tbuckley/cabot-search huggingface dataset:
Differential expression in potential therapeutic target protein by treatment in small cell lung cancer with and without transformation.
Authors: Saori Murata, Hidehito Horinouchi, Yasushi Yatabe, Jumpei Kashima, Ken Masuda, Yuki Shinno, Yusuke Okuma, Tatsuya Yoshida, Yasushi Goto, Noboru Yamamoto, Shun-ichi Watanabe, Yuji Matsumoto, Kae Okuma, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2024)

202 Background: Small cell lung cancer (SCLC) is a disease with a poor prognosis. Besides combination strategy with immune checkpoint inhibitors (ICIs) and cytotoxic agents, antibody-drug conjugates (ADCs) and bispecific T-cell engagers (BiTE) are being developed. These drugs target tumor-associated surface protein. Whether prior treatment affect the transition of protein expression has not been fully investigated especially in the era of ICIs. The purpose of this study is to evaluate changes in protein expression in SCLC tissues before and after treatment. Methods: We included patients diagnosed with SCLC by surgery or biopsy and underwent re-biopsy after treatment (non-transformed group) at the National Cancer Center Hospital between 2014 and 2023. Patients who were initially diagnosed with non-small cell lung cancer and underwent transformation to SCLC (transformed group) were also included. Tissues were obtained by surgery, bronchoscopy, or CT-guided biopsy with an interval of at least 100 days. We investigated clinicopathological features in paired specimens focusing on DLL3, ASCL1, NEUROD1, POU2F3, and YAP1, which have been reported to be expressed in SCLC, as well as tumor-associated surface proteins potentially related to novel drug development. Results: Fourteen non-transformed group cases and 9 transformed group cases were included. Of these, pathology specimens were evaluable in a total of 15 cases: 9 for the non-transformed group and 6 for the transformed group. The median age was 68 years, 11 (73%) were male, 11 (73%) were smokers, 8 (53%) were in clinical stages I-IIIA, 1 (7%) in stages IIIB and 6 (40%) in stage IV. Among the transformed group, 4 of them were treated by Osimertinib before transformation. Progression free survival from first-line therapy was 298 days (255-446) vs. 314 days (245-NA) and overall survival was 1239 days (567-NA) vs. NA days (517-NA), respectively for non-transformed group and transformed group. For both these group of cases, we have evaluated several protein expressions as described above. The transition of these proteins within each group is presented in the conference. Conclusions: In this study, we focused not only on proteins already reported to be expressed in SCLC, but also on proteins that are potential new therapeutic targets and evaluated changes in protein expression. [Table: see text]
Patient-reported outcomes (PROs) from a randomized, phase 3 trial of enfortumab vedotin plus pembrolizumab (EV+P) versus platinum-based chemotherapy (PBC) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC).
Authors: Eiji Kikuchi, Shilpa Gupta, Yohann Loriot, Michiel Simon Van Der Heijden, Jens Bedke, Begoña Pérez Valderrama, Aude Flechon, Daniel P. Petrylak, Maria De Santis, Matt D. Galsky, Jae Lyun Lee, Umang Swami, Srikala S. Sridhar, Ugo De Giorgi, Phoebe Wright, Yi-Tsung Lu, Xuesong Guan, Ryan Dillon, Blanca Homet Moreno, Thomas Powles
Journal: Journal of Clinical Oncology (2024)

108 Background: EV+P nearly doubled median progression-free survival and overall survival vs PBC in patients (pts) with previously untreated la/mUC in the phase 3 EV-302 trial. PROs are reported here. Methods: In EV-302 (NCT04223856) pts were randomized 1:1 to EV+P or PBC (gemcitabine with cisplatin or carboplatin). PRO assessments included the EORTC Quality of Life Questionnaire (EORTC QLQ-C30), and the Brief Pain Inventory Short Form (BPI-SF) completed at baseline, weekly for 12 weeks (wks), then every 3 wks through survival follow-up, inclusive of the time post-progression. Time to pain progression (TTPP) and mean change from baseline in worst pain at wk 26 using the BPI-SF were prespecified analyses statistically tested using a gatekeeping strategy. Mean change from baseline through wk 26 and time to confirmed deterioration (TTCD) of EORTC-QLQ-C30 and BPI-SF domains were prespecified descriptive analyses. TTPP and TTCD were assessed using Kaplan-Meier methods. Results: Of 886 pts randomized, 731 (376 received EV+P; 355 PBC) completed baseline PRO questionnaires. Compliance rates