tbuckley/cabot-search huggingface dataset:
Association of a clinical model based on skeletal muscle radiation attenuation with efficacy for patients with gastric cancer treated with chemotherapy plus PD-1 antibodies: A single-center retrospective study.
Authors: Chenfei Zhou, Yan Sun, David P.J. van Dijk, Wenqi Xi, Jinling Jiang, Liting Guo, Junwei Wu, Feng Qi, Xuekun Zhang, Jun Ji, Qu Cai, Zhenggang Zhu, Sander S.M. Rensen, Steven W.M. Olde Damink, Jun Zhang
Journal: Journal of Clinical Oncology (2024)

e16029 Background: Biomarkers to select gastric cancer (GC) patients who can benefit from PD-1 antibody-based treatment are under investigation. We aimed to assess the association between body composition parameters and efficacy of chemotherapy plus PD-1 antibodies in GC patients. Methods: Clinical information of GC patients receiving perioperative chemotherapy with or without PD-1 antibodies was reviewed. Tumor regression grade (TRG) of gastric cancer was recorded after resection. Radiation attenuation and index of skeletal muscle, visceral adipose tissue and subcutaneous adipose tissue were calculated based on computed tomography (CT) images at the third lumbar (L3) level using SliceOmatic software. Associations between clinical parameters and patients’ outcomes including TRG, progression-free survival (PFS), and overall survival (OS) were analyzed. Results: A total of 120 patients treated with chemotherapy plus PD-1 antibodies (IO cohort) and 82 patients treated with chemotherapy alone (CTx cohort) were enrolled. TRG0/1 rates in the IO cohort and CTx cohort were 45.8% and 32.9%. High skeletal muscle radiation attenuation (SMRA), neutrophil to lymphocyte ratio (NLR) &lt; 2.65, and weight loss &lt; 5% were associated with TRG0/1 in the IO cohort but not in the CTx cohort. High SMRA was an independent prognostic factor of PFS in the IO cohort (HR = 0.333, 95%CI 0.115-0.970, P= 0.044). A clinical model based on SMRA, NLR and weight loss was established to stratify patients into 3 groups, including group 1: High SMRA with NLR &lt; 2.65 and weight loss &lt; 5%, group 2: High SMRA with NLR≥2.65 and/or weight loss≥5%, and group 3: Low SMRA. In the IO cohort, patients in group 1 showed higher TRG0/1 rate (n = 27/40, 67.5%, P&lt; 0.001) than group 2 (n = 26/63, 41.3%) and group 3 (n = 2/17, 11.8%). The clinical model was also associated with patients’ survival. Conclusions: A clinical model combining baseline SMRA, NLR and weight loss could identify well-responding GC patients treated with chemotherapy plus PD-1 antibodies.
Gastric juice piR-015551: A promising prognostic biomarker for gastric cancer.
Authors: Xuezhong Ji, Weitai Liu, Xinhua Wu, Jifeng Feng, Xia He, Guoren Zhou, Wei Peng
Journal: Journal of Clinical Oncology (2024)

e16074 Background: Emerging reports demonstrated that PIWI-interacting RNAs (piRNAs) played an indispensable role in tumorigenesis. However, it still remains elusive whether piR-015551 in gastric juice specific in stomach could be employed as a biomarker for gastric cancer (GC). The present work is aiming at exploring the possibility of piR-015551 in gastric juice as a potential marker to judge for diagnosis and prognosis of gastric cancer. Methods: Gastric juice was collected from 66 GC patients and 66 healthy individuals. Quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) was employed to measure the levels of piR-015551 expression. Then, the pattern of piR-015551 expression in gastric juice was determined between GC patients and healthy individuals. A receiver operating characteristic (ROC) curve was constructed for distinguishing GC from healthy individuals. Results: Gastric juice piR-015551 levels in GC were higher than those of controls (P &lt; 0.0001). The value of area under ROC (AUC) was 0.885 (sensitivity, 90.9%; specificity, 74.2%; 95% confidence interval, 0.8286 to 0.9414). High gastric juice piR-015551 expression was signally correlated with tumor size (P = 0.013) and TNM stage (P = 0.001). GC patients with high piR-015551 expression in gastric juice exerted a poorer overall survival (OS) (P = 0.0152) and progression-free survival (PFS) (P = 0.013). COX regression analysis verified that gastric juice piR-015551 expression was an independent prognostic risk variable for OS (P &lt; 0.05). Conclusions: The current study suggested that piR-015551 in gastric juice had the potential to be a useful biomarker for GC detection and prognosis prediction.
Effect of AFPGC immune-microenvironment and resistance to immunotherapy.
Authors: Xiaoyi Chong, Jialin Lu, Yakun Wang, Xiaotian Zhang
Journal: Journal of Clinical Oncology (2024)

