tbuckley/cabot-search huggingface dataset:
Co-treatment of human GBM cell lines with imipridone ONC206 and tumor treating fields: Effect on on cell death and p-AKT.
Authors: Vida Tajiknia, Wafik S. El-Deiry, Maximilian Schwermann, William J. MacDonald, Nolan Stubbs
Journal: Journal of Clinical Oncology (2024)

e14033 Background: Glioblastoma (GBM) is the most common primary brain malignancy with dismal prognosis. Tumor Treating Fields (TTFields) therapy is available for the treatment of both newly diagnosed and recurrent glioblastoma and represents a new category of treatment modalities in oncologic therapy. Despite decades of study, few FDA approved modalities are available for GBM and provide limited survival improvements for patients. AKT functions as a key serine/threonine kinase in the RTK/PTEN/PI3K pathway, and extensive genomic analysis of GBM has revealed that this pathway is mutated in a significant majority of GBM cases. Activation of this pathway ultimately leads to the activation of AKT, and phospho-AKT levels are elevated in the majority of GBM tumor samples and cell lines. Studies have shown that increased p-AKT levels contribute to uncontrolled growth, resistance to apoptosis, and enhanced invasive capabilities of glioma cells, which are characteristics of tumor progression in GBM. AKT serves as a critical hub in this pathway, enabling the amplification of growth signals, thereby making the inhibition of AKT an appealing and promising therapeutic target for treating GBM. Imipridone ONC206 is under clinical development for treatment of pediatric and adult patients with primary brain tumors (NCT04732065 and NCT04541082). Here we show inhibition of p-AKT as well as upregulation of cleaved PARP following cotreatment of ONC206 and TTFields. Methods: We investigated the effect of ONC206 at IC50s plus TTFields in LN229, U138, U251 and T98G human GBM cell lines at different time points. Effect of treatment on cPARP, BCL-2, CHOP, caspase-10, and p-AKT were investigated using western blot. Results: Treatment with ONC206 at the IC50 in T98G cells with TTFields at 24h showed synergistic upregulation of cPARP as well as inhibition of BCL-2. At 96hour time point, inhibition of p-AKT was observed following all treatments (ONC206, TTFields, and co-application compared to control. In U251 cells, following treatment of ONC206 and TTFields, inhibition of BCL-2 was observed at 24h time point. Upregulation of CHOP and Casapse-10 at 96h time point was seen, as well as inhibition of p-AKT. Spheroid models showed structure disruption and growth arrest following combination treatment. At 72 h time point co treatment with ONC206 and TTFields resulted in synergistic upregulation of cleaved PARP. Conclusions: Here we showed cotreatment with TTFields and ONC206 results in inhibition of p-AKT, the key node in GBM growth pathway. This is the first report of cleaved PARP upregulation following TTFields and ONC206 in Human GBM cell line. Further studies to investigate the in vivo efficacy of TTField treatment in GBM with ONC206 are warranted. More studies are needed to understand the exact mechanism of synergy.
Epidemiological investigation of neuroendocrine differentiation in carcinomas: Focus on pancreatic and cholangiocarcinoma cohorts.
Authors: Yaru Wen, Susheng Shi
Journal: Journal of Clinical Oncology (2024)

e16375 Background: Neuroendocrine differentiated (NED) occurs in various non-neuroendocrine organs and is associated with unique clinical profiles, disease progression, and poorer prognosis. However, global research on NED is scarce. To address this, our study utilized standardized detection methods to explore NED's prevalence in several solid tumors. This research aims to clarify NED pathological characteristics and prognostic significance, enhancing diagnostic and treatment approaches in clinical practice. Methods: Patients (18-75 years) with cancers including pancreatic, cholangiocarcinoma, gastric, colorectal, lung, breast, and prostate, were analyzed post-surgery at our hospital (January 2017- June 2018). Criteria for inclusion were normal organ function and no pre-surgery neoadjuvant therapy. Tumors were staged postoperatively using AJCC 8th criteria (stages I-III), followed by standard adjuvant chemotherapy. NED markers like Chromogranin A, Synaptophysin, and CD56 were detected in tumors via immunohistochemical staining. Results: Between January 2017 and June 2018, over 450 cases were enrolled. Initial analysis included 46 pancreatic cancer and 49 cholangiocarcinoma samples. NED markers were found in 11 (23.9%) of the pancreatic cancer patients, comprising 5 Syno (+), 10 ChrA (+), and 1 CD56 (+) cases. In cholangiocarcinoma patients, 12 (24.5%) expressed NED markers, including 4 Syno (+) and 11 ChrA (+) cases. Conclusions: This study reveals a significant occurrence of neuroendocrine differentiation in pancreatic cancer and cholangiocarcinoma. The notable prevalence of NED underscores its potential as a reference for tailoring clinical treatments. The association between NED and patient prognosis warrants further investigation.
Bi-institutional spline curve analysis of lymph node mapping in gallbladder cancer operated over 12 years: Impact of location and number of lymph nodal stations.
Authors: Shraddha Patkar, Prabhat Ghanshyam Bhargava, Vikas S. Ostwal, Anant Ramaswamy, Swapnil Patel, Mahesh Goel
Journal: Journal of Clinical Oncology (2024)

