institutional clinical trials are currently ongoing for each of these therapies. There remains a need for community oncology institutional data regarding their use.
Incidence of hepatitis associated with addition of immune checkpoint blockade to conventional solid tumor therapy: A meta-analysis of phase 3 randomized clinical trials.
Authors: Yu Fujiwara, Nobuyuki Horita, Ho Namkoong, Hirotaka Miyashita, Matthew Harrington, Matt D. Galsky
Journal: Journal of Clinical Oncology (2021)

2645 Background: Immune checkpoint blockade (ICB) has emerged as a promising treatment strategy for many solid tumors. Although safe for many patients, ICB causes immune-related adverse events (irAEs) including hepatitis, which may result in morbidity and treatment disruption. Severe hepatitis requires immunosuppression, including corticosteroids and mycophenolate mofetil. We conducted a meta-analysis of clinical trials to investigate the effect of adding ICB to conventional solid tumor therapy on the incidence of hepatitis. Methods: Phase 3 randomized clinical trials (RCTs) comparing ICB and conventional therapy to conventional therapy alone were chosen by database search on PubMed, Embase, Web of Science, and Cochrane Library. The odds ratios [OR] of any-grade and grade ≥3 hepatitis, elevated aspartate aminotransferase (AST), and elevated alanine aminotransferase (ALT) were calculated. Meta-analysis was conducted to determine the incidence of hepatitis, elevated AST, and elevated ALT among patients receiving ICB and those receiving conventional therapy alone. Subgroup analysis based on the mechanism of ICB (Cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] inhibitor, programmed cell death protein 1 [PD-1] inhibitor, and programmed death-ligand 1 [PD-L1] inhibitor) was also conducted. Results: A total of 29 randomized controlled trials (RCTs) enrolling 18,829 participants were analyzed. Incidence of hepatitis was derived from 24 RCTs enrolling 15,183 patients, and incidence of grade ≥3 hepatitis was derived from 22 RCTs enrolling 13,846 patients. Incidence of elevated AST was extracted from 18 RCTs, and incidence of elevated ALT was extracted from 20 RCTs. Addition of ICB to conventional therapy was associated with an increase in incidence of any-grade hepatitis (OR 2.54, 95% confidence interval [CI] 1.82-3.55) and grade ≥3 hepatitis (OR 4.22, 95% CI 2.51-7.11). The addition of ICB was also associated with an increase in incidence of elevated AST (any grade: OR 2.19, 95% CI 1.59-3.03; grade ≥3: OR 3.18, 95% CI 1.85-5.48) and elevated ALT (any grade: OR 2.08, 95% CI 1.47-2.92; grade ≥3: OR 2.41, 95% CI 1.40-4.14). Subgroup analysis based on the mechanism of ICB demonstrated increased incidence of grade ≥3 hepatitis associated with CTLA-4 inhibitor, PD-1 inhibitor, and PD-L1 inhibitor therapy (OR 2.78, 95% CI 1.26-6.14; OR 6.30, 95% CI 2.23-17.78; OR 4.73, 95% CI 1.83-12.23, respectively). No significant difference of heterogeneity was observed among subgroups ( I 2 = 0%, p = 0.43). Conclusions: Addition of ICB to conventional solid tumor therapy was associated with increased incidence of any-grade and severe hepatitis, and elevations of AST and ALT, regardless of the mechanism of ICB. Clinicians should weigh the risk of liver toxicity when considering addition of ICB therapy in patients with solid tumors.
Taletrectinib (AB-106; DS-6051b) in metastatic non-small cell lung cancer (NSCLC) patients with ROS1 fusion: Preliminary results of TRUST.
Authors: Caicun Zhou, Huijie Fan, Yongsheng Wang, Huijuan Wu, Nong Yang, KunYan Li, Xicheng Wang, Xintian Qin, Qitao Yu, Yong Fang, Min Tao, Xue Meng, Baohui Han, Xiaorong Dong, Bing Yan
Journal: Journal of Clinical Oncology (2021)

