tbuckley/cabot-search huggingface dataset:
Development of a prediction model for lung metastasis by using postoperative circulating tumor DNA binding clinicopathological risk factors in patients with colorectal cancer.
Authors: Bohan Han, Weiyao Li, Jianxia Li, Huabin Hu, Jianwei Zhang, Xiaoyu Xie, Qinli Mo, Yanhong Deng
Journal: Journal of Clinical Oncology (2024)

e15035 Background: Lung metastasis is common in patients with colorectal cancer (CRC). However, diagnosing lung metastasis in CRC is challenging due to slow-growing pulmonary lesions. Circulating tumor DNA (ctDNA) testing provides a direct indication of the presence of minimal residual disease (MRD) which contributing to cancer recurrence. Yet, there are no reports on the potential indications of ctDNA for the site of metastasis. The objective of this study is to develop a predictive model for lung metastasis in CRC patients who have received adjuvant therapy by integrating ctDNA with clinicopathological factors. Methods: Two independent cohorts' series were evaluated including 299 patients from China as training cohort and 134 patients from Spain as validation cohort from 2012-2020. We specifically focused on the detection of ctDNA in these patients. We employed LASSO regression for optimal feature selection and built a predictive model by multivariable logistic regression. Results: In training cohort, 59/299(19.7%) patients have detectable ctDNA. In validation cohort, 24/134 (18.6%) patients have detectable ctDNA. Patients who tested ctDNA-positive had a significantly higher incidence of lung metastasis (33.9% vs. 11.2%, P&lt;0.001) compared to ctDNA-negative patients. A predictive model for lung metastasis was developed by multivariable logistic regression analysis. The model incorporated factors such as ctDNA status, preoperative carcinoembryonic antigen (CEA) level, presence of cancerous nodes, and the mutation status of Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) in plasma. The lung metastasis prediction nomogram demonstrated a favorable ability to distinguish with a concordance index of 0.775 (95% CI: 0.706-0.775) during internal validation. The Hosmer-Lemeshow test, with p-value of 0.967, indicated that prediction nomogram model had a good fit. In addition, the prediction model of validation cohort demonstrated a discriminative performance with a concordance index of 0.724(95% CI: 0.698-0.724). Furthermore, the DCA (Decision Curve Analysis) and CIC (Clinical Impact Curve) in both cohorts indicated that the lung metastasis nomogram exhibited a favorable clinical net benefit. Finally, through multi-model comparison, it was found that the predictive performance of the model, which includes ctDNA and blood PIK3CA mutation status, was significantly superior to all clinical prediction models. Conclusions: A lung metastasis prediction nomogram was developed by integrating postoperative ctDNA and clinicopathological risk factors. The purpose of this nomogram is to assist clinicians in predicting the probability of lung metastasis in patients who have undergone surgery for CRC, with the aim to facilitate prompt intervention.
Circulating tumor cells enumeration and characterization in patients with lung cancer treated with immunotherapy.
Authors: Jacques Raphael, Daniel Adam Breadner, Andrew Warner, Morgan Black, David Goodale, Mark David Vincent, Keith Kwan, Phillip S. Blanchette, Megan Slade, Santosh Gupta, Rick Wenstrup, Alison L Allan
Journal: Journal of Clinical Oncology (2024)

e15030 Background: Programmed death-ligand 1 (PD-L1) is a predictive biomarker for immunotherapy in the treatment of non-small cell lung cancer (NSCLC). Assessing PD-L1 expression from the tumor specimen can be challenging because of tissue accessibility, heterogeneity, and dynamic changes in PD-L1 expression that may impact the status of PD-L1 during disease evolution and treatment. Hence, assessing PD-L1 status from archival tumor might not reflect its actual state on the tumor and having a real-time assessment of its expression with the use of non-invasive techniques such circulating tumor cells (CTCs) is useful. Methods: We conducted a single centre prospective study to detect CTCs in the blood of patients with stage III-IV NSCLC treated with immunotherapy using the standard CellSearch technology for CTC enumeration and the Epic Sciences technology for CTCs enumeration and assessment of PD-L1 protein expression on CTCs. CTCs were detected at baseline before treatment initiation and after 2 cycles of treatment. Study endpoints included CTCs detection and