e16274 Background: Current staging system for gallbladder cancers (GBC) takes into account only the number of metastatic lymph nodes without addressing their location. The current study evaluates the prognostic impact of lymph node mapping (number and location) in node positive GBCs. Methods: Prospectively maintained operative database of GBC patients with positive lymph nodes were analysed from two tertiary cancer care centers in a retrospective cohort study design between April 2010 till March 2022. Nodal burden was assessed including both, the number of metastatic nodes and the lymph node station. Impact of lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS) was evaluated using regression and spline curve analysis. Results: Amongst 1312 operated GBC patients, 272 patients with node positive disease were included. The median nodal yield was 8. The median LNR and LODDS was 0.222 and -0.48 respectively. The 5-year DFS and OS for patients with only cystic node metastases was 52.3% and 50.8% respectively (median: not reached), as compared to 24.6% and 35.2% for involvement of regional nodal stations beyond cystic nodes. Higher LODDS was associated with inferior DFS and OS when compared to the LNR. On multivariate analysis, multi-station involvement was the only factor associated with inferior DFS (p &lt; 0.001) and OS (p = 0.007). Conclusions: Station wise pathological assessment of lymph nodal involvement could potentially provide superior prognostic information, in addition to number of involved nodes. Involvement of cystic lymph node alone has relatively superior prognosis as compared to multi-station involvement.
A pilot trial of personalized neoantigen pulsed autologous dendritic cell vaccine as adjuvant treatment in hepatocellular carcinoma.
Authors: Qiuji Wu, Qiu Li
Journal: Journal of Clinical Oncology (2024)

e16264 Background: The primary treatment for hepatocellular carcinoma (HCC) is radical surgery. However, HCC has a high propensity to recur postoperatively and no standard adjuvant therapies have been approved. This Phase I trial aims to evaluate the safety and efficacy of an adjuvant personalized neoantigen pulsed autologous dendritic cell vaccine (Neo-DCVac-02) in patients with HCC. Methods: Eligible patients had histologically confirmed high-risk HCC after radical surgery. After obtaining the necessary baseline biopsy specimens and PBMCs of appropriate quality for DNA and RNA sequencing, neoantigen prediction, screening and synthesis were performed. Subsequently, leukapheresis was performed and DCs were isolated and cultured. DCs were then pulsed with neoantigen peptides to produce Neo-DCVac-02. On day 0, patients were treated with cyclophosphamide at a dose of 250 mg/m2. The prepared Neo-DCVac-02 vaccine was administered subcutaneously to the axillary and inguinal regions bilaterally on day 1, followed by daily administration of GM-CSF at a dose of 0.075 mg for 5 days (days 2-6). The primary objectives of this study were to assess feasibility and safety/tolerability. Secondary objectives included evaluation of immune responses (via vaccine response: IFNγ ELISpot), relapse-free survival (RFS) and overall survival (OS). Results: A total of 32 patients provided informed consent to initiate the process of personalized neoantigen discovery, of which 26 (81%) met the requirements for successful product selection for clinical manufacturing. Feasibility was demonstrated with 13 patients receiving Neo-DCVac-02. 13 patients did not receive the neoantigen vaccine (7 due to progressive disease, 6 due to withdrawal of informed consent because of COVID-19). The treatment was well tolerated with no grade 2+ treatment-related adverse events (TRAEs). The most common Grade 1 TRAEs were injection site reactions (75%), rash (16.7%), fatigue (8.3%), neutropenia (8.3%), and headache (8.3%). Five of 13 evaluable patients showed increased antigen-specific T-cell activity and more than 50% of the neoantigen peptides in Neo-DCVac-02, and sustained cellular responses were observed up to one year. Increases in T-cell activation/co-stimulation seen after treatment with Neo-DCVac-02, as demonstrated by flow cytometric analysis, suggest immune priming. At a median follow-up of 29.7 months, median RFS was not reached, with 1- and 2-year RFS of 84.6% and 60%, respectively, and all patients are alive. Patients with a strong immune response had a longer median relapse-free survival (not reached) compared to patients with a weak immune response (17.6 months, P = 0.003). Conclusions: These data demonstrate that Neo-DCVac-02 is safe, well tolerated and capable of inducing durable antigen-specific lymphocyte immune responses that may correlate with delayed HCC recurrence. Clinical trial information: NCT04147078 .
Diagnosis and genetic characterization of CNS metastases in lung cancer via shallow whole-genome sequencing of CSF cell-free DNA.
Authors: Yubin Li, Zongkun Shi, Beihe Cao, Juan An, Xiaosheng Ding, Weiran Xu, Dandan Cao, Xiaoyan Li
Journal: Journal of Clinical Oncology (2024)

