tbuckley/cabot-search huggingface dataset:
Predictors of venous thromboembolic complications in patients with pancreatic cancer.
Authors: Oksana V. Katelnitskaya, Oleg I. Kit, Elena M. Frantsiyants, Yuriy A. Gevorkyan, Oleg Yu. Kaymakchi, Aleksandr V. Snezhko, Natalya V. Soldatkina, Vladimir E. Kolesnikov, Andrey V. Dashkov, Sergey I. Poluektov, Maksim K. Aleksandrovich, Dmitry O. Kaymakchi, Vladislav K. Pavlov, Maksim A. Vereshchak, Dmitriy A. Savchenko, Roman E. Tolmakh
Journal: Journal of Clinical Oncology (2021)

e16220 Background: Patients with pancreatic cancer are at high risk for venous thrombosis. Thrombotic episodes are most often recorded at the tumor diagnosis, surgical treatment and chemotherapy courses, or the disease recurrence. This complication postpones the beginning of treatment of the underlying disease and increases the mortality rate of cancer patients. The purpose of the study was to reveal the relationship between clinical characteristics and disorders of hemostasis indicators in patients with pancreatic cancer, and to identify predictors of venous thrombosis. Methods: 246 patients diagnosed with pancreatic cancer were recruited in 2019. The most common histological tumor type was pancreatic ductal adenocarcinoma (91.9%). The most common tumor site was the head of the pancreas (68.3%). Almost half of the patients were initially diagnosed with stage IV cancer (TanyNanyM1). Surgery was performed in 28% of patients. VTEC incidence during the 12-month follow-up period was 15.4%. Results: Analysis of the clinical characteristics and initial hemostasis parameters in patients with and without venous thrombosis revealed that the risk of thrombosis was higher in patients with larger tumors and the presence of distant metastases. High levels of D-dimers at diagnosis doubled the risk of venous thrombosis during antitumor treatment. Conclusions: The most significant predictors of venous thrombosis in patients with pancreatic cancer are tumor size, stage IV, and initially high levels of D-dimer. The study of hemostasis indicators at the stage of diagnosis of pancreatic cancer (D-dimer) can help to identify patients with a high risk of VTEC, for whom anticoagulant prophylaxis with a low hemorrhagic risk is advisable.
KRYSTAL-12: A randomized phase 3 study of adagrasib (MRTX849) versus docetaxel in patients (pts) with previously treated non-small-cell lung cancer (NSCLC) with KRAS<sup>G12C</sup> mutation.
Authors: Tony S. K. Mok, William E. Lawler, Merrill Kingman Shum, Shaker R. Dakhil, Alexander I. Spira, Fabrice Barlesi, Martin Reck, Marina Chiara Garassino, David R. Spigel, Delia Alvarez, Thian Kheoh, William Paxton, Richard C. Chao, Enriqueta Felip
Journal: Journal of Clinical Oncology (2021)

TPS9129 Background: Despite significant advances in chemotherapy and immunotherapy for advanced NSCLC, the majority of pts ultimately develop progressive disease associated with poor outcomes. KRAS is a key mediator of the RAS/MAPK signaling cascade that promotes cell growth and proliferation. KRAS G12C mutations occur in 14% of NSCLC (adenocarcinoma), and mutations in KRAS are associated with a poor prognosis. Although KRAS has historically been undruggable, recent research into the development of agents that specifically bind mutant KRAS has led to the development of direct inhibitors of KRAS G12C . Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRAS G12C that irreversibly and selectively binds to and locks KRAS G12C in its inactive state. Adagrasib was optimized for favorable pharmacokinetic (PK) properties, including oral bioavailability, long half-life (̃24 h), and extensive tissue distribution. Initial results have demonstrated encouraging antitumor activity and tolerability of adagrasib monotherapy in pts with NSCLC harboring a KRAS G12C mutation. Methods: KRYSTAL-12 is a multicenter, randomized Phase 3 study evaluating the efficacy of adagrasib (600 mg BID) vs docetaxel in pts with advanced NSCLC harboring a KRAS G12C mutation who have progressed during or after treatment with a platinum-based regimen and an immune checkpoint inhibitor. The study is designed to demonstrate improvement in the dual primary endpoints of progression-free survival (PFS) and overall survival (OS). Secondary endpoints include safety, objective response rate (ORR) per RECIST 1.1, duration of response (DOR), plasma PK parameters of adagrasib, and patient-reported outcomes (PROs). The study will also explore correlations between gene alterations (at baseline and upon development of treatment resistance) and efficacy. Approximately 450 patients will be randomized in a 2:1 ratio to receive adagrasib or docetaxel and will be stratified by region (United States/Canada vs other countries) and sequential vs concurrent administration of prior platinum-based chemotherapy and anti–PD-1/PD-L1 antibody. The planned sample size is sufficiently powered for the hypothesized treatment effect of the endpoints. Pts will receive study treatment until disease progression, unacceptable adverse events, investigator decision to terminate treatment, or patient withdrawal. This study is currently enrolling and will be open at sites in the United States, Europe, and Asia. Clinical trial information: NCT04685135.
Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian cancer (HGOC).
Authors: Tanya Kwan, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Peter Dean, Nicoletta Colombo, Johanne I Weberpals, Andrew R. Clamp, Giovanni Scambia, Alexandra Leary, Robert W. Holloway, Margarita Amenedo, Peter C.C. Fong, Jeffrey C. Goh, David M. O'Malley, Lara Maloney, Sandra Goble, Jonathan A. Ledermann, Robert L. Coleman
Journal: Journal of Clinical Oncology (2021)