concordance between the 2 technologies, PD-L1 expression assessment on CTCs with the Epic Sciences technology, and concordance with tissue-based expression. Comparisons were made using Pearson correlation coefficient (PCC) and intraclass correlation coefficient (ICC) for count data and percentage of perfect agreement. Results: Between 2019 and 2022, 48 patients treated with immunotherapy were enrolled in the study. The mean ± standard deviation (SD) age was 66.8 ± 10.3 years, 63% were females, 42% received combination chemotherapy and immunotherapy, and 44% had adenocarcinoma histology. The tissue PD-L1 expression was high (≥50%), intermediate (1-49%), and low (&lt;1%) in 36%, 31% and 33% of patients respectively. The mean ± SD baseline CTCs count per 7.5ml was 1.97 ± 4 with CellSearch and 1.38 ± 2.72 per ml with Epic Sciences. After 2 treatment cycles, 22% and 41% of patients had an increase in their CTCs count with CellSearch and Epic Sciences, respectively and 30% and 29% had a decrease in their CTCs. The PCC and ICC for baseline CTCs detected by CellSearch and Epic Sciences were 0.72 and 0.61, respectively and for CTCs detected after 2 cycles of treatment by the 2 technologies were -0.16 and 0.45 respectively. One patient had PD-L1 expression on their CTCs with the Epic Sciences technology and there was no association between the PD-L1 expression on CTCs and on matched tissue samples. Conclusions: This study showed a moderate to strong correlation between the 2 technologies for baseline CTCs detection and moderate to poor correlation for CTCs detection after 2 cycles of therapy. No association was found between CTCs and tissue PD-L1 expression. Future work needs to further investigate the role of PD-L1 expression on CTCs.
Pharmacodynamics of venetoclax plus cirtuvivint a first-in-class splice variant regulator.
Authors: Jeevan P Govindharajulu, Kelly Dougherty, Tiffanie Miner, Melinda G. Hollingshead, Steven Gore, Ralph E. Parchment, James H. Doroshow, Apurva K. Srivastava
Journal: Journal of Clinical Oncology (2024)

e15093 Background: NSC835563 (SM08502, cirtuvivint) is a first-in-class pan CDC-like kinase (CLK) and dual specificity tyrosine kinase (DYRK) inhibitor that targets alternative splicing of genes in multiple pathways and modifies their protein expression. Preclinical screening of hematologic malignancy models has shown sensitivity to cirtuvivint, leading to proposed clinical trials in AML in combinations with venetoclax. We performed pharmacodynamic studies to identify probable mechanisms of combination activity in AML models. Methods: In vivo tolerability, efficacy and pharmacodynamic (PD) studies were performed in two AML xenograft models, MV411 and KG1a in NSG mice, at 6.25-25 mg/kg PO cirtuvivint and 25 mg/kg PO venetoclax. Body weights (BW) and tumor volumes were recorded periodically to assess toxicity and anti-tumor efficacy. Tumor tissue samples were collected at 6 and 24 h post venetoclax to assess PD response. Multiplexed analysis of apoptosis pathway proteins/protein-protein complexes was performed by clinically validated assays (PMID 26446940). Results: Cirtuvivint alone at high doses (25 mg/kg) caused tumor regressions in MV411 but only a modest tumor growth inhibition (TGI) in KG1a, a resistant AM model. Importantly, the lowest dose of 6.25 mg/kg cirtuvivint combined with 25 mg/kg venetoclax led to tumor regression in the MV411 model and a moderate TGI in KG1a. Cirtuvivint alone caused a transient 25% reduction (p&lt;0.05) in Mcl-1 levels at 6 h post dose in MV411. The venetoclax combination triggered a sustained (for 24 h) 50-75% disruption of Bcl-2 and Mcl-1 complexes with Bax and Bim, resulting in &gt;20-fold increased mitochondrial Bax/Bak heterodimer and &gt;10-fold increased cytosolic cleaved caspase-3. In KG1a, combination treatment resulted in only modest (&lt;20%) changes in biomarkers. Overall, biomarkers provided evidence of the combination MoA. Conclusions: Venetoclax and cirtuvivint in combination effectively induced tumor regressions at low tolerable doses in an AML model. Mitochondrial Bax/Bak heterodimer provided a sensitive biomarker of combination activity. Cirtuvivint contributed its combinatorial effect primarily through disruption of Bim complexes and inhibition of Mcl-1. PD biomarkers identified in this study can confirm MoA of drug combination in ongoing clinical trials.
Baseline value and longitudinal kinetics of circulating nucleosomes during neo-adjuvant chemotherapy in newly diagnosed ovarian cancer: Results from the randomized phase II trial CHIVA (GINECO).
