tbuckley/cabot-search huggingface dataset:
Association between Kidney Stones and CKD
Authors: Le-Ting Zhou, Ahmed E. Ali, Muthuvel Jayachandran, Zejfa Haskic, Peter C. Harris, Andrew D. Rule, Kevin Koo, Shannon K. McDonnell, Nicholas B. Larson, John C. Lieske
Journal: Journal of the American Society of Nephrology (2024)

Key Points Common kidney stones are unlikely to be an independent and direct cause of CKD in the general population. CKD may protect against kidney stones because of changes in key urinary factors critical for stone formation. Background Kidney stones and CKD are common disorders with a substantial interaction. Although observational studies have suggested a potential for enhanced CKD risk after prior kidney stones, the exact relationship remains ambiguous. Methods Shared comorbidities between two diseases were identified using unbiased screening. Genome-wide association study summary statistics were obtained from the UK Biobank (UKBB), FinnGen, and CKDGen, followed by genetic association analyses across various traits. Bidirectional Mendelian randomization (MR) analyses were performed to define causal links, complemented by multivariable MR that included the shared comorbidities including hypertension, diabetes, and obesity. Observational analyses were undertaken using cohorts from the Mayo Clinic and a UKBB subset. Results Despite identifying a total of 123 conditions as shared comorbidities, there was no significant genetic correlation between kidney stones and CKD. Unadjusted MR analysis revealed no significant association between kidney stones and CKD risk (UKBB [exposure]/FinnGen [outcome]: odds ratio [OR]=0.97, 95% confidence interval [CI], 0.88 to 1.06; FinnGen/UKBB: OR=1.17, 95% CI, 0.98 to 1.39). Kidney stones did significantly associate with a higher urinary albumin-creatinine ratio ( β =0.014, 95% CI, 0.002 to –0.025), but this association disappeared in the multivariable MR model ( β =0.009, 95% CI, −0.003 to 0.020). Furthermore, in a cross-sectional analysis limited to the UKBB cohort, a robust regression model did not detect an independent association between kidney stones and urinary albumin-creatinine ratio ( β =0.16, 95% CI, −0.04 to 0.35) or eGFR ( β =0.10, 95% CI, −0.07 to 0.28). Conversely, CKD associated with a diminished risk of kidney stones in multivariable MR models (UKBB/FinnGen: OR=0.77, 95% CI, 0.69 to 0.87; FinnGen/UKBB: OR=0.73, 95% CI, 0.66 to 0.81). Furthermore, in the Mayo Clinic cohort with available urinary biochemistries, lower eGFR was associated with lower urinary calcium excretion and urinary calcium oxalate/phosphate supersaturation. Conclusions In this study, kidney stones were not independently associated with CKD. Conversely, CKD was associated with a lower risk of calcium kidney stones likely via changes in key urinary traits, including lower calcium excretion.
Robot-assisted kidney transplantation: a propensity score-matched cohort analysis of early experience
Authors: Seung J. J. Kim, Sangwan Kim, Ara Cho, Ahram Han, Jongwon Ha, Sangil Min
Journal: International Journal of Surgery (2024)

Background: Kidney transplantation is the preferred treatment for patients with end-stage kidney disease. Since the introduction of robot-assisted kidney transplantation (RAKT), several centers have applied this technique as an alternative to open kidney transplantation (OKT). The objective of this study is to analyze our early experience, focusing on surgical technique and learning curve, and postoperative outcomes of RAKT. Methods: The authors retrospectively reviewed 782 living donor kidney transplantation recipients between January 2018 and January 2024. A propensity score-matched cohort of 50 RAKT and 150 OKT patients was evaluated for intraoperative and postoperative variables. Shewhart control charts and CUSUM analysis were used to evaluate the technical outcomes and learning curves of RAKT. Postoperative eGFR values, complications, and biopsy results were compared for overall graft function and safety. Results: RAKT patients were associated with significantly longer overall operative, rewarming, and anastomosis times. Although overall postoperative eGFR trends showed comparable graft function between RAKT and OKT recipients (51.35±2.64 vs. 54.01±1.45; P =0.315), RAKT patients with extremely long rewarming times exhibited aggravated chronic scores at 1-year protocol biopsies (Δ Chronicity Index=4.45±1.92, P &lt;0.001). CUSUM analysis of rewarming time revealed that proficiency in RAKT is achieved after ~15 cases. Conclusions: Despite longer anastomosis and ischemic times, even during the early stages of RAKT adoption, the RAKT group did not differ significantly in graft function or postoperative complications from the OKT group.