5537 Background: ARIEL3 is a placebo-controlled randomized trial of the PARP inhibitor (PARPi) rucaparib as maintenance treatment in HGOC patients (pts) who responded to the latest line of platinum therapy (NCT01968213). Rucaparib improved progression-free survival (PFS) across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. Methods: Pts were randomized 2:1 to receive rucaparib 600 mg BID or placebo. At the data cutoff of Dec 31, 2019, 33/375 (9%) and 1/189 (0.5%) pts were still ongoing and receiving rucaparib or placebo, respectively. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were compared between pts who derived exceptional benefit (PFS ≥2 yrs), and those with disease progression on first scan (≈12 wks; the short-term [ST] subgroup) within each treatment arm. Results: Of 564 pts, 83 (15%) showed exceptional benefit: 79/375 (21%) in the rucaparib arm and 4/189 (2%) in the placebo arm. Within the rucaparib arm, exceptional benefit pts had more favorable clinical prognostic factors at baseline compared with the ST subgroup (Table). While BRCA mutations were enriched in the rucaparib exceptional benefit subgroup, 34/79 (43%) of these pts were BRCA wild type. Among other biomarkers, RAD51C/D mutations were associated with exceptional benefit; low genome-wide loss of heterozygosity was enriched within the ST subgroup; and high BRCA1 methylation was present at similar fractions. Trends were similar in the placebo arm (Table). Conclusions: Exceptional benefit in ARIEL3 was more common in, but not exclusive to, pts with favorable clinical characteristics and known mechanisms of PARPi sensitivity. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of HGOC pts. Clinical trial information: NCT01968213. [Table: see text]
A prospective data analysis of targeted therapy combined with concurrent radiation therapy for brain metastasis from NSCLC with driver gene mutation.
Authors: Xiaotong Duan, Xiaoxia Zhu, Lijuan Wang
Journal: Journal of Clinical Oncology (2021)