e14013 Background: The genetic characterization of CNS metastases in lung cancer is hindered by the limited sampling opportunities and genetic heterogeneity between intracranial and extracranial lesions. To address these challenges, this study uses cerebrospinal fluid (CSF) and blood samples, to detect and characterize CNS metastasis variants through shallow whole-genome sequencing (sWGS). Methods: From Dec. 2021 to Aug. 2023, 57 lung cancer patients were recruited, comprising 29 with leptomeningeal metastases (LMs) and 28 with only parenchymal brain metastases (PMs). A total of 66 blood and 112 CSF samples were collected for cfDNA sWGS to analyze chromosomal arm CNVs, focal amplifications (CN &gt; 5) and SNV/InDels. Cytology was also conducted on 95 of these CSF samples. Variant differences between PMs and extracranial metastases (EMs) were analyzed using the MSK-MET database. Results: CSF cfDNA concentration was significantly lower than that in plasma (p &lt; 0.0001), with 41.7% of samples unquantifiable, yet all samples successfully completed sWGS. The cfDNA tumor fraction in CSF was significantly higher than in paired plasma (p &lt; 0.0001), and most arm CNVs and gene amplifications exclusively detected in CSF. Cytology, as the gold standard for LM diagnosis, had a sensitivity of 0.76. The sensitivity for LM diagnosis based on aneuploidy and genomic amplification fraction (GAF) were 0.51 and 0.80, respectively, without compromising specificity. Gains in 1p, 7p, 11q, 16p, and 17q, as well as losses in 9p and 9q, were significantly more frequent in PMs compared to EMs and further increased in the LMs (p &lt; 0.05). Notably, losses in 1p, 4p, 5q, and 11p, significantly more frequent in PMs than in extracranial metastases, but showed a significant increase in gain frequency in LMs (p &lt; 0.05). In the LM group, the frequency of EGFR L858R and amplification of nearly the entire 7p where the EGFR located, were significantly increased, whereas KRAS G12D frequency significantly decreased (p &lt; 0.05). Conclusions: The characteristics of extremely low concentration but high tumor fraction of CSF cfDNA make it suitable for sWGS, enhancing LM diagnostic sensitivity without compromising specificity, and identifying molecular characteristics of CNS metastasis. These molecular features require further validation in larger prospective clinical cohorts, offering potential for personalized diagnosis and treatment of CNS metastases.
Stereotactic radiosurgery (SRS) for non-small cell lung cancer (NSCLC) in the oncogene-addicted era: A real-world UK tertiary center experience.
Authors: David Mcmahon, James De Boisanger, Alexius John, Martin Brewer, Elizabeth Cartwright, Thubeena Manickavasagar, Charlotte Milner-Watts, Liam Welsh, Antonia Creak, Nadia Yousaf, Michael Davidson, Jaishree Bhosle, Anna Rachel Minchom, Mary E.R. O'Brien, Sanjay Popat, Francesca Solda, Helen Taylor, Jessica Konadu, Nadza Tokaca, Nicola Rosenfelder
Journal: Journal of Clinical Oncology (2024)