Authors: Pauline Corbaux, Olivier Colomban, Gaelle Lescuyer, Christine Haon, Isabelle Laure Ray-Coquard, Gaetan De Rauglaudre, Florence Joly, Cyril Abdeddaim, Pierre Combe, Alain Lortholary, Salima Hamizi, Clothilde Deldycke, Gwenael Ferron, Jérôme Meunier, Jerome Alexandre, Dominique Berton-Rigaud, Marie-Christine Kaminsky, Eric Pujade-Lauraine, Lea Payen, Benoit You
Journal: Journal of Clinical Oncology (2024)

e15029 Background: Nucleosomes (DNA wound around histone proteins) were reported as potential cancer biomarkers (1). The links between circulating nucleosomes and clinical endpoints in advanced ovarian cancer (OC) patients treated with neo-adjuvant chemotherapy (NACT) +/- interval debulking surgery (IDS) were retrospectively assessed in the randomized phase II CHIVA trial (2). Methods: The diagnostic concentration and the longitudinal kinetics of 2 nucleosomes (H3K27 and H3K36, log-scale) were investigated at baseline, during NACT, after IDS, and at progression. The baseline titer measured with Nu.Q prototype immunoassays (H3K27Me3, H3K36Me3 (Belgian Volition SRL, Belgium)) was compared to those of a cohort of 201 cancer-free subjects. Their prognostic values regarding the probability of obtaining a complete IDS and progression-free survival (PFS) were assessed with respect to the modeled CA-125 KELIM (3), classical clinical covariates and treatment arms. The maximum selected rank statistics was used to determine the optimal cut-off at different disease management times. Results: H3K27 and H3K36 nucleosome concentrations were available for 148/188 patients. H3K36 and H3K27 baseline concentrations were correlated and significantly higher in OC patients compared to cancer-free subjects (H3K36, 2.8 vs 2.4 ng/mL, P&lt;0.0001; H3K27, 3.2 vs 2.1, P&lt;0.0001), without difference according to BRCA status. The baseline titer of H3K36 was an independent predictor of the completeness of IDS (OR=0.33; 95% CI=0.13-0.71, p=0.009). The baseline concentration of H3K27 was independently associated with PFS (&lt; or ≥3.8 ng/mL, HR=1.84, 95%CI=1.11-3.02, p=0.016), complementary to the CA-125 KELIM. Both nucleosome longitudinal kinetics showed a decrease during NACT, but there was no significant statistical association between their kinetics and radiological response rate, completeness of IDS or PFS. Conclusions: Baseline values of H3K36 and H3K27 could represent a non-invasive method for detecting OC, with potential relevant prognostic value of initial titers in newly diagnosed OC patients. 1. McAnena, Cancers 2017. 2. Ferron, Gynecol Oncol 2023. 3. You, CCR 2020.
Adverse events of patients treated with antibody-drug conjugates in phase 1 clinical trials at the Royal Marsden Drug Development Unit from 2014 to 2024.
Authors: Harold Nathan Tan, Marta Ascanio Morcillo, Johann S. De Bono, Juanita Suzanne Lopez, Anna Rachel Minchom, Adam Sharp, Alec Paschalis, Udai Banerji
Journal: Journal of Clinical Oncology (2024)

e15020 Background: Antibody-drug conjugates (ADCs) are designed to improve therapeutic indices of cytotoxic agents. Nevertheless, they may induce unexpected toxicities not observed with parent payloads. This study aimed to characterize the adverse events (AEs) seen in patients treated with ADCs in Phase 1 trials at The Royal Marsden Drug Development Unit (DDU). Methods: This is a retrospective cohort analysis of consecutive patients who received at least one dose of an ADC in a phase I trial from January 2014 to January 2024 at The Royal Marsden DDU. Descriptive statistics of patient characteristics, ADCs, and treatment-related AEs were performed. Univariate and multivariate logistic regression will be utilized to assess correlations among patient and ADC characteristics and adverse events. P values of &lt; 0.05 will be considered significant. Results: A total of 131 patients who participated in twelve ADC trials were included. The median age of participants was 63 years (range: 31-84) and 61% were females. Patients received a median of three prior lines of systemic treatment. The most common type of ADC target, antibody, linker and payload were receptor tyrosine kinase (51%), humanized IgG monoclonal antibody (69%), valine-citrulline (VC) cleavable linker (85%), and a tubulin-binding payload (59%), respectively. Most patients received an ADC dose of 1-3 mg/kg (76%) with each cycle given once every 3 weeks (64%). The median number of cycles was 3 with an average treatment duration of 63 days. Within the cohort, 89% of patients developed any grade AE and 17% experienced grade 3 or higher AEs. The major treatment-related AEs were fatigue (48%), nausea/vomiting (27%), ocular toxicity (26%), neuropathy (26%), skin rash (20%) and pneumonitis (8%). The median time to first onset of treatment-related adverse events were 37 days for ocular toxicity, 46 days for pneumonitis, and 54 days for neuropathy. ADC-related AEs led to treatment interruptions (51%), dose reductions (13%), and treatment discontinuations (28%). Two treatment-related grade 5 events occurred. The objective response rate was 18%, with 1 complete response and 22 partial responses. Conclusions: Despite being designed to minimize side effects, ADCs were associated with significant toxicities, including unexpected adverse events unrelated to target, antibodies or the payloads, limiting their therapeutic indices. Further analysis of the relationship between different components of the wide range of ADCs and AEs are warranted to better understand the potential mechanisms of ADC toxicity.