e14006 Background: Previous studies have shown that brain metastases of non-small cell lung cancer (NSCLC) with positive driver genes have poor prognosis. There is still lack of prospective studies on the efficacy and safety of targeted therapy combined with concurrent radiotherapy for brain metastases(BM). Methods: NSCLC patients, with ECOG score 0-2, having MRI confirmed brain or meningeal metastases were eligible. Patients must have driver gene mutation and received corresponding targeted therapy. The intracranial radiotherapy regimen was SRS or whole brain radiotherapy. The primary objective was iPFS (intracranial progression-free survival); Secondary objectives were: iORR (intracranial objective response rate), PFS (progression-free survival), OS (overall survival). MMSE (Mini Mental State Examination) and FACT-Br was carried out before/after weekly radiotherapy and during systematic treatment. Treatment-related toxicities were assessed according RTOG/EORTC criteria. Tumor responses were evaluated using RECIST V1.1 criteria. Survival analysis was performed using the Graphprism version 6.0 by Kaplan-Meier method and log-rank test. Results: 23 NSCLC with BM was included. Among them, 10 patients were newly diagnosed with NSCLC BM. 2 patients’ BM progressed after targeted therapy. 11 NSCLC patients were newly diagnosed with BM after targeted therapy. 91.3% of patients presented an EGFR mutation, including primarily EGFR 19-exon deletion, EGFR 21-L8585R. 11.5% presented with c-MET mutation. Median age was 58.34 yrs(44-71yrs). Patients were mostly treated with Erolotinib and Gefitinib. All patients were adenocarcinoma. At last follow-up, for patients newly diagnosed with NSCLC BM, 8 patients had achieved intracranial progression, and 7 patients had reached OS, of which 1 died before completing WBRT. The median iPFS was 9.3m(95%CI:0.571-4.055) and the median OS was 11.9m (95%CI:0.2752 -2.732). As for patients who progressed after targeted therapy, one patient’s OS was 4.4m, iPFS of the other patient was 3.9m. Among NSCLC patients who were newly diagnosed with BM after targeted therapy, 8 patients had achieved intracranial progression and 5 patients had reached OS. The median iPFS was 6.13m (95%CI:0.247-1.751) and the mOS was 13.8m (95%CI:0.3660-3.634). Common adverse effects include dry skin, fatigue, dizziness, headache, anorexia, and grade I myelosuppression and no serious adverse events (SAEs); MMSE and FACT-Br scores were no significant differences at baseline and follow-up. Conclusions: In stage IV brain metastatic NSCLC with driver gene mutation, targeted therapy combined with concurrent radiotherapy for BM is tolerable, and there is no significant impact on the quality of life and cognitive function after radiotherapy. The evaluation of efficacy requires further follow-up. Support:LC2019ZD009,81972853 and 81572279.
Quantitative immunofluorescence and mRNA analysis of immune-related biomarker groups in matched paired tumor samples from OPHELIA window study in head and neck squamous cell carcinoma (HNSCC).
Authors: Amanda Psyrri, Myrto Moutafi, Georgia-Angeliki Koliou, George Papaxoinis, Niki Gavrielatou, Panagiota Economopoulou, Ioannis Kotsantis, Maria Gkotzamanidou, Maria Anastasiou, Dimitrios G. Pectasides, Aileen Fernandez, Vesal Yaghoobi, Saba Shafi, Ioannis Vathiotis, Thazin Nwe Aung, Stavros Gkolfinopoulos, Periklis Foukas, George Fountzilas, David L. Rimm
Journal: Journal of Clinical Oncology (2021)

6064 Background: Preclinical models suggest that PARP inhibitor-induced DNA damage can promote immune priming through a range of mechanisms including STING pathway activation. PARP inhibition also leads to adaptive upregulation of PD-L1 expression in preclinical models. To understand the distinct effects that different forms of DDR defects may have on tumor immunogenicity we decided to integrate genomic profiling with gene expression profiling and immunohistochemistry (IHC)/fluorescent assessments of PD-L1 expression, CD8 T-cell infiltration, and broad immune infiltrate, in order to define the overlap between DDR and immune-related biomarker groups and to build a deeper understanding of how DNA damage interfaces with antitumor immunity. Methods: 39 patients were enrolled in OPHELIA phase II trial in which pts were randomized 3:3:3:1 to Cisplatin (C) 60 mg/m2 on d1 followed by Olaparib (O) 75mg d 1-5 (Arm A), O 300 mg bid for 21-28 days (Arm B), no treatment (ARM C) or D 1500 mg on d1 followed by O 600 mg daily for 21-28 days (Arm D). PD-L1, STING, Ki67 and γ-H2AX were assessed using quantitative immunofluorescence (QIF). The GeneXpert (GX) closed system real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used for quantitative assessment of CD274 (PD-L1), PDCD1LG2 (PD-L2), CD8A, and IRF1 multiplex mRNA panel in pre- and post-treatment samples. Results: Ki67 was decreased in 23 out of 29 (79.3%) available samples when assessed by QIF; 13 / 23 had a decrease of at least 25%. Δγ-H2AX did not differ among treatment groups. A significant increase was observed in PD-L1 and PD-L2 mRNA levels after treatment with D-O (p = 0.023 and p = 0.016, respectively). An increase trend in posttreatment CD8A mRNA was observed in 23 out of 29 cases in the three treatment arms (p = 0.21, ARM A; p = 0.082, ARM B; p = 0.16, ARM D). IRF1 mRNA and STING protein levels were not upregulated after olaparib- based treatment in the available paired treatment samples. Conclusions: This window study demonstrated a significant upregulation of PD-L1 mRNA, corresponding to our previous data of increased Combined Positive Score (CPS) in the D-O arm post-treatment. Our findings suggest that addition of D to O leads to PD-L1 upregulation. Dual blockade of PARP and PD-1 can boost immune response and antitumor activity in HNSCC. Clinical trial information: NCT02882308.
Toripalimab plus intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma: An open-label single-arm, phase II trial.
Authors: Mingyuan Chen, Yijun Hua, Rui You, Zhi-Qiang Wang, Peiyu Huang, Mei Lin, Yan-Feng Ouyang
Journal: Journal of Clinical Oncology (2021)