9066 Background: Taletrectinib (AB-106; DS-6051b) is a potent, selective ROS1/NTRK inhibitor. In two phase I trials, NSCLC patients (pts) with ROS1 fusion who received taletrectinib as first line ROS1 TKI had an objective response rate (ORR) of 66.7% (6/9) and median progression-free survival (PFS) of 29.1 mo (Sai-Hong Ignatius Ou et al., JTO Clinical and Research Reports, 2020). TRUST (NCT04395677) is an ongoing, multicenter, phase II study of taletrectinib in Chinese NSCLC pts with ROS1 fusion. Methods: The ROS1 TKI naïve or crizotinib pre-treated NSCLC patients with ROS1 fusion were treated with taletrectinib 400 or 600 mg QD. ROS1 testing was performed in each center and confirmed by central lab using RT-PCR. The primary endpoint was ORR (complete response [CR] + partial response [PR]) by IRC assessment. Secondary endpoints were disease control rate (DCR; CR + PR + stable disease), PFS and safety, etc. The pharmacokinetics (PK) of taletrectinib following 400 or 600 mg QD regimen was also evaluated. Results: As of the data cutoff (15 Jan 2021), 22 pts had received taletrectinib treatment. Median age was 54.5 years (range, 32-77 years;); 18.2% (4/22) had central nervous system metastases; ECOG performance status was 0 in 13.6% (3/22) of pts and 1 in 86.4% (19/22) of pts. Most pts (54.5%, 12/22) had prior systematic chemotherapy; 31.8% (7/22) of pts had prior crizotinib treatment. ORR by investigator among the crizotinib naïve pts with tumor assessment (N = 11) was 100% (95% CI, 72%-100%); 81.8% (18/22) of pts had treatment-emergent adverse events (TEAEs), including nausea, vomiting, diarrhea, transaminase elevation, white blood cell count decrease/neutrophil count decrease, etc. 13.6% (3/22) were grade ≥ 3, including fatigue (4.5%, 1/22), white blood cell decrease (4.5%, 1/22) and transaminase elevation (4.5%, 1/22).TEAEs led to dose interruption in 3 pts (13.6%), including dose reduction in 2 pts (9.1%). Taletrectinib in plasma approximately reached steady state on Cycle 1 Day 8 with 2- to 3- fold accumulations of exposure, which was consistent with results observed in the phase I trials. Conclusions: Taletrectinib demonstrated promising clinical activity with high ORR and good tolerability in ROS1 fusion positive NSCLC patients. The safety and PK profiles following taletrectinib treatment was generally consistent with the phase I trials. Clinical trial information: NCT04395677. Clinical trial information: NCT04395677.
背景,CAG知見,心不全及び心室性不整脈と遅延ガドリニウム増強MRIにより評価した微小血管閉塞との関係
Authors: Kawade Masafumi, Teraoka Kunihiko, Suzuki Yoshinori, Takazawa Kenji, Yamashina Akira
Journal: Circulation (2010)
Anti-tumor effects of duramycin-IgG conjugate
Authors: Jin He, Philip E. Thorpe
Journal: Cancer Research (2004)

4561  Duramycin is a nonadecapeptide antibiotic obtained from Streptoverticillium Cinnamomeus which recognizes strictly the structure of phosphatidylethanolamine (PE) and forms an equimolar complex with the phospholipids on biological membranes. The molecule has a high amount of cross-linking, including thioester linkage of lanthionine and an imino bridge of lysinoalanine which may account for its unique stability. Duramycin forms aqueous pores in the membranes after its binding to PE. It shows hemolytic activity against erythrocytes of various animal species. We hypothesized that PE, like phosphatidylserine, would become exposed on tumor vasculature as a result of exposure to stress conditions in the tumor microenvironment. It is known that PE as well as PS is exposed on the cell surface during the early stages of apoptosis, resulting in the loss of asymmetric distribution of phospholipids in the plasma membrane bilayer. To detect cell surface phosphatidylethanolamine, we generated duramycin-IgG conjugate which retains its PE binding capacity while losing its hemolytic effect. The mouse IgG2a was used as the carrier protein to bring host defenses to act against cells that bind duramycin-IgG. Duramycin mouse IgG2a conjugate bound effectively to the apoptotic cell surface, but not to non-apoptotic cells. The binding to apoptotic cells was not uniform and the intense staining was observed on surface blebs of apoptotic cells. The conjugate enhanced the phagocytosis of apoptotic cells by murine bone-marrow derived macrophages in vitro. After intravenous injection into mice bearing solid tumors, duramycin-IgG localized to tumor endothelium. Between 15% and 40% of tumor blood vessels were stained. Necrotic regions of tumors were also stained. In contrast, none of the blood vessels in normal tissues were stained. The duramycin-IgG conjugate inhibited the growth of syngeneic MethA tumors in BALB/c mice. No toxicity was observed in mice treated with the conjugate. Histological examinations of mouse MethA tumors from duramycin-IgG treated mice revealed large numbers of macrophages in the tumor interstitium and attachment to the tumor endothelium. Conclusion: Duramycin-IgG is a promising reagent for clinical studies of cancer patients.
Trends in incidence and mortality of squamous cell carcinoma of the skin: An observational analysis of the Global Burden of Disease database from 1990 to 2017.
Authors: Dorothy Yang, Chinmay Jani, Conor Crowley, Richard Goodall, Joseph Shalhoub, Justin D Salciccioli, Dominic C Marshall
Journal: Journal of Clinical Oncology (2021)