Multidimensional tumor profiling and its meaningful impact on personalized therapy outcomes: Insights from a real-world study.
Authors: Dorthe Schaffrin-Nabe, Tim Crook, Sewanti Limaye, Stefan Schuster, Anke Josten-Nabe, David Reismann, Darshana Patil, Vineet Datta, Adrian Heinze, Merle Schaffrin, Rudolf Voigtmann, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2024)

e15064 Background: This real-world study underscores the transformative potential of multidimensional tumor profiling, including tissue and blood-based markers, in guiding personalized oncology treatments. We established a robust link between comprehensive diagnostics and improved clinical outcomes by correlating extensive profiling data with progression-free survival (PFS), the ratio of PFS2 to PFS1, and comparing these with treatment modalities. Methods: Over five years, 44 patients with advanced-stage solid tumors underwent comprehensive tumor profiling, including genetic markers from tissue and blood, mRNA expression, circulating tumor cells, pharmacogenomics, and immunohistochemistry, to tailor therapies. These multidimensional datasets were rigorously analyzed applying machine learning algorithms against responses to target, chemo, and combo therapies, using robust statistical frameworks to elucidate the impact of advanced diagnostics on therapy effectiveness. Results: Multidimensional tumor testing markedly extended progression-free survival, with median PFS1 and PFS2 at 22.5 and 30 weeks, respectively t(43) = 1.76, p = 0.043, and a significant median PFS2/1 ratio of 1.31. Targeted therapies achieved the highest median PFS2 at 61 weeks, surpassing chemo alone (10.5 weeks) and combination therapy (29.5 weeks) significantly. Patients treated based on gene expression, including mRNA profiling and immunohistochemistry/immunocytochemistry (n = 22), had a median PFS of 37.5 weeks, outperforming those treated based on NGS (n = 12) with 27.5 weeks significantly. Those not fully adhering to guideline treatments due to divergent findings had a median PFS2 of 16.5 weeks. Notably, 26 out of 44 patients with critical illness had a PFS2 over 6 months. Conclusions: A clear linkage was established between comprehensive profiling indicators, including genetic, molecular, and cellular markers, and the observed therapeutic outcomes. The study reaffirms the critical importance of multidimensional tumor profiling in the era of precision oncology. However, we proceed monitoring this growing group of patients to establish a clearer picture how to adapt complex diagnostic tools into modern oncological practice.
Safety, efficacy, pharmacokinetics, and pharmacodynamics of the illudofulvene drug CAP-0121.