6023 Background: Toripalimab is a humanized immunoglobulin G 4 monoclonal antibody against programmed death 1 (PD-1). We aimed to investigate the efficacy and safety of toripalimab in combination with intensity-modulated radiotherapy (IMRT) for recurrent nasopharyngeal carcinoma (rNPC). Methods: We conducted a single-arm, phase II trial with rNPC patients who had biopsy-proven disease and were unsuitable for local surgery. Eligible patients received IMRT in combination with toripalimab administered via intravenous infusion of 240 mg once every 3 weeks for a maximum of seven cycles. The primary endpoint was the objective response rate (ORR). The secondary endpoints included safety profiles, progression-free survival (PFS). Results: Between May 2019 and January 2020, a total of 25 rNPC patients were enrolled (18 men [72.0%] and 7 women [28.0%]; median [IQR] age, 49.0 [43.5-52.5] years). With a median (IQR) follow-up duration of 14.6 months (13.1-16.2) months, 19 patients (79.2%) achieved an overall response, and disease control was achieved in 23 (95.8%) patients at 3 months post radiotherapy. The 12-month progression-free survival was 91.8% (95% CI 91.7% - 91.9%). The incidences of acute (grade ≥3) blood triglyceride elevation, creatine phosphokinase elevation, skin reaction, and mucositis were 1 (4.0%), 1 (4.0%), 2 (8.0%), and 1 (4.0%), respectively. The incidences of late severe (grade ≥3) nasopharyngeal wall necrosis, nasal bleeding, and trismus were 28.0%, 12.0%, and 4.0%, respectively. Conclusions: Toripalimab combined with IMRT was tolerable and showed promising antitumor activity in rNPC patients. Clinical trial information: NCT03854838.
It is time to crowd your cell culture media – Physicochemical considerations with biological consequences
Authors: Dimitrios Tsiapalis, Dimitrios I. Zeugolis
Journal: Biomaterials (2021)

In vivo, the interior and exterior of cells is populated by various macromolecules that create an extremely crowded milieu. Yet again, in vitro eukaryotic cell culture is conducted in dilute culture media that hardly imitate the native tissue density. Herein, the concept of macromolecular crowding is discussed in both intracellular and extracellular context. Particular emphasis is given on how the physicochemical properties of the crowding molecules govern and determine kinetics, equilibria and mechanism of action of biochemical and biological reactions, processes and functions. It is evidenced that we are still at the beginning of appreciating, let alone effectively implementing, the potential of macromolecular crowding in permanently differentiated and stem cell culture systems.
Incidence and severity of systemic allergic reactions (SAR) reported with chemotherapeutic drugs.
Authors: Beulah Elsa Thomas, Anju Murugan, Hrishi Varayathu, Lalram Sangi, Sonia Rani, Shalaka Somayaji, Smruthy Ann Mathew, Hephzibah Sara Mathew, Sunny Kumar Gupta, Dr Goutham Kumar, Priyank Tripathi, Suhail Sayeed Mufti, Radheshyam Naik, Basavalinga Sadasivaiah Ajaikumar
Journal: Journal of Clinical Oncology (2021)

