tbuckley/cabot-search huggingface dataset:
Correlation of noninvasive imaging of tumour-infiltrating lymphocytes with survival and BCG immunotherapy response in patients with bladder cancer：a multicentre cohort study
Authors: Ke Chen, Xiaoyang Li, Libo Liu, Bo Wang, Weiming Liang, Junyu Chen, Mingchao Gao, Xiaodong Huang, Bohao Liu, Xi Sun, Tenghao Yang, Xiao Zhao, Wang He, Yun Luo, Jian Huang, Tianxin Lin, Wenlong Zhong
Journal: International Journal of Surgery (2024)

Tumour-infiltrating lymphocytes (TILs) are strongly correlated with the prognosis and immunotherapy response in bladder cancer. The TIL status is typically assessed through microscopy as part of tissue pathology. Here, the authors developed Rad-TIL model, a novel radiomics model, to predict TIL status in patients with bladder cancer. The authors enrolled 1089 patients with bladder cancer and developed the Rad-TIL model by using a machine-learning method based on computed tomography (CT) images. The authors applied a radiogenomics cohort to reveal the key pathways underlying the Rad-TIL model. Finally, the authors used an independent treatment cohort to evaluate the predictive efficacy of the Rad-TIL model for Bacillus Calmette-Guérin (BCG) immunotherapy. The authors developed the Rad-TIL model by integrating tumoral and peritumoral features on CT images and obtained areas under the receiver operating characteristic curves of 0.844 and 0.816 in the internal and external validation cohorts, respectively. Patients were stratified into two groups based on the predicted radiomics score of TILs (RSTIL). RSTIL exhibited prognostic significance for both overall and cancer-specific survival in each cohort (hazard ratios: 2.27-3.15, all P<0.05). Radiogenomics analysis revealed a significant association of RSTIL with immunoregulatory pathways and immune checkpoint molecules (all P<0.05). Notably, BCG immunotherapy response rates were significantly higher in high-RSTIL patients than in low-RSTIL patients (P=0.007). The Rad-TIL model, a noninvasive method for assessing TIL status, can predict clinical outcomes and BCG immunotherapy response in patients with bladder cancer.
Efficacy and safety of SHR-2554 in advanced epithelioid sarcoma: A phase 2 trial.
Authors: Yan Zhou, Xiaomin Ding, Yawen Zhang, Jinrong Liang, Hongli Xu, Luyuan Tian, Changhong Zhao, Haiyan Hu
Journal: Journal of Clinical Oncology (2024)

11549 Background: Epithelioid sarcoma (ES) is a rare and aggressive subtype of soft-tissue sarcoma. The loss of SMARCB1 (INI1) expression which leads to oncogenic dependence on the transcriptional repressor EZH2 has been observed in over 90% of ES. Patients (pts) with metastatic ES have a poor prognosis. We investigated the efficacy and safety of SHR-2554, an oral selective EZH2 inhibitor, in pts with refractory ES. Methods: To be eligible for inclusion, pts had to fulfill the following criteria: 8 years or older; histologically confirmed advanced or metastatic ES with loss of INI1 or upregulated mRNA level of EZH2; progressive disease after at least one line of doxorubicin-containing chemotherapy; the presence of measurable disease according to RECIST 1.1; an ECOG performance status of 0-1. Pts received SHR2554 (350 mg, bid, po) until disease progression or unacceptable toxicity. The primary endpoint was progression-free rate at 12 weeks. A Simon two-stage design was applied. If there were 3 pts remaining progression-free at 12 weeks within the first 9 pts, the cohort would expand to 17 pts and the outcome would be positive if more than 7 pts remained progression-free at 12 weeks. Results: Between Jul 2021 and Dec 2023, a total of 17 pts were enrolled and received at least 1 dose of SHR-2554. The median age was 32 years (range 8-57) and 41.2% were males. 9 (52.9%) pts had received immunotherapy targeting PD-1/L1 and 6 (35.3%) pts had received anti-angiogenesis therapy before enrollment. The median line of previous treatment was 2 (range 1-4). Loss of INI1 was confirmed in 14 (82.4%) pts. Tumor response was evaluated in 14 pts at data cutoff. 9 (64.3%) of 14 pts remained progression-free at 12 weeks. The primary endpoint was met. Based on investigator assessment, 3 (21.4%) of 14 pts achieved partial response and 8 (57.1%) pts had stable disease as best response. Adverse events (AEs) were generally mild. The most common treatment-related hematological AEs were anaemia, platelet count decreased and hyperuricaemia. Conclusions: SHR-2554 showed promising efficacy and an acceptable safety profile in pts with refractory ES, warranting further investigation. Clinical trial information: ChiCTR2100046099.
Engineered autologous nasal cartilage for repair of nasal septal perforations – a case series
Authors: Benedict Kaiser, Sylvie Miot, Anke Wixmerten, Oliver Pullig, Matthias Eyrich, Ilario Fulco, Josef Vavrina, Dirk J. Schaefer, Ivan Martin, Andrea Barbero, Martin D. Haug
Journal: International Journal of Surgery (2024)