<sup>68</sup>Ga-FAPI-04 positron emission tomography/computed tomography (PET/CT) for detecting occult peritoneal metastasisin locally advanced gastric cancer: A single-center prospective cohort study.
Authors: Qiancheng Hu, Hongfeng Gou, Jiankun Hu
Journal: Journal of Clinical Oncology (2024)

4081 Background: Occult peritoneal metastasis (OPM) is a common finding in patients diagnosed with advanced gastric cancer. Preoperative diagnosis of OPM is crucial for developing treatment strategies and for evaluating the prognosis of patients with locally advanced gastric cancer. To evaluate the accuracy of 68 Ga-FAPI-04 PET/CT in diagnosing OPM in locally advanced gastric cancer. Methods: This was a prospective, observational, single-center, single-blind, cohort study. Patients with histologically proven locally advanced gastric or gastroesophageal junction adenocarcinoma on initial staging evaluation were recruited. Laparoscopic staging and cytological analysis of peritoneal washing served as reference standards for the final diagnosis. The primary outcome was the proportion of participants changing treatment strategy from curative to palliative treatment. Results: A total of 49 patients were recruited between November 2022 and July 2023 .Nine of the 49 patients were diagnosed with OPM following 68 Ga-FAPI-04 PET/CT examinations. A total of 18.4% (n=9) of patients with locally advanced disease on initial staging evaluation by contrast-enhanced CT were upstaged to stage IV for peritoneal metastasis on 68 Ga-FAPI-04 PET/CT. The sensitivity of 68 Ga-FAPI-04 PET/CT in detecting OPM was 85.7%, and the specificity was 92.3%. The overall diagnostic accuracy of 68 Ga-FAPI-04 PET/CT was 91.8%. Based on ROC curve analysis, the area under the curve (AUC) was 0.893 (95% CI: 0.734–1). Conclusions: The findings of this study suggest a significantly additional value of 68 Ga-FAPI-04 PET/CT in detecting OPM. Thus, it would be useful to include 68 Ga-FAPI-04 PET/CT in the guidelines for staging locally advanced gastric cancer, instead of laparoscopic staging. Clinical trial information: ChiCTR2300067591.
A phase 2 study of trifluridine/tipiracil (FTD/TPI) in recurrent/metastatic nasopharyngeal (r/m NPC) carcinomas with or without prior exposure to fluoropyrimidines.