e14011 Background: 30-50% of NSCLC patients develop brain metastases (BM). Re-evaluation of the role of SRS is required with evolving understanding of molecular subtypes of NSCLC and increasing intracranial efficacy of systemic agents. Methods: We conducted a retrospective analysis of NSCLC patients receiving SRS at our centre from 05/16-11/23. Primary objective was median overall survival (mOS months). Analysis was performed on Prism 10.1.1. Multivariate analysis was conducted using Cox Proportional Hazards Regression, with age, gender, KPS, BM size, total BM volume and oncogene status as predictor variables. Extraction from medical records was undertaken by authors, with local R&amp;D committee approval. Results: 237 patients were evaluable. 59% (N=139) were oncogene-addicted (oNSCLC) and 41% (N=98) non-oncogene-addicted (non-oNSCLC). Median duration of follow up was 43.3m. m OS was 11.9m overall. For oNSCLC mOS was 13.1m vs 8.8m for non-oNSCLC (HR 1.49, P=0.02). mOS was 20.7m for EGFR sensitizing NSCLC (N=48) vs 10.5m without (HR 1.40 P=0.12). mOS for ALK+ (N=22) was 29.3m vs 11.6m for non-ALK+ (HR 1.90, P=0.05). mOS for KRAS+ (N=32) was 11.6m vs 12.0m without (HR 0.91, P=0.68). Significantly inferior mOS was seen for single (N=186 [78%]) vs multiple (N=51[22%]) SRS courses (8.4m vs 38.8m, [HR 0.34 P=&lt;0.0001]). SRS at diagnosis of BM (N=118) had a mOS of 12.3m vs at nadir (N=9, not reached [HR0.44, P=0.18]), progression on 1 st line TKI (N=31, 22.1m [HR 1.1, P=0.79]) and at any other time (N=157, 7.8m [HR 1.33, P=0.11 ]). There was no significant difference in survival for patients diagnosed with brain metastases at the diagnosis of metastatic disease compared to those who developed brain metastases during their disease course (12.3m vs 10.6m [HR 1.18, P=0.33]). Survival of those with 1 site of metastatic disease (18.3m) was numerically improved compared to those with 2 (10.7m, HR 1.26, P=0.25) sites, and statistically significant compared to those with 3 (10.1m, HR 1.69, P&lt;0.02) and ≥4 (4.4m, HR 4.41, P&lt;0.0001) sites. Conclusions: Median OS in oNSCLC was superior to non-oNSCLC, driven by numerically superior survival in EGFR+ and ALK+ cohorts. Significantly improved OS was observed in patients with multiple vs single SRS treatments, however this may be confounded by biases. Patients treated with SRS at nadir had numerically superior OS to those treated at other timepoints, however this must be interpreted with caution due to small sample size. Further prospective research is needed to interrogate these findings and guide local therapies in NSCLC with BM. [Table: see text]
Laparoscopic versus open hepatectomy for hepatocellular carcinoma following conversion therapy: A systematic review and meta-analysis.
Authors: Gabriele Eckerdt Lech, Patricia Viana, Raquel Oliveira de Sousa Silva, Bárbara Melão, Camila Mariana de Paiva De Paiva Reis, Edgar Paulo da Silva Neto, João Luís Reis Freitas, Rafael Morriello
Journal: Journal of Clinical Oncology (2024)

e16272 Background: Conversion therapy for hepatocellular carcinoma (HCC) has emerged as a novel strategy allowing patients with previously unresectable HCC to transition to a resectable disease through a combination of therapies. Laparoscopic hepatectomy is associated with reduced blood loss and early recovery without compromising oncological results in cirrhotic patients. However, the specific benefits of laparoscopic hepatectomy in patients who have undergone conversion therapy are not clear. Methods: We searched PubMed, Embase, and Cochrane Central for any studies that compared laparoscopic versus open hepatectomy after the use of conversion therapy (transarterial chemoembolization, portal vein embolization, hepatic arterial infusion chemotherapy, or liver ablation) in patients with hepatocellular carcinoma. The outcomes of interest were length of hospital stay, blood loss, operative time, pedicle clamping, postoperative complications, and transfusion. Statistical analysis was performed using R statistical software 4.2.1. Heterogeneity was assessed with I². Results: We included 535 patients from 4 retrospective nonrandomized studies. The mean age in the laparoscopic group was 60.33, ranging from 29 to 83. Length of hospital stay was significantly reduced in the laparoscopic group (MD -5.01; 95% CI -9.76–-0.27; p = 0.04; I² = 92%), as well as the blood loss (MD -97.26; 95% CI -200.54–6.01; p = 0.06; I² = 76%). Postoperative complications also favored the laparoscopic group (OR 0.40; 95% CI 0.17–0.94; p = 0.035; I² = 0%). The endpoints of pedicle clamping (OR 0.7; 95% CI 0.11–4.36; p = 0.70; I² = 91%), transfusion (OR 0.69; 95% CI 0.36–1.33; p = 0.273; I² = 0%), and operative time (MD 34.21; 95% CI -36.68–105.10; p = 0.34; I² = 97%) did not favor any of the groups. Conclusions: In this meta-analysis, laparoscopic hepatectomy after conversion therapy was proven to be safe and feasible, without significant differences compared to open hepatectomy regarding pedicle clamping, transfusion, and operative time. Furthermore, the laparoscopic group presented less blood loss and a significantly reduced length of hospital stay. These findings suggest that laparoscopic resection could be safely used after conversion therapy and may improve surgical outcomes in these patients.
FOLFOX as a therapeutic option in patients with hepatic failure due to liver metastasis of gastrointestinal (GI) system malignancies: A case series.
Authors: Kadriye Başkurt, Osman Sütcüoğlu, Dilsa Mizrak Kaya
Journal: Journal of Clinical Oncology (2024)