e16041 Background: Alpha-fetoprotein producing gastric cancer (AFPGC) is a rare subtype GC with high with high morbidity and mortality rates. Even though immunotherapy has become the cornerstone of first-line treatment, our previous results suggest that AFPGC was resistant to immunotherapy, standard regimen remains unclear. It is warranted to explore precision immunotherapy strategies for AFPGC. Methods: A retrospective cohort of 98 patients with gastric cancer receiving mono-immunotherapy was included. Kaplan-Meier survival plots for PFS and OS were generated based on the AFP levels. Log-rank tests were used to compare the survival curves. Chi-square test was used to analyze the differences in the efficacy of immunotherapy between patients with different levels of AFP. AFPGC in vivo models were constructed, and after in vivo administration, RNA-seq, flow cytometry, and Western blot were used to explore and validate the features of the AFPGC microenvironment and explore immunotherapy combination strategies. Results: Retrospectively analysis demonstrated that the response of mono-immunotherapy in AFPGC was inferior to that in non-AFPGC (ORR: 16.7% vs 29.3%; DCR: 33.0% vs 55.4%). The response of the subcutaneous transplant tumor model with AFP overexpression to PD-1 antibody was significantly reduced. Meanwhile, RNA-seq results from the secondary PD-1 antibody resistant model showed that the mRNA level of AFP was significantly upregulated in the resistant model. RNA-seq results from transplant tumors of AFPGC compared to nAFPGC revealed that the differentially expressed genes were significantly enriched in pathways related to neutrophil chemotaxis and angiogenesis. Flow cytometry confirmed that the proportion of neutrophils in AFPGC was significantly higher than that in nAFPGC. SB265610 (neutrophil chemokine receptor inhibitor) combined with PD-1 antibody and apatinib (anti-angiogenesis) plus PD-1 antibody were administrated in animal models. Both of the regimens could release the primary resistance to PD-1 antibody. Based on these preclinical findings, we designed and conducted a clinical study (NCT04609176) to explore the reponse of apatinib combined with PD-1 antibody in AFPGC. Primary endpoints were achieved and will be announced in the near future. Typical case is depicted as follows: A 79 years old male patients diagnosed with low-differentiated adenocarcinoma of GC, AFP: 135220 ng/ml. After fail in chemotherapy, patients were treated with third-line apatinib 250mg po d1-d21, PD-1 monoclonal antibody 200mg d1, q21d for 6 cycles. Patient was evaluated as partial response (PR) for 4 months and AFP sharply decreased to 945 ng/ml. Conclusions: AFPGC is resistant to PD-1 monoclonal antibody. Combined treatment with SB265610 or apatinib can alleviate or reverse the resistance, making it the most promising treatment regimen for AFPGC.
Effect of PLCE1-driven aerobic glycolysis through ENO1 modulation on immune evasion in esophageal squamous cell carcinoma (ESCC).
Authors: Xiaobin Cui, Ju Yang, Mengfei Sun, Shangfeng He, Ziru Zhou, Yunzhao Chen
Journal: Journal of Clinical Oncology (2024)