Authors: Jia Li Low, Wan Qin Chong, Edwin Pun Hui, Winky Lai, Candice Le, Kenneth Sooi, Robert John Walsh, Anthony T. C. Chan, Boon C. Goh, Brigette Ma
Journal: Journal of Clinical Oncology (2024)

6032 Background: Despite effective local treatment, up to 30% of patients with nasopharyngeal carcinoma (NPC) relapse and require systemic treatment. There are limited therapeutic options beyond cisplatin, gemcitabine and immunotherapy and the median survival of r/m disease is about 20 months. Capecitabine, a fluoropyrimidine, has shown some efficacy with a median time to progression of 4.9 months in heavily pretreated r/m NPC but there is a need for alternative treatments. FTD/TPI is an oral drug combination of trifluridine and tipiracil, a thymidine phosphorylase inhibitor preventing rapid degradation of trifluridine, thus increasing its exposure. It has shown activity in colorectal, gastric and breast cancers despite prior fluoropyrimidines. This study explores the efficacy and safety of FTD/TPI in r/m NPC, with or without prior exposure to fluoropyrimidines. Methods: In this single-arm phase II trial, patients were administered oral FTD/TPI twice daily at 35mg/m 2 on days 1-5 and 8-12 of a 28-day cycle. The primary endpoint was disease control rate (DCR) at 12 weeks, with secondary endpoints including progression-free survival (PFS), overall response rate (ORR), safety, and tolerability. Results: A total of 33 patients were recruited. Median age was 56 years (range: 34-82), most were males (n=27, 82%), with median of 3 (range: 1-12) prior lines of treatment in the metastatic setting. Approximately half (48.5%) received prior fluoropyrimidines. DCR at 12 weeks was 63.6%, with an ORR of 18.2%. DCR was 68.8% and 58.8% in patients with and without prior fluoropyrimidine exposure respectively. Median PFS was 6.5 months (95% CI 2.8-10.2) and overall survival was 13.1 months (95% CI 7.1-19.2). FTD/TPI demonstrated a manageable safety profile, with most common treatment-related adverse events of neutropenia, anaemia, fatigue, nausea and anorexia. 60% of patients required dose modifications, most commonly due to neutropenia, that could be overcome by dose reduction or prolongation to 5-weekly cycles. 1 patient required discontinuation due to anaemia resulting in syncope. Conclusions: FTD/TPI is well tolerated, compares favorably to Capecitabine and showed promising anti-tumor activity with meaningful clinical benefit regardless of prior exposure to fluoropyrimidines. This oral chemotherapy offers an attractive choice for patients valuing quality of life, minimizing hospital visits and resource utilization such as chemotherapy infusions. Further investigations in randomized studies are warranted. Clinical trial information: NCT04627961 .
Neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin for locally advanced resectable esophageal squamous cell carcinoma: A prospective phase 2 study.
Authors: Haiping Jiang, Peng Ye, Ning Li, Hui Wu, Yongfeng Ding, Xin Xu, Ying Ma, Xiao-Dong Teng, Songxiao Ji, Jingjie Li
Journal: Journal of Clinical Oncology (2024)

e16097 Background: Whether combined immunotherapy on the basis of neoadjuvant chemotherapy is beneficial for locally advanced esophageal squamous cell carcinoma (ESCC) remain to be inconclusive. This phase 2 study (ChineseClinical Trial Registry: ChiCTR2000041081) evaluate the efficacy and safety of neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin in locally advanced ESCC. Methods: Patients with locally advanced ESCC (T2N+M0, T3N0-2M0, T4aN0-2M0, or no distant metastases, or viable or potentially viable) were enrolled and received 3 cycles of neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin. Surgery was scheduled within four to six weeks of completing the neoadjuvant treatment. Three additional cycles of adjuvant sintilimab monotherapy or sintilimab plus chemotherapy were scheduled after a multidisciplinary discussion. The primary endpoint was the MPR rate. Results: From November 2020 to November 2021, twenty-four patients (median age: 64.5 years, men: 21/24,lower segment tumor location12/24,stage IV disease 15/24) were included in this study. All patients completed three cycles of neoadjuvant treatment and surgery. The median dose intensities for sintilimab, carboplatin and albumin-bound paclitaxel were 100% (range, 66.7–105.0%), 98.4% (range, 64.1–104.0%), and 100% (range, 38.1–105.8%), respectively. The R0 resection rate was 100%. The pCR rate and MPR rate was 33.3% and 41.7%. Among the 10 patients with PD-L1 CPS of ≥1, the pCR and MPR rates were 40% and 50%. 20 (83.1%) had TNM downstaging. The median DFS and median OS had not been reached yet, 500 days DFS and OS rate was 85.3% (95%CI 85.4%-97.2%) and 94.1% (95%CI 94.8%-100.0%). PD-L1 protein expression showed a higher life expectancy trend in the post-neoadjuvant therapy esophageal tissue samples than in the pre-therapy samples. The most common grade 3-4 treatment-related adverse events were anemia (29.2%), increased gamma-glutamyl transferase level (4.2%) and hyponatremia (4.2%). Emergency reoperation and intensive care were not required, and there were no postoperative mortalities. Conclusions: Neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin preliminarily demonstrate encouraging clinical benefits and acceptable safety. Preoperative immunotherapy combined with chemotherapy alters the immune microenvironment of locally advanced resectable ESCC. Clinical trial information: ChiCTR2000041081.