differed between arms and remained &gt;70% through wk 29 for EV+P and through only wk 17 for PBC. Median TTPP was 14.2 months (mos) with EV+P and 10.0 mos with PBC (hazard ratio [HR]=0.92; 95% CI=0.72, 1.17; 2-sided p-value=0.48). The least squares (LS) mean reduction in worst pain at wk 26 was numerically greater with EV+P vs PBC (-0.61 vs -0.03, LS mean difference [95% CI]: -0.58 [-1.05, -0.11] [nominal 2-sided P = 0.015]). Pts with moderate to severe pain at baseline who were treated with EV+P (n=128, 34%) had a meaningful (&gt;2 pt) improvement from baseline in BPI worst pain from wk 3 through 26. In EORTC QLQ-C30 Global Health Status/Quality of Life [GHS/QoL], EV+P demonstrated a transient worsening at week 3 (-6.3) that returned to baseline from weeks 4 through 26, while patients treated with PBC demonstrated deterioration from week 1 through week 17 (range -1.2 to -7.1) where scores returned to baseline. TTCD for EORTC QLQ-C30 GHS/QoL was 5.9 mos with EV+P vs 3.2 mos with PBC (HR = 0.98 [95% CI]: 0.79 – 1.2). Conclusions: Pts treated with EV+P have improved survival compared with PBC without detriment to quality of life and functioning, further supporting the value of EV+P for pts with la/mUC. Compliance, especially after progression, was lower than expected (particularly in the PBC arm) and may have impacted the results. Clinical trial information: NCT04223856 .
Anti-tumor effect of zartoprofen, a non-steroidal anti-inflammatory drug, targeting PPARγ (peroxisome proliferator-activated receptor gamma) on chondrosarcoma.
Authors: Takashi Higuchi, Akihiko Takeuchi, Shinji Miwa, Katsuhiro Hayashi, Norio Yamamoto, Hiroyuki Tsuchiya
Journal: Journal of Clinical Oncology (2024)

232 Background: Peroxisome proliferator-activated receptor gamma (PPARγ) plays a central role in the differentiation of adipocytes. Anti-tumor effects by activating PPARγ have been reported on chondrosarcoma. We revealed that zaltoprofen, a non-steroidal anti-inflammatory drug (NSAID), could activate and induce PPARγ in chondrosarcoma cells. We report antitumor effects of zaltoprofen targeting PPARγ on chondrosarcoma. Methods: PPARγ activation by zaltoprofen was assessed with luciferase assay. Human chondrosarcoma cells and PPARγ-silencing cells established with shRNA were subjected to the anti-tumor analyses, western blotting, RT-PCR, and zymography. For in vivo study, chondrosarcoma cells were subcutaneously inoculated into nude mice. Zaltoprofen was administered to mice (30 mg/kg/day). Tumors were pathologically assessed. We obtained tumor tissue specimens from a patient who underwent several surgeries for recurrent spinal chondrosarcoma. The patient was administered zaltoprofen as a therapeutic agent for algia the tumor remained stable for more than 2 years. Pathological analyses were performed on the specimen before and after administration of zaltoprofen). Results: Zaltoprofen significantly increased PPARg activation (EC 50 47.3 uM). Treatment with 200–400 uM zaltoprofen significantly inhibited cell viability and induced PPARγ protein and mRNA expression in chondrosarcoma cells. Zaltoprofen (400 uM) significantly decreased the cell proliferation, migration, invasion, and MMP2 expression in control cells, whereas these were significantly increased in PPARγ-silencing cells. Also, zaltoprofen (400 uM) induced p21, p27, and p53 expression in control cells, whereas these effects were canceled in PPARg-silencing cells. Upregulation of KROX20 followed by CEBP-α and –β, all of which were reported to induce PPARγ in normal adipose tissue, were detected after zaltoprofen administration. Tumor growth was significantly inhibited in mice administered zaltoprofen. Apoptotic indices in the TUNEL-labeled area were significantly larger and Ki-67 positive cells were significantly lower in tumor specimens from mice administered zaltoprofen. Patient’s specimens revealed that PPARγ expression was stronger and MMP2 expression was weaker in post-administration specimens. Conclusions: Zaltoprofen suppressed tumor progression by inhibiting cell proliferation, migration, and invasion with induction of PPARγ expression in chondrosarcoma cells. The suppressing effect on tumor progression by zaltoprofen was also observed in vivo. Zaltoprofen induced PPARγ expression and MMP2 downregulation in clinical specimens with expected antitumor effects. This is the first study demonstrating that one of the NSAIDs, zaltoprofen, may act as an antitumor agent by targeting PPARγ for chondrosarcoma.