Authors: Raymond T. Suhandynata, TK Nguyen, Venkata R. Kotamraju, Jeremiah D Momper, Michael J. Kelner
Journal: Journal of Clinical Oncology (2024)

e15120 Background: Irofulven is an anticancer agent derived from illudin S initially investigated due to its unique mechanism of action and potential to overcome multi-drug resistance. This study investigates the pharmacokinetics/pharmacodynamics (PK/PD) and efficacy and safety of the second-generation drug, CAP-0121 (Califia Pharma). Methods: 24-hour comprehensive PK was performed at two different intravenous (IV) doses in canines for irofulven (0.2 mg/kg and 1 mg/kg; MTD) and CAP-0121 (1 mg/kg and 3 mg/kg). Plasma concentrations were measured by LC-MS/MS and PK parameters were calculated for both drugs using noncompartmental methods (Phoenix WinNonlin, version 8.4). PK parameters included area under the concentration vs time curve (AUC), maximum observed concentration (C max ), clearance (CL), volume of distribution (Vd), and elimination half-life (t 1/2 ). Canine chemistry/hematology/coagulation/urine panels, were measured across 28 days to ascertain the maximum tolerated dose (MTD). Both platelet and neutrophil count reversibility was also assessed. Mice xenograft models implanted with a drug resistant human ovarian cancer (A2870), or a drug-resistant human metastatic lung cancer (MV522), were dosed with irofulven (9 mg/kg; MTD) and CAP-0121 (15, 20, and 25 mg/kg) and resulting tumor mass, % change in body weight, and platelet counts were compared relative to vehicle only. Results: Systemic exposure, CL, Vd, and t 1/2 were similar between irofulven and CAP-0121 at a 1 mg/kg IV dose. For irofulven, AUC increased approximately proportionally at doses of 0.2 mg/kg and 1 mg/kg. For CAP-0121, exposure also increased proportionally at doses of 1 mg/kg and 3 mg/kg. MTD of CAP-0121 was found to be 3-fold higher in canines compared to irofulven as 3-fold more CAP-0121 was required to match the platelet reduction observed with irofulven; platelet and neutrophil nadir was rapidly reversible for CAP-0121. Canine nadir platelets and neutrophil counts were 3-fold higher for CAP-0121 vs irofulven at the same dose (1 mg/kg). There was no evidence of any canine systemic organ toxicity (gross, histologic, blood and urine analysis) for CAP-0121 at either dose. CAP-0121 was superior to irofulven (p &lt; 0.02) with regards to final tumor weights in mice xenograft models, even though MTD was not reached for CAP-0121; a change in body weight and platelet loss was not observed for CAP-0121 at up 25 mg/kg in mice. With regards to in vitro anticancer cytotoxic activity, the two drug-resistant xenograft models confirm the superiority of CAP-0121 over irofulven. This study demonstrates that CAP-0121 has favorable PK parameters and a wider therapeutic window in humans compared to irofulven, emphasizing the potential anticancer utility of CAP-0121 for solid cancers without prolonged thrombocytopenia. Conclusions: Further investigation in clinical trials is warranted to confirm these preclinical observations.
Effects of moderate alcohol consumption and hypobaric hypoxia: implications for passengers’ sleep, oxygen saturation and heart rate on long-haul flights
Authors: Rabea Antonia Trammer, Daniel Rooney, Sibylle Benderoth, Martin Wittkowski, Juergen Wenzel, Eva-Maria Elmenhorst
Journal: Thorax (2024)

Background Passengers on long-haul flights frequently consume alcohol. Inflight sleep exacerbates the fall in blood oxygen saturation (SpO 2 ) caused by the decreased oxygen partial pressure in the cabin. We investigated the combined influence of alcohol and hypobaric hypoxia on sleep, SpO 2 and heart rate. Methods Two groups of healthy individuals spent either two nights with a 4-hour sleep opportunity (00:00–04:00 hours) in the sleep laboratory (n=23; 53 m above sea level) or in the altitude chamber (n=17; 753 hPa corresponding to 2438 m above sea level, hypobaric condition). Participants consumed alcohol before one of the nights (mean±SE blood alcohol concentration 0.043±0.003%). The order of the nights was counterbalanced. Two 8-hour recovery nights (23:00–07:00 hours) were scheduled between conditions. Polysomnography, SpO 2 and heart rate were recorded. Results The combined exposure to alcohol and hypobaric condition decreased SpO 2 to a median (25th/75th percentile) of 85.32% (82.86/85.93) and increased heart rate to a median (25th/75th percentile) of 87.73 bpm (85.89/93.86) during sleep compared with 88.07% (86.50/88.49) and 72.90 bpm (70.90/78.17), respectively, in the non-alcohol hypobaric condition, 94.97% (94.59/95.33) and 76.97 bpm (65.17/79.52), respectively, in the alcohol condition and 95.88% (95.72/96.36) and 63.74 bpm (55.55/70.98), respectively, in the non-alcohol condition of the sleep laboratory group (all p&lt;0.0001). Under the combined exposure SpO 2 was 201.18 min (188.08/214.42) below the clinical hypoxia threshold of 90% SpO 2 compared with 173.28 min (133.25/199.03) in the hypobaric condition and 0 min (0/0) in both sleep laboratory conditions. Deep sleep (N3) was reduced to 46.50 min (39.00/57.00) under the combined exposure compared with both sleep laboratory conditions (alcohol: 84.00 min (62.25/92.75); non-alcohol: 67.50 min (58.50/87.75); both p&lt;0.003). Conclusions The combination of alcohol and inflight hypobaric hypoxia reduced sleep quality, challenged the cardiovascular system and led to extended duration of hypoxaemia (SpO 2 &lt;90%).