e16378 Background: The treatment options for patients with hepatic metastasis presenting with liver dysfunction, particularly those experiencing severe hyperbilirubinemia, are limited. The oxaliplatin and fluorouracil/folinic acid regimen, known as FOLFOX, stands out as a viable option based on its pharmacokinetics. However, clinical data regarding the specific dosage and tolerability of this regimen are limited, and clear recommendations are not currently available. Patients and Methods: Patients who presented with severe hyperbilirubinemia immediately after the diagnosis of GI adeno cancer, and who were not eligible for drainage options, were prospectively observed in our clinic in Turkey throughout the year 2023. Severe hyperbilirubinemia was defined as a bilirubin level &gt; 5mg/dL. The FOLFOX regimen was administered every two weeks, and the fluorouracil dose was initially reduced by 50% for the first two cycles. Subsequently, the dose was increased to the total amount if no toxicity occurred. Results: Six cases of GI cancer patients meeting the criteria were identified. Subsequent laboratory data for these six patients were collected after initiating the FOLFOX regimen. All six patients underwent the FOLFOX regimen with dose reduction for the first two cycles. Following the first cycle of chemotherapy, bilirubin levels dropped and normalized (Table 1), leading to an improvement in the patients' clinical condition. Conclusions: While our series is limited by a small number of patients, treatment with FOLFOX has proven to be feasible and may yield significant benefits in patients with severe liver dysfunction caused by GI cancer, especially when no further drainage options are available. [Table: see text]
Alterations of the tumor microenvironment (TME) in recurrent glioblastoma following apatinib in combination with temozolomide.
Authors: Junping Zhang, Jingjing Ge, Cheng Li, Fengjun Xue, Chi Zhao, Chenchen Kong, Shaopei Qi, Qianqian Duan, Qin Zhang, Xia You
Journal: Journal of Clinical Oncology (2024)

e14018 Background: Glioblastoma (GBM) is the highly malignant primary central nervous system tumor. The standard treatment for glioblastoma is maximal surgical resection followed by concomitant radiotherapy and temozolomide chemotherapy, but patient’s survival still remains poor. At present, apatinib in combination with temozolomide (TMZ) has achieved reasonable clinical efficacy in the treatment of recurrent glioblastoma (rGBM), however, there are currently no clear biomarkers related to clinical efficacy or prognosis. Methods: This retrospective study was enrolled 22 rGBMs treated with apatinib in combination with TMZ and 6 patients who received standard radiotherapy combined with TMZ and experienced recurrence. At the same time, we collected their tissue samples for RNA transcriptome analysis by the Nanostring nCounter platform. In prognosis analysis, long survival benefit is defined as a PFS≥4.2 months, and short survival benefit is defined as a PFS&lt;4.2 months. This PFS threshold was primarily referenced from a Phase III study of bevacizumab combined with chemotherapy for rGBM. The study was approved by the institutional ethics committee of Sanbo Brain Hospital, Capital Medical University (SBNK-YJ-2021-010-02) and informed consent was also obtained from the patients. Results: The differential gene of pre and post standard chemoradiotherapy results suggest that standard treatment has reduced the expression of genes associated with tumor proliferation and up-regulated the expression of the genes associated with the immune response in rGBM. In apatinib combined TMZ patients, compared to the non-response group, the response group had significantly up-regulated expression of genes related to endothelial cells and apoptosis. Enrichment analysis revealed that signaling pathways related to cell proliferation were down-regulated in the response group. In terms of prognosis, compared with the short-survival benefit group (&lt; 4.2 months), four tumor progression-associated genes were down-regulated in response group (≥4.2 months). Hypoxia related-genes was significantly up-regulated in the long survival benefit group. Enrichment analysis showed that genes related to cell proliferation were also down-regulated in the long-survival benefit group, while the expression of signaling pathway genes related to cell activation, and immune response was significantly up-regulated. Conclusions: Our study suggests that the combination of apatinib and TMZ may potentially provide clinical benefits in treating rGBM by modulating genes associated with cell proliferation, promoting apoptosis, regulating hypoxia, and enhancing immune response within the tumor microenvironment. Clinical trial information: NCT04814329 .