Hypomagnesemia as a predictor of the efficacy of combination EGFR-targeted drugs versus EGFR ADCs alone in HNSCC.
Authors: Siqing Jiang, Hanchun Liu
Journal: Journal of Clinical Oncology (2024)

146 Background: EGFR-targeted drugs and ADCs in combination with EGFR-conjugated chemotherapy drugs can both cause hypomagnesemia. However, the predictive value of hypomagnesemia in response to treatment for head and neck squamous cell carcinoma (HNSCC) is unclear. Methods: This study retrospectively analyzed patients who participated in clinical trials of EGFR-targeted drugs and EGFR ADCs for HNSCC and solid tumors, from February 24, 2022, to March 25, 2024. The primary endpoint of the study was time to treatment failure (TTF). Results: This study conducted a retrospective analysis of 68 patients . All patients exhibited normal baseline serum magnesium levels prior to treatment, but following two cycles of treatment, varying degrees of hypomagnesemia were observed among them. Among the 46 patients who received 2 cycles of combination therapy with EGFR-targeted drugs, 33 were hypomagnesemia and 13 were normal serum magnesium, ORR[90.9%vs. 8.5%,(P=0.002)] (Table), TTF [151 days (95% CI: 212-380) vs. 87 days (95% CI: 52-230), HR 0.576 (95% CI: 0.270–1.230,P = 0.021)]. Among the 22 patients who received EGFR ADC alone for 2 cycles, 8 were hypomagnesemia and 14 were normal serum magnesium, ORR [37.5% vs.28.6%, (P=0.549)] (Table), TTF [97.5 days (95% CI: 68-300) vs. 108.5 days (95% CI: 60-160), HR of 0.877 (95% CI: 0.339–2.263; P = 0.547)]. Conclusions: The study demonstrates that, the occurrence of hypomagnesemia is associated with ORR and TTF following two cycles of combination of EFGR-targeted drugs, not observed in patients receiving EGFR ADCs as monotherapy in HNSCC. [Table: see text]
Exploration of the application of the sprayed γ-GGT fluorescent probe for visual imaging of epithelial ovarian cancer.
Authors: Manlin Zhang, Zhihui Liu, Lin Qiu, Wenxin Ma, Zhuo Yang
Journal: Journal of Clinical Oncology (2024)

127 Background: To explore the feasibility, accuracy and related influencing factors of spraying γ -GGT fluorescent probe in visual imaging of epithelial ovarian cancer. Methods: This study employed a previously developed spray-type γ-GGT fluorescent probe in fresh ex vivo epithelial ovarian cancer tissues. The experimental group selected ovarian cancer lesions of varying sizes and observed fluorescence imaging after spraying different concentrations of the probe. The optimal imaging concentration and observation time were determined based on pathological results. The validation group then used the optimal parameters to image primary and metastatic lesions, normal tissue, and suspicious areas, confirming the probe's accuracy. Clinical data from patients, such as age and stage, were analyzed to identify factors affecting probe imaging. Results: A total of 16 cases of epithelial ovarian cancer were included in this study, 8 cases were in the experimental group and 8 cases were in the validation group, and the samples were collected from the primary ovarian lesions, omental metastases and peritoneal metastases. In the experimental group, 42 lesions of 3 different diameters were collected. The visible lesions were not found to have any changes in the imaging within 1min-1h after spraying the γ-GGT fluorescent probe, and the SBR value within 1min-1h was between 1.26-1.29, with no statistical difference ( P&gt;0.05), and the visible effect of 5 h was weaker or even invisible to the naked eye, and the best observation time was 1min-1h after spraying the γ-GGT fluorescent probe, and the SBR value of 1min-1h after spraying 10 μM of γ-GGT fluorescent probe was significantly higher than that of 1 μM and 5 μM ( P&lt;0.05), and the best visible effect was achieved by the naked eye, resulting in a minimum effective imaging concentration of 10 μM. A total of 27 points were collected from the lesion with a diameter of &lt;0.3 cm and its surrounding normal tissues with a distance of 1 cm or tissues with a diameter of 1-1.5 cm with a height of suspicion but normal to the naked eye, and 26 of the 27 tissues were confirmed by pathology to be cancerous and 1 was non-cancerous, with a true positive rate of 96.3% and a false positive rate of 3.7%. The overall true positive rate of fluorescence imaging was 98.6%. Univariate analysis showed that there were significant differences in the level of preoperative γ-GGT and the SBR value of preoperative treatment (all P&lt;0.05), and the results of multivariate analysis showed that preoperative treatment was an independent influencing factor for fluorescence imaging of γ-GGT fluorescent probe ( P&lt;0.05). Conclusions: This study tested the γ-GGT fluorescent probe for ovarian cancer imaging, finding 10 μM as the effective concentration and 1 minute to 1 hour as the optimal observation window. The probe's effectiveness is influenced by preoperative treatments.