10569 Background: Epidemiological data relating to non-melanoma skin cancer (NMSC), including squamous cell carcinoma (SCC), is highly under-reported and under-studied due to its lower metastatic potential. In recent years, incidence and prevalence of SCC has increased in many countries due to earlier detection, increased ultraviolet light exposure, as well as increasing life expectancy. This investigation compared trends in SCC incidence, mortality and disability-adjusted life years (DALYs) in 33 countries. Methods: We utilized the Global Burden of Disease (GBD) database for 33 countries, including the European Union nations as well as other selected high-income countries including the UK and USA. We extracted data including age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs) and DALYs for SCC of the skin from 1990 to 2017. Joinpoint regression analysis was used to describe the trends. Results: For both sexes, the highest ASIRs were seen in the USA and Australia: ASIRs were 362.8/100,000 and 283.7/100,000 respectively for males, and 171.2/100,000 and 152.4/100,000 respectively for females. Males had higher ASIRs than females at the end of the observation period in all countries. In contrast, the highest ASMRs for males were observed in Australia (2.77/100,000) and Latvia (2.44/100,000), while the highest ASMRs for females were observed in Romania (0.95/100,000) and Croatia (0.90/100,000). The highest DALYs for both sexes were seen in Australia and Romania: DALYs were 58.4/100,000 and 43.8/100,000 respectively for males, and 16.9/100,000 and 14.9/100,000 respectively for females. Over the observation period, there were more countries demonstrating decreasing trends in mortality than in incidence. There was also a disparity between which countries had comparatively high mortality rates and which had high incidence rates – for instance, the USA, which had by far the highest SCC incidence rates, had among the lower mortality rates. Overall reductions in DALYs were observed in 24 of 33 countries for males, and 25 countries for females. Conclusions: Over the past 27 years, although trends in SCC incidence have risen in most countries, there is evidence that mortality rates have been decreasing, especially towards the end of the observation period. Overall, burden of disease as assessed using DALYs has decreased in the majority of countries. Future work will explore potential explanatory factors for the observed disparity in trends in SCC incidence and mortality.
Response rates in acute myeloid leukemia patients treated with attenuated durations of venetoclax in combination with hypomethylating agents.
Authors: Dena Blanding, Bakos Keegan Jonathan, Christopher Andrew Rangel, Sarah Pasyar, Elizabeth Goodwin Hill, James Davis, Brian T. Hess, Praneeth Baratam, Irl Brian Greenwell
Journal: Journal of Clinical Oncology (2021)

e19008 Background: The combination of the Bcl-2 inhibitor, venetoclax, with hypomethylating agents (HMA) recently emerged as an efficacious treatment for older adults with acute myeloid leukemia (AML) who are not eligible for intensive induction therapy. In a phase III randomized controlled trial of HMA +/- venetoclax, DiNardo et al demonstrated impressive composite complete response rate and complete response with incomplete recovery (CR+CRi) of 66% in the venetoclax arm as compared to 28% in the placebo arm. Despite HMA/Venetoclax being lower intensity, 83% of patients developed grade 3 hematologic adverse events, and 42% of patients experienced febrile neutropenia in the venetoclax arm, as compared to 19% in the placebo arm. In the trial, venetoclax was given continually for 28 day cycles, with some patients receiving shortened durations of venetoclax (21 days) due to toxicity. To reduce toxicity, some institutions have further limited the duration of venetoclax in cycle 1. Here, we report response rates with attenuated durations of venetoclax with HMA. Methods: We conducted a retrospective study of AML patients who received venetoclax in combination with HMA, excluding those with prior chemotherapy for AML or MDS, or previous exposure to HMA or venetoclax. Demographic, cytogenetic, pathology, and outcome data were collected including bone marrow biopsy results at diagnosis and after cycle 1 (day +28) or cycle 2 (day +56). The primary outcome was composite response rate (CR+CRi) following cycle 1 or cycle 2 defined by 2017 ELN criteria. Results: 25 patients were identified with median age of 73 (range 63-82). 9 patients received 14 or less days of venetoclax (attenuated duration): &lt; 8 days in 1 patient and 8-14 days in 8 patients. 16 patients received 21 days or more (standard duration): 21 days in 14 patients, and 28 days in 2 patients. Of the patients who received an attenuated duration, the median age was 74 (68-82), 22% had either a TP53 mutation or deletion, 56% had complex karyotype, and 44% had received prior cytotoxic chemotherapy. Of the patients who received standard duration therapy, the median age was 71 (63-81), 44% had either a TP53 mutation or deletion, 75% had complex karyotype, and 6% had received prior cytotoxic chemotherapy. The composite response rate was 78% in the attenuated duration group and 75% in the standard duration group (p &gt; 0.99). Conclusions: Though a limited sample size, this data suggests high response rates can be observed with attenuated courses of venetoclax. With appropriately selected patients, the feasibility of attenuated venetoclax courses could be further explored in larger prospective studies.[Table: see text]
Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade
Authors: Chi Yan, Nabil Saleh, Jinming Yang, Caroline A. Nebhan, Anna E. Vilgelm, E. Premkumar Reddy, Joseph T. Roland, Douglas B. Johnson, Sheau-Chiann Chen, Rebecca L. Shattuck-Brandt, Gregory D. Ayers, Ann Richmond
Journal: Molecular Cancer (2021)