Phase 1 trial of TU2218, TGFβ-RI and VEGF-R2 dual inhibitor in monotherapy and combination with pembrolizumab in patients with advanced solid tumors.
Authors: Do-Youn Oh, Anthony W. Tolcher, Arvind Chaudhry, Arielle Shebay Lee, Marya F. Chaney, Kyu-Pyo Kim, Hun-taek Kim
Journal: Journal of Clinical Oncology (2024)

2613 Background: Pembrolizumab interrupts PD-1/-L1 interaction and is efficacious in many cancers. However, resistance may emerge in some of the patients treated. VEGF and TGF-β pathways play an important role in the development and function of the tumor-microenvironment (TME), contributing to be the immunosuppressive. TU2218 is a highly potent, orally available dual inhibitor against TGFβ type I receptor (ALK5) and VEGFR2. This was a first-in-human study to investigate the safety and tolerability of TU2218 monotherapy and combination therapy with pembrolizumab. Methods: This non-randomized, open-label, multinational, multicenter study evaluated the safety, tolerability, PK, and preliminary efficacy of TU2218 alone and combination with pembrolizumab to determine the Recommended Phase 2 Dose of the Combination (RP2DC) in advanced solid tumors. Eligible patients were ≥ 18 years of age, ECOG performance status of 0 or 1 and had measurable lesion per RECIST 1.1. Part A of monotherapy was sequentially escalated to 6 dose levels of TU2218 ranging from 30 to 270 mg/day on a 2 weeks-on/1 week-off regimen using a BOIN design. In part B, patients received TU2218 doses of 105, 150 and 195 mg/day on a 2 weeks-on/1 week-off cycle in combination with pembrolizumab 200mg once every 3 weeks. Dose escalation followed a 3+3 design with a DLT evaluation period. Results: In the TU2218 monotherapy dosed BID (n=22), no Grade 3 or higher treatment related AE was reported, while all Grade 2 TRAEs were tolerable. Systemic exposure to TU2218 increased in a dose dependent manner. Following seven days of administration, TU2218 demonstrated reductions in PD markers and a correlation was observed between TU2218 exposure and the decrease of PD markers, particularly TGF-β1 (-16.5%) and CTGF (-45.4%) blood levels in groups of TU2218 Cmax ≥ 1.0 μM. Patients (n=12) received TU2218 at doses levels of 105 to 195mg/day in combination with pembrolizumab 200mg once every 3 weeks. The most frequently observed TRAE was pruritus (25%, n=3) and one patient experienced Grade 3 TRAE with maculo-papular rash (8.3%, n=1). No DLT was observed during the dose escalation and the MTD was not identified. The best ORR in the combination cohort demonstrated PR at 8.3% (n=1), SD 50% (n=6) and PD at 33% (n=4). The dose level at 195mg/day of TU2218 in combination with pembrolizumab was safe and tolerable. Conclusions: TU2218, a first-in-class oral dual inhibitor against TGFβRI and VEGFR2 was well-tolerated in the monotherapy and in the combination therapy with pembrolizumab. The RP2DC was established for subsequent trials in specific cancer types. Clinical trial information: Phase 1a: NCT05204862 / Phase 1b: NCT05784688 .