The dynamic changes of circulating myeloid-derived suppressor cells (MDSCs) subsets in patients with colorectal cancer undergoing oxaliplatin-based chemotherapy.
Authors: Dilafitria Fauza, RALPH G Manuel, Aru Wisaksono Sudoyo, Ricci Steven, Fajar Lamhot Gultom, Ibrahim Basir, Dicky Kurniawan, Akterono Dwi Budiyati
Journal: Journal of Clinical Oncology (2024)

62 Background: Increased level of circulating myeloid-derived suppressor cells (MDSCs) have been associated with higher tumor stage, poorer survival, and poorer response to therapeutic agents in colorectal cancer (CRC). It has been reported that the common first-line chemotherapy involving combination with oxaliplatin mediated MDSCs depletion via induction of cell death. However, this phenomenon is yet to be further investigated since it only occurred in polymophonuclear MDSC (PMN-MDSC) subset, not in monocytic MDSC (M-MDSC). The present study aims to learn deeper on the dynamic changes of circulating MDSCs in response to oxaliplatin-based treatment in CRC patients. Methods: This was a prospective study that recruited 30 treatment-naïve patients with varying stage of CRC who were scheduled to receive oxaliplatin-based chemotherapy. Blood sampling was conducted prior and at several time points during and after chemotherapy. Multicolor flow cytometry assay was used to analyze the proportion of HLA-DR-, CD33+, and CD15+ (PMN-MDSC) and CD14+ (M-MDSC) cells within peripheral blood mononuclear cells (PBMCs). Other essential tumor biomarkers such as carcinoembryonic antigen (CEA) and tumor infiltrating lymphocytes (TILs) were assessed as well. As control, 14 healthy subjects were recruited. Results: Our result showed that circulating PMN-MDSCs was significantly higher in CRC patients compared to healthy subjects (p=0.003), whilst insignificant result was shown by M-MDSCs (p=0.890). Following chemotherapy, MDSCs level showed dynamic changes. Interestingly, a subgroup of CRC patients with decreased in both PMN- and M-MDSCs levels on D-14 chemotherapy were consistently showed a significant decreased of MDSCs level during and after therapy completion compared to baseline (p=0.0078). Conclusions: Circulating MDSCs level, particularly PMN-MDSCs in CRC patients was significantly higher compared to healthy subjects. Changes in both circulating PMN- and M-MDSCs levels at D-14 chemotherapy might have prognostic value in oxaliplatin-based chemotherapy.
Deciphering the prognostic value of <i>FGFR2b/2c</i> isoform expression levels in advanced esophagogastric cancer through whole-transcriptome sequencing.
Authors: Tadayoshi Hashimoto, Naoko Iida, Yoshiaki Nakamura, Saori Mishima, Daisuke Kotani, Akihito Kawazoe, Izuma Nakayama, Yasutoshi Kuboki, Taro Shibuki, Mitsuho Imai, Takao Fujisawa, Hideaki Bando, Takayuki Yoshino, Kohei Shitara
Journal: Journal of Clinical Oncology (2024)

53 Background: Fibroblast growth factor receptor (FGFR) isoform switching from FGFR2b to FGFR2c has been implicated in epithelial-to-mesenchymal transition and enhanced invasive potential in various malignancies and potentially be involved in resistance mechanisms to FGFR2b targeted therapy (e.g., bemarituzumab). This study sought to investigate the potential of respective FGFR2 isoform expression evaluation utilizing whole-transcriptome sequencing (WTS) and its correlation with therapeutic efficacy and clinical outcomes in patients with advanced G/GEJ cancer. Methods: Patients with advanced G/GEJ cancer who received systemic therapy at the National Cancer Center Hospital East between May 2021 and September 2023, and were enrolled in the immunological profiling study (UMIN000019129) and MONSTAR-SCREEN-2 (UMIN000043899) were included. FGFR2 protein and RNA expression were assessed via immunohistochemistry (IHC) and WTS with Caris MI Profile, respectively. FGFR2b and FGFR2c isoforms were distinguished by the detection of their respective splice junctions using WTS data. The FGFR2b/(2b+2c) ratio was stratified into FGFR2b-dominat and -containing subtypes using the median value. The log-rank test was used to discern differences in overall survival (OS). Results: Among the 129 patients, 21 (16.3%) exhibited FGFR2-positivity