e18802 Background: SAR, a known adverse event of cancer therapy has variable severity. Despite the availability of many approved grading tools, there is still a lack of a globally applicable grading system. To address this, World Allergy Organization (WAO) created a uniform 5-grade classification system which was modified recently to be applicable for all SAR’s. This study aims to understand the incidence and severity of chemotherapy induced SAR and overall response rate (ORR) of rechallenged drugs in a tertiary cancer center. Methods: A retrospective single centered analysis of 103 patients with chemotherapy induced SAR was carried out. Patients were stratified based on age, gender, drugs given, dose number and severity of reaction. We used Modified WAO Grading System for assessing the severity. Descriptive statistics was applied to decipher the data. ORR is defined as the proportion of patients who have a partial or complete response to rechallenged drugs using RECIST Criteria for solid tumors and Lugano Classification for lymphoma. Results: Among 103 patients who reported SAR, 63.1% were female and 64.1% patients were less than 60 years of age. Among the 22 drugs, median dose number was high for Oxaliplatin (6) and Carboplatin (5). SAR was more observed with Paclitaxel (20.39%), Carboplatin (17.48%) and Rituximab (13.59%). However, carboplatin and rituximab had more incidence of grade 1 SAR(25.92% and 29.63% respectively). Grade 1 SAR (39.80%) were reported the highest followed by grade 3 (29.13%), grade 5 (13.59%), grade 2 (11.65%), and grade 4 (5.83%). Cetuximab precipitated the most grade 5 reactions (33.33%). Among patients exhibiting SAR with Paclitaxel, 42.86% were switched to alternatives, Nab-paclitaxel (28.57%) being preferred the most. Carboplatin was changed to cisplatin in 16.66% patients and Nanosomal docetaxel lipid suspension replaced docetaxel in 42.86% patients who reported SAR with carboplatin and docetaxel respectively. Rituximab was rechallenged the most (11.65%) off which one patient had reaction. ORR was observed to be 62.5% and 50% among rechallenged Paclitaxel and Rituximab respectively. The incidence of SAR is depicted in the below table. Conclusions: The study inferred that most SAR reactions occurred with Paclitaxel and Carboplatin. Oxaliplatin and Carboplatin presented with delayed SAR. Grade 1 and grade 3 reaction were relatively more. Cetuximab reported the most grade 5 reactions. ORR of rechallenged drugs should be monitored in further larger studies.[Table: see text]
Liver regeneration after radiotherapy in patients with hepatocellular carcinoma: A simple-to-use model and nomogram.
Authors: Ting-Shi Su, Li-Qing Li, Shi-Xiong Liang
Journal: Journal of Clinical Oncology (2021)

e16115 Background: In the past clinical practice of radiotherapy for liver cancer, liver regeneration (LR) which is beneficial to the prevention or recovery of radiation-induced liver injury, has not received enough attention. In current study, we aimed to build and validate multivariate model for liver regeneration after radiation therapy for hepatocellular carcinoma (HCC) based on data from 2 prospective studies. Methods: Thirty patients treated with preoperative downstaging radiotherapy were prospectively included in the training cohort, and 21 patients treated with postoperative adjuvant radiotherapy were included in the validation cohort. Liver regeneration was defined as an increase of more than 10% of normal liver volume in the areas of the protected hepatic segment or lobe, without Child-Pugh class decreased and tumor progression compared to pre-radiotherapy. Model and nomogram of liver regeneration after radiotherapy were developed and validated. The cut-off points of each optimal predictors were obtained using receiver-operating characteristic analysis. Risk stratification based on the cut-off point was conducted to compare the proportion of patients with liver regeneration between subgroups. Results: After radiotherapy, 12 (40%) cases in the training cohort and 13 (61.9%) cases in the validation cohort experienced liver regeneration. The model and nomogram of liver regeneration based on SVs20 (standard residual liver volume spared from at least 20 Gy) and alanine aminotransferase (ALT) showed good prediction performance (AUC = 0.759) in training cohort and performed well (AUC = 0.808) in the validation cohort. The risk stratification according to the cutoffs of SVs20 with 303.4 mL and ALT with 43 U/L demonstrated clear differentiation in risk of liver regeneration between the training(P = 0.049) and entire cohort (P = 0.032). The proportion of patients with liver regeneration decrease progressively with 88.9% in high-probability group (ALT＜43 U/L and SVs20＜303.4 mL), 60% in high-intermediate probability group (ALT ≥43 U/L and SVs20＜303.4 mL), 43.75% in low-intermediate probability group (ALT＜43 U/L and SVs20≥303.4 mL) and 33% in low- probability group (ALT≥43 U/L and SVs20≥303.4 mL). Conclusions: SVs20 and ALT are optimal predictors for liver regeneration. This simple-to-use nomogram is beneficial to the constraints of normal liver outside the radiotherapy target area and make prognosis-based decision without complex calculations. Clinical trial information: ChiCTR1800015350. [Table: see text]