Initial results from phase I trial of a novel oncolytic adenovirus Ad-TD-nsIL12 in recurrent glioblastoma connecting to ventricular system.
Authors: Xiao Qian, Weihai Ning, Yuduo Guo, Shenglun Li, Dixiang Song, Deshan Liu, Lixin Ma, Yujia Chen, Chao Zhao, Jiacheng Xu, Yanming Qu, Haoran Wang, Chunyu Gu, Mingshan Zhang, Yaohe Wang, Louisa Chard Dunmall, Shengdian Wang, Hongwei Zhang
Journal: Journal of Clinical Oncology (2024)

2057 Background: Glioma is the most common primary central nervous system malignancy in adults, of which glioblastoma (GBM) accounts for more than 50% of the incidence and is the most aggressive subtype of glioma, with a median survival of about 15 months. Oncolytic virus emerges as a promising therapy for recurrent GBM (rGBM), but its safety and efficacy are not evaluated in patients with rGBM connecting to ventricular system. Methods: This is a dose-escalating trial to study the safety and efficacy of Ad-TD-nsIL12, a novel oncolytic adenovirus, in patients with rGBM connecting to the ventricular system. The assigned dose levels of Ad-TD-nsIL12 were 5x10 9 vp, 1x10 10 vp, and 5x10 10 vp. Adverse events (AEs) associated with the virus were graded using the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0), and Grade ≥ 3 AEs identified the dose-limiting toxicity (DLT). Tumor response was evaluated based on the Response Assessment in Neuro-Oncology (RANO) criteria. Results: Eight patients, aged from 45 to 71 years, were enrolled between December 2019 and September 2022, with treatment doses ranging from 5x10 9 to 5x10 10 vp. Grade 3 seizure according to CTCAE occurred in two patients from Cohort 3 (5x10 10 vp) after AD-TD-nsIL12 injection. Minimal adverse events were observed at a treatment dose of 1x10 10 vp, even after multiple injections. Complete response (CR) was demonstrated in one patient, partial response (PR) in one patient, stable disease (SD) in four patients and progressive disease (PD) in two patients. Immunohistochemical staining showed higher infiltrations of CD3 + , CD4 + and CD8 + T cells and positivity of E1A and Hexon in virus post-treated tissues. Inflammation associated cytokines in the blood were not significantly elevated by Ad-TD-nsIL12. Conclusions: AD-TD-nsIL12 treatment was safe and effective in patients with rGBM and warrants examination in a phase II clinical study. Clinical trial information: ChiCTR2000032402.
Efficacy and safety of recombinant human adenovirus type 5 (H101) combined with immune checkpoint inhibitors (ICIs) in patients with liver metastatic gastric cancer: A prospective multicenter phase II study (the TROJAN 021 study).
Authors: Min Yuan, Jing Xu, Zhongzheng Zhu, Zhuqing Liu, Wei Mao, Hui Wang, Dongliang Mao, Qiong Zhan, Xiaoping Li, Leizhen Zheng, Xiaohua Liang, Mei Wang, Qing Xu
Journal: Journal of Clinical Oncology (2024)

2635 Background: Immune checkpoint inhibitors (ICIs) have shown significant efficacy in metastatic gastric cancer, but some patients may not respond to them because of immune resistance. Recombinant Human Adenovirus Type 5 (H101), the world’s first oncolytic virus antitumor drug in China, can induce cell death, expose tumor antigens, provide adjuvants for anti-tumor immune priming, and potentially increase responsiveness to immunotherapies. Here, we presented the efficacy and safety of H101 combined with immune checkpoint inhibitors (ICIs) in patients with liver metastatic gastric cancer. Methods: In this multi-center, phase II trial (the TROJAN 021 study, ChiCTR1900027922), patients with liver metastatic gastric cancer received 2 cycles of H101 ultrasound guided injections into liver lesions, bi-weekly in combination with anti-PD-1 antibodies and chemotherapy bi-weekly until progression or intolerable toxicity. The primary objective was safety and objective response rate (ORR). Secondary objective included progression-free survival (PFS), overall survival (OS) and disease control rate (DCR). Efficacy assessments were performed every 4 weeks following RECIST v1.1 criteria. PFS and OS were estimated using the Kaplan-Meier method. Results: From September 2020 to September 2022, 21 patients were enrolled. Of them, 18 were males, median age was 66 years (range: 36-71) and ECOG performance status was either 0 (n=15) or 1 (n=6). 