by IHC (staining intensity 2+ or 3+≥1% membranous staining of tumor cells), and a significant correlation was observed between FGFR2 IHC status and RNA expression levels (TPM: transcript per million) in WTS (FGFR2-positive, median TPM=11.1; FGFR2-negative, median TPM=4.7; P=0.002). The distribution of FGFR2b/(2b+2c) ratio (median, 0.89) was: 10.9% (0≤x&lt;0.2), 5.4% (0.2≤x&lt;0.4), 7.0% (0.4≤x&lt;0.6), 12.4% (0.6≤x&lt;0.8), 43.4% (0.8≤x&lt;1.0), and 20.9% (x=1.0). Among 58 patients treated with 1 st line therapy, no significant difference in treatment response was observed between the FGFR2b-dominat (67.9%) and FGFR2c-containing subtypes (53.3%) (P=0.259). Overall, the FGFR2c-containing subtype was associated with significantly shorter OS compared to the FGFR2b-dominat subtype (median OS, 10.1 vs. 17.9 months; hazard ratio, 1.72; 95% confidence interval, 1.03-2.86; log-rank P=0.037). Conclusions: Our findings underscore the substantial concordance between IHC and WTS analysis of FGFR2, the feasibility of distinguishing FGFR2 isoforms using WTS, and the prognostic implications of FGFR2c isoform in patients with advanced G/GEJ cancer. Further analysis is warranted in patients receiving FGFR2b targeted treatment.
Does liver cirrhosis affect outcomes in non-metastatic esophageal squamous cell carcinoma (ESCC) undergoing radiotherapy-based treatment?
Authors: YuYang Hua, Shih Yu Huang, Shau-Hsuan Li
Journal: Journal of Clinical Oncology (2024)

89 Background: Liver cirrhosis frequently coexists with esophageal squamous cell carcinoma (ESCC), as both conditions share alcohol consumption as a common etiological factor. Surgical intervention is often contraindicated or associated with significant morbidity in patients with non-metastatic ESCC and liver cirrhosis. Consequently, radiotherapy-based therapy is commonly employed. This study aims to investigate prognostic factors for overall survival in such patients undergoing radiotherapy-based therapy. Additionally, we will evaluate predictors for the 90-day mortality rate, proposed as a measure to mitigate treatment-related toxicity and prevent unwarranted or excessive medical interventions. Methods: From January 2001 to December 2021, we conducted a retrospective review of the medical records of 1298 patients diagnosed with esophageal squamous cell carcinoma (ESCC). Within this cohort, we identified 103 patients with concomitant liver cirrhosis, diagnosed through abdominal ultrasonography, computerized tomography, and/or liver biopsy, as appropriate. Of these individuals, 78 patients with non-metastatic ESCC and liver cirrhosis were included in our analysis. We collected clinicopathologic parameters and examined their correlation with overall survival and the 90-day mortality rate. Results: Univariate analysis revealed several factors significantly associated with inferior overall survival: Child-Pugh classification B/C (P&lt;0.001, compared to A), radiotherapy alone (P=0.03, compared to chemoradiotherapy), prothrombin time prolonged by ≥2 seconds (P=0.024), albumin levels ≤3.5g/dl (P&lt;0.001), controlled/refractory ascites (P=0.01, compared to no ascites), and total bilirubin levels ≥1.5mg/dl (P=0.004). In multivariate analyses, albumin levels ≤3.5g/dl (P=0.001, odds ratio: 2.500) and total bilirubin levels ≥1.5mg/dl (P=0.019, odds ratio: 2.012) were identified as independent prognostic factors. Among the 78 patients receiving radiotherapy-based therapy, the 90-day mortality rate was 10.3% (n=8). Clinical 8th AJCC stage IVA (P=0.02), clinical T classification T3/4 (P=0.049), prothrombin time prolonged by ≥4 seconds (P=0.009), and albumin levels ≤3.5g/dl (P=0.027) were significantly correlated with higher 90-day mortality rate. The logistic model indicated that albumin levels ≤3.5g/dl (P=0.015, odds ratio: 16.129) and clinical 8th AJCC stage IVA (P=0.012, odds ratio: 17.544) were independently associated with higher 90-day mortality rate. Conclusions: In patients undergoing radiotherapy-based therapy for non-metastatic esophageal squamous cell carcinoma (ESCC) and liver cirrhosis, pretreatment hypoalbuminemia has been associated with increased 90-day mortality and unfavorable prognosis.