e16016 Background: Our prior investigations have demonstrated that PLCE1 actively promotes tumorigenesis, angiogenesis, and cell cycle progression in ESCC. However, the precise role of PLCE1 in glycolysis and its influence on the tumor immune microenvironment (TIME) remain elusive. Methods: To elucidate potential pathways regulated by PLCE1, we applied Affymetrix GeneChip, Affymetrix ClariomD Array, and IP-MS techniques to identify molecules interacting with PLCE1. Subsequently, we validated the involement of PLCE1 in glycolysis through assessments of glycolytic product production in both in vivo and in vitro assays. The underlying mechanisms by which PLCE1 influences glycolysis were further probed through a combination of IP assays, tumor growth experiments, and ubiquitination assays. Next, we conducted multi-color immunofluorescence staining to examine the infiltration of immune cells in human ESCC tissues. We utilized a transgenic PLCE1 -/- C57BL/6 mice model to investigate the immune cell distribution in TIME. Results: PLCE1 emerges as a pivotal regulator in glycolytic processes within ESCC cell lines. Knockdown of PLCE1 instigates a notable attenuation of glycolysis, achieved through the modulation of ENO1 expression, a key enzyme in glycolysis. This effect was also observed in vivo. We have elucidated a novel pathway in which PLCE1 orchestrates a reduction in the expression of FBXW7, an E3 ubiquitin ligase, thereby attenuating FBXW7-mediated ubiquitination of ENO1 and fostering ENO1 stability. Based on mutations identified through sequencing of ESCC tissue and drawing from previous studies, we have pinpointed the specific interacting sites between FBXW7 and ENO1. Substrate phosphorylation is necessary for the recognition of FBXW7. We unveil a mechanism wherein PLCE1 interacts with CDK2 to augment ENO1 phosphorylation, potentiating FBXW7 recognition. Nonetheless, CDK2-mediated ENO1 phosphorylation fails to elicit FBXW7-mediated ubiquitination due to limited FBXW7 expression in ESCC. Elevated tumor glycolysis induced by PLCE1 via ENO1 engenders heightened lactate production, thereby dampening cytokine production and CD8 + T cell activation. In human ESCC tissues, a diminished CD8+ T cell population is observed proximal to PLCE1 + ENO1 + tumor cells, concomitant with an augmented accumulation of exhausted CD8 + PD1 + T cells in their vicinity. In an ESCC murine model, a more robust infiltration and cytokine production, coupled with diminished PD-1 expression on both CD4 + and CD8 + T cells, is noted in the PLCE1 -/- genotype. This effect was particularly prominent upon ENO1 inhibitor administration. Conclusions: Our investigation elucidates that PLCE1 orchestrates the glycolytic pathway in ESCC by upregulating the expression of ENO1, consequently hindering the infiltration and activation of CD8 + T cells, thus fostering an immunosuppressive TIME.
Relapse Hodgkin lymphoma autologous stem cell transplant long term follow up.
Authors: Sabree Abedrabo
Journal: Journal of Clinical Oncology (2024)

e19031 Background: Autologous Stem Cell Transplantation (ABMT) is a standard treatment approach for patients with relapsed Hodgkin’s Lymphoma (HL). We wish to report long term (&gt;10 year) outcomes for patient’s with HL treated with ABMT at our institution. Methods: We treated 35 patients over a 30 year time period (1992-2022). Of these 35 patients, there were 19 males and 16 females with a median age of 41 years (range 21-70 years) and a median performance status of 1 (0-1). The preparative regimen was carmustine, etoposide, and melphalam (CEM, 1992-2005) and BCNU, etoposide, cytarabine and melphalan (BEAM, 2006 to present). Bretuximab was added to BEAM in 2018 as post-transplant consolidation therapy in 13 patients. All patients underwent mobilized peripheral blood stem collections with high dose filgrastim, and starting in 2008 were mobilized with both filgrastim and plexiform. The required stem cell product was at a minimum of 2 million CD34+ cells per kilogram of body weight. Results: Fifteen patients received CEEM and 9/15 (60%) achieved a complete response (CR). Twenty patients received BEAM and 16/20 (80%) achieved a CR, p=0.27 (Fisher’s exact test). The median time to hematological recovery was 12 days (range 8-21). Treatment related complications included: S. epidermis sepsis (3 patients), E. coli sepsis (3 patients), and esophageal perforation that lead to death in 1 patient. With a median follow up 13 years (range 1-23 years), the actual 10 year disease free survival (DFS) is 52% and overall survival (OS) is 64%. The actuarial DFS and OS at 15 years are 52% and 64% respectively. Six patients are in continuous CR for greater than 20 years. Long term complications at greater than 15 years include: cardiomyopathy (5 patients), breast cancer (1 patient), and liposarcoma (1 patient). Conclusions: Patients with relapsed HL can achieve long term curative outcomes when treated with ABMT with most frequent long term complication being cardiomyopathy.
Efficacy and safety of SOX regimen combined with inetetamab as first-line treatment for HER2-positive advanced gastric cancer.
Authors: Ying Kong, Qi Dong, Peng Jin, Yan Ming Li, Li Ma, Yan Hai Liu
Journal: Journal of Clinical Oncology (2024)