Abstract Background While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy. Methods Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAF wt and BRAF mut melanoma and analyzed in reference to patient data. Results RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8 + cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40 + SOX10 + melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB. Conclusions Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone. Trial registration NCT01205815 (Sept 17, 2010). Graphical abstract
Neoadjuvant programmed death-1 blockade plus chemotherapy in locally advanced esophageal squamous cell carcinoma.
Authors: Xu Zhang, Guozhen Yang, Xiaodong Su, Guangyu Luo, Peiqiang Cai, Yating Zheng, Ting Bei, Chan Gao, Mengli Huang
Journal: Journal of Clinical Oncology (2021)

e16076 Background: Immunotherapy is effective in treating advanced esophageal squamous cell carcinoma (ESCC), but little is known about its role in the setting of neoadjuvant therapy. Methods: Data from a retrospective cohort and a prospective cohort of locally advanced ESCC patients were analyzed. All patients included had received neoadjuvant camrelizumab plus nab-paclitaxel and S1 capsule followed by radical esophagectomy. The main purpose of this study was to evaluate the safety and feasibility of the neoadjuvant treatment. In addition, pathological response and the relationship between tumor immune microenvironment features (TIME)/tumor mutational burden (TMB) and treatment response were also explored. Results: A total of 25 locally advanced ESCC patients from both cohorts were included, of which 12 from the retrospective cohort and 13 from the prospective cohort. Only two patients experienced grade 3 or 4 adverse events, including onehad anemia and the other (4%) had limb numbness. No surgical delay or perioperative death was reported. Sixteen patients (64%) responded to the treatment, eight (32%) with a complete pathological response and eight (32%) with a major pathological response. Neither programmed death-ligand 1 expression nor TMB was correlated with treatment response. In terms of TIME analysis, patients with better pathological response in the primary tumor had significantly higher abundance of CD56 dim natural killer cells (109 vs 32, P= 0.01), while lower density of M2-tumor-associated macrophages was associated with numerically better pathological response in the lymph nodes (47 vs 163.1, P= 0.55). Conclusions: Neoadjuvant camrelizumab plus nab-paclitaxel and S1 is safe, feasible and effective, and the efficacy could be predicted by TIME, which is worthy of further investigation. Clinical trial information: ChiCTR2000029807.
Selenium Nanoparticles for Biomedical Applications: From Development and Characterization to Therapeutics
Authors: Cláudio Ferro, Helena F. Florindo, Hélder A. Santos
Journal: Advanced Healthcare Materials (2021)

Abstract Selenium (Se) is an essential element to human health that can be obtained in nature through several sources. In the human body, it is incorporated into selenocysteine, an amino acid used to synthesize several selenoproteins, which have an active center usually dependent on the presence of Se. Although Se shows several beneficial properties in human health, it has also a narrow therapeutic window, and therefore the excessive intake of inorganic and organic Se‐based compounds often leads to toxicity. Nanoparticles based on Se (SeNPs) are less toxic than inorganic and organic Se. They are both biocompatible and capable of effectively delivering combinations of payloads to specific cells following their functionalization with active targeting ligands. Herein, the main origin of Se intake, its role on the human body, and its primary biomedical applications are revised. Particular focus will be given to the main therapeutic targets that are explored for SeNPs in cancer therapies, discussing the different functionalization methodologies used to improve SeNPs stability, while enabling the extensive delivery of drug‐loaded SeNP to tumor sites, thus avoiding off‐target effects.