10 patients (47.6%) received as first-line therapy, 1 (4.8%) as second-line and 5 (23.8%) as third line and above therapy. The primary endpoint was met with a median PFS of 4.8 months. The median OS was 13.2 months. Objective tumor responses were CR (n=0), PR (n=7), SD (n=12) and PD (n=2). ORR was 33.3% (7/21), and DCR was 90.5% (19/21). Treatment related adverse events (TRAE) occurred in 12 patients (57.1%). The most frequently observed TRAEs were injection site pain (48.1%), fever (57.1%) and fatigue (23.8%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included neutropenia (2/21, 9.5%) and hypertension (1/21, 4.8%). Conclusions: These promising results show that combination of Recombinant Human Adenovirus Type 5 (H101) and ICIs demonstrated acceptable toxicity and promising antitumor efficacy in patients with liver metastatic gastric cancer. Further validation of the efficacy in a randomized prospective trial is warranted. Clinical trial information: ChiCTR1900027922.
Efficacy and safety of chidamide in combination with serplulimab and standard third-line treatments in advanced colorectal cancer: A single arm, exploratory phase 2 trial.
Authors: Wei Li, Mengdan Xu, Caihua Xu, Mengyao Wu, Kai Chen
Journal: Journal of Clinical Oncology (2024)

TPS3637 Background: The efficacy of third line and subsequent treatments for advanced colorectal cancer (mCRC) is suboptimal, and the available drug options are limited. Approximately 95% of mCRC patients belong to the type of satellite stability (MSS), which often shows poor response to single immunotherapy. Previous clinical trials have preliminarily demonstrated that the potential application of combining anti-angiogenesis drugs with immune checkpoint inhibitors (ICIs) in mCRC. Chidamide is an isoform selective inhibitor of histone deacetylase (HDAC). Studies have shown its synergistic effect with PD-1 monoclonal antibody in anti-tumor activity. Therefore, we aim to conduct further investigations centered on the combination of Chidamide+Serplulimab+standard third-line treatments in mCRC. Methods: This prospective, open-label, single-arm, exploratory multi-center clinical trial has been planned to enroll 30 patients with advanced CRC who have progressed after two lines of standard therapies. The key inclusion criteria are: pathologically confirmed colorectal malignancy; age ≥18 years, regardless of gender; estimated survival ≥3 months; ECOG score 0-1; at least one measurable lesion according to iRECIST criteria; requiring third-line or beyond treatment and no prior treatment with PD1 monoclonal antibody, regorafenib/fruquintinib or TAS-102±bevacizumab; adequate major organ function; and signed informed consent and good compliance, agreeing to cooperate with survival follow-up. Enrolled patients receive Chidamide (20mg twice a week), Serplulimab (3mg/kg on day 1 every two weeks), and standard third-line treatments (TAS-102 35mg/m² twice daily on days 1-5 and 8-12 of a 28-day cycle ± bevacizumab 5mg/kg on day 1 every two weeks or regorafenib 120mg daily or fruquintinib 5mg daily for three weeks followed by one week off ).The primary endpoints are safety and objective response rate (ORR) determined by investigators. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate(DCR), PFS rate at 6 months and 12 months, OS rate at 6 months and 12 months, DCR, quality of life score(QoL), and nutritional score PG-SGA. As of February 2024, eight patients have been enrolled in the study. Trial registration number: ChiCTR2300077213. Clinical trial information: ChiCTR2300077213.