e16028 Background: Patients with HER2-positive advanced gastric cancer have a poor prognosis. Trastuzumab combined with chemotherapy is the first-line standard treatment. Inetetamab is a novel anti-HER2 drug, and its efficacy and safety in gastric cancer have not been reported yet. Methods: Thirty-eight patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma were randomly divided into two groups: one group received inetetamab combined with the SOX regimen, and the other group received trastuzumab combined with the SOX regimen. After 4-6 cycles, patients with stable disease received maintenance therapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Results: Thirty-seven patients completed the trial, with 18 patients in the inetetamab group and 19 patients in the trastuzumab group. In the inetetamab group, the median PFS was 8.5 months, compared to 7.3 months in the trastuzumab group (P = 0.046), indicating a significant difference. The median OS was 15.3 months vs. 14.3 months (P = 0.46), and the ORR was 50% vs. 42% (P = 0.63), with no significant differences between groups. Common AEs included leukopenia, thrombocytopenia, nausea, and vomiting. The incidence rates of grade ≥ 3 AEs were 56% in the inetetamab group and 47% in the trastuzumab group (P = 0.63), with no significant difference. Conclusions: In the first-line treatment of HER2-positive advanced gastric cancer, the efficacy of inetetamab and trastuzumab was comparable. The inetetamab group had superior PFS benefits, and both groups had good safety.
Efficacy and safety of surufatinib, toripalimab, nab-paclitaxel in combination with radiotherapy or surgery in the first-line treatment of esophageal squamous cell cancer: A single-centered prospective clinical trial.
Authors: Xiang Huang, Jing Chen, Hongchi Wang, Yang Cong, Ye Li, Fang Liu
Journal: Journal of Clinical Oncology (2024)

e16047 Background: Chemotherapy(CT) plus immune checkpoint inhibitors (ICIs) has become the current standard of care in the first-line treatment of metastatic esophageal squamous cell cancer(ESCC). In locally advanced setting, radiochemotherapy with or without resection remains the standard of care. Surufatinib, a novel small-molecule kinase inhibitor targeting VEGFR1-3, FGFR and CSF-1R, in combination with PD-1 inhibitors have demonstrated synergistic anti-tumor activities in previous studies. This single-centered prospective clinical trial aims to evaluate the efficacy and safety of surufatinib(SUR), toripalimab(TOR), nab-paclitaxel(NAB) in combination with radiotherapy or surgery in the first-line treatment of locally advanced(LA) or metastatic(R/M) ESCC. Methods: Eligible patients(pts) with confirmed LA or R/M, ECOG PS 0-2 and no prior systematic treatment were enrolled in the trial. Pts would receive 260mg/m 2 NAB and TOR 240mg on day 1 and SUR 250mg once daily in each 21-day cycle as induction therapy for two cycles, followed by surgery or another two cycles of concurrent chemoradiotherapy(CCRT) with NAB, SUR and radiotherapy, in which involved-field irradiation were conducted at the dose of 50-63 Gy/25-30F, 1.8-2 Gy per fraction, 5 fractions per week. As maintenance therapy, daily SUR and TOR every three week were administered until disease progression or unacceptable toxicities. Progression-free survival (PFS) was the primary endpoint. Results: As of Jan 7, 2024, 16 pts were enrolled, of whom 15 were evaluable. 14(87.5%) pts were male. The median age was 69.5 (range: 45-79). Tumor located in upper(18.8%), middle(25%) and lower(56.2%) thoracic. 1(6.2%) is Stage II disease, 12(75%) Stage III and 3(18.8%) Stage IV. 8 (50%) pts were with PD-L1 CPS greater than 1, 5 (31.25%) pts greater than 5, and 3 (18.75%) pts greater than 10. PD-L1 CPS of 6(37.50%) pts was unknown. With a median follow-up time of 5 (range: 1-12) months, despite the immatureness of PFS, the 12-month PFS rate was 77.14% (95% CI: 48.89%-100%). The objective response rate was 93.3% (14/15), and disease control rate was 100% (15/15). Five of the included pts met the resection criteria during treatment and underwent subsequent R0 resection. The most common adverse events (≥20%) of all grades were hypoesthesia (62.5%), nausea and vomiting (50%), and white blood cell decrease (43.75%). Conclusions: The combination ofsurufatinib, toripalimab, nab-paclitaxel with radiotherapy or surgery has demonstrated promising efficacy and a well-tolerated safety profile as a potential first-line treatment for LA or R/M ESCC. This ongoing trial merits further investigation and holds significant implications for clinical practice.
A phase 1, first-in-human study of CUSP06, a cadherin-6 (CDH6) -directed antibody-drug conjugate, in patients with platinum-refractory/resistant ovarian cancer and other advanced solid tumors.
Authors: Alexander I. Spira, Elizabeth Katherine Lee, Roisin Eilish O'Cearbhaill, Patricia LoRusso, Gerald Steven Falchook, Manish R. Patel, Debra L. Richardson, Nicole Covino, Wei Lu, Priya Marreddy, Daphne L. Farrington, Jennifer J. Wheler, Eric Daniel Slosberg, Vivek Subbiah, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2024)

TPS3166 Background: Cadherin-6 (CDH6) is a transmembrane glycoprotein involved in cancer metastasis and invasion expressed in various tumor types including ovarian cancer (OC), renal cell carcinoma (RCC), papillary thyroid cancer, cholangiocarcinoma, hepatocellular cancer, glioma, uterine serous carcinoma and non-small cell lung cancer. CUSP06 is an antibody-drug conjugate composed of a human IgG1 monoclonal antibody against CDH6 conjugated with a protease-cleavable linker, T1000, to exatecan, a topoisomerase I inhibitor payload. In preclinical studies, CUSP06 showed CDH6-dependent cell growth inhibition in ovarian cancer cell lines. High CDH6-expressing ovarian and renal CDX and PDX models demonstrated tumor regression after treatment with CUSP06, as did low CDH6-expressing PDX models of other solid tumors. Methods: This is a Phase 1a/1b, open-label, multicenter dose escalation and expansion study to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), recommended Phase 2 dose (RP2D), and preliminary efficacy of CUSP06 in patients with platinum-refractory/resistant ovarian cancer (PRROC), advanced RCC and other advanced CDH6-positive solid tumors. Patients with advanced solid tumors previously treated with standard of care systemic therapy, or for whom no standard therapy is available are eligible for enrollment. Prescreening for CDH6 expression will be required for those patients with solid tumors other than PRROC or RCC. CUSP06 will be administered intravenously every 21 days. Phase 1a will follow a standard 3+3 dose escalation design. Phase 1a also includes up to 3 dose enrichment cohorts at doses that have demonstrated safety, each with a maximum of 18 patients, to generate additional safety, PK, PD, and preliminary efficacy data to support an optimized dose for expansion. Phase 1b consists of several dose expansion cohorts including PRROC, RCC, and other CDH6-positive solid tumors, to be enrolled according to Simon's 2-stage design. Mandatory pre- and on-study biopsies in dose expansion cohorts will support a robust exploratory biomarker plan that may include correlation of CDH6 levels with response, and other RNA and protein markers of sensitivity and resistance. The study is currently enrolling in Phase 1a dose-escalation. Clinical trial information: NCT06234423 .
Polymeric micellar paclitaxel plus cisplatin combined with tislelizumab as the first-line treatment of advanced unresectable esophageal squamous cell carcinoma: A phase II study.
Authors: Guochun Cao, Xiaoyou Li, Delin Liu, Jinghua Zhu
Journal: Journal of Clinical Oncology (2024)

e16022 Background: Immunotherapy combined with chemotherapy has become the standard first-line treatment for advanced and metastatic esophageal squamous cell carcinoma (ESCC). However, the prophylactic use of hormones, a routine preconditioning regimen of paclitaxel, may weaken the immune response. Polymeric micellar paclitaxel is a new formulation of paclitaxel without polyoxyethylene castor oil solvent, which do not need for pretreatment with anti-allergy drugs before administration. We aimed to evaluate the efficacy and safety of polymeric micellar paclitaxel (pm-Pac) plus cisplatin combined with tislelizumab for unresectable advanced ESCC. Methods: This is a single-center, single-arm, prospective phase II clinical trial. Stage IV ESCC patients diagnosed histologically or cytologically without systemic treatment are eligible for this study. Polymeric micellar paclitaxel plus cisplatin combined with tislelizumab was treated for 2 cycles. After imaging evaluation, if there was no disease progression, an additional two cycles of treatment were completed, followed by maintenance treatment with tislelizumab for one year. At day 1 of each therapy cycle, patients were given pm-Pac 230 mg/m2 followed by cisplatin 70 mg/m2 combined with tislelizumab 200 mg via intravenous infusion, every three weeks. This trial planned to include 30 patients. The primary endpoint was objective response rate (ORR) determined by the independent review committee. And the secondary endpoints included overall survival, progression-free survival evaluated based on the Response Evaluation Criteria in Solid Tumors (version 1.1), as well as the incidence and severity of adverse events. Results: From September 2022 to January 2024, 31 patients were included in the trial. Median age was 65 years, 29 (93.5%) patients were male. Median follow-up was 13.1 months, 2 patient achieved complete response (CR), 19 of them showed partial response (PR), 8 stable disease (SD), illustrating an ORR of 67.7% and a DCR of 93.5%. Median PFS was 7.3 months. The most common AEs were neutropenia (90.3%), nausea(83.8%) and thrombocytopenia (25.8%). No grade 3 or higher immune-related AE was observed, and there were no treatment-related deaths. Conclusions: The pm-Pac plus cisplatin combined with tislelizumab as first-line treatment of unresectable advanced ESCC showed effective without new safety signal. This combination therapy may have great efficacy, but multi-center randomized trials with larger sample size are warranted in further.