This phase I clinical trial assessed the use of autologous nasal chondrocyte tissue-engineered cartilage (N-TEC) for functional repair of nasal septal perforations (NSP).
Camrelizumab combined with chemotherapy followed by maintenance camrelizumab and apatinib as first-line therapy for extensive-stage small cell lung cancer: A phase II, single-arm, exploratory study.
Authors: Yanbin Zhao, Minghui Zhang, Jinglei Liu, Haihong Pu, Yinghong Li, Xin Li, Yan Wang
Journal: Journal of Clinical Oncology (2024)

e20107 Background: Extensive-stage small-cell lung cancer (ES-SCLC), a type of aggressive tumor known as with limited therapeutic options and poor prognosis in the past decades, had recently been proved curatively effective by the combination of immune checkpoint inhibitor and platinum-based chemotherapy. Nonetheless, it is still worthy and necessary to explore the new treatment pattern considering the rapid disease progression feature of ES-SCLC. Whereupon, this study aims to explore the effectiveness and safety of camrelizumab combined with chemotherapy followed by maintenance camrelizumab and apatinib in the first-line treatment of ES-SCLC. Methods: In this phase II study, 40 patients with pathological diagnosis of ES-SCLC and without receiving prior systemetic therapy are anticipated to be enrolled, and will be dosed camrelizumab (200 mg, iv, q3w) combined with etoposide (80-100 mg/m 2 , iv, q3w, 4-6 cycles) and platinum drugs (selected by the researcher accordingly, iv, q3w, 4-6 cycles), followed by maintenance with camrelizumab and apatinib (250 mg, qd). The primary endpoint is 6-month progress-free survival (6-month PFS) rate while the secondary endpoints are objective response rate (ORR), disease control rate (DCR), progression-free survival, overall survival and safety. Results: Up to January 24, 2024, 31 patients with a median age of 60 years (ranged from 38 to 75 years of age) were enrolled. Among them 28 patients out of 31 were capable for efficacy analysis, of which 23 patients achieved partial response, 3 had stable disease and 2 progressive disease. The ORR and DCR reached 82.14% and 92.86%, respectively. The 6-month PFS rate in evaluable patients was 75.44% and the median PFS was and 7.56 months. The median OS was 15.38 months. During the course of therapy, the grade 3 or worse treatment-related adverse events were hypertension (6.45%), increased ALT level(3.26%), increased AST level(3.26%), increased γ-GT(3.26%)and hypertriglyceridemia (3.26%). Common grade 1-2 adverse reactions included anemia(54.84%), nausea (54.84%), vomiting(45.16%). The treatment was well tolerated and no toxic death occurred. All the adverse events can be controlled and alleviated after symptomatic treatment. Conclusions: Camrelizumab with chemotherapy followed by maintenance camrelizumab plus apatinib showed preliminary efficacy and acceptable safety profile, and might be a promising regimen as first-line treatment in ES-SCLC. Clinical trial information: ChiCTR2000035599.
A phase II clinical trial of metformin combined with FOLFIRI plus bevacizumab as second-line therapy in patients with <i>RAS</i>-mutant metastatic colorectal cancer.
Authors: Wen-zhuo He, Chang Jiang, Jiahong Yi, Ju Xue, Zhao-feng Yin, Wen-jing Dong, Liang-Ping Xia
Journal: Journal of Clinical Oncology (2024)

3534 Background: Metastatic colorectal cancer (mCRC) patients with RAS mutations are confronted with limited novel targeted therapy. We previously reported that KRAS mutation mediated MATE1 down-regulation sensitizes colorectal cancer cells to metformin. Based on our preclinical research, we designed a study to explore whether metformin combined with FOLFIRI plus bevacizumab would improve efficacy in RAS mutant mCRC. Methods: This single-arm, multicenter trial (ChiCTR2000037943) recruited patients with RAS mutant mCRC that had failed to first-line bevacizumab plus an oxaliplatin-based regimen of systemic therapies. Patients received metformin 1000mg PO twice daily on day 1-14, plus irinotecan 180 mg/m² IV, calcium folinate 400 mg/m² IV, fluorouracil 400 mg/m² IV, and a 46-h CIV of fluorouracil 2400 mg/m², and bevacizumab 5 mg/kg IV, repeated every 14 days. We used Simon's two-stage design. The primary endpoint was objective response rate (ORR). The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: One hundred sixteen patients were recruited between July 2020 and March 2023. KRAS codon 12 mutations were present in 81 cases (69.8%), codon 13 mutations in 17 cases (14.7%), codon 61 mutations in 6 cases (5.2%), and codon 146 mutations in 3 cases (2.6%). For the 81 patients with KRAS codon 12 mutation, 42 were with G12D (51.9%), 21 with G12V (25.9%), 7 with G12A (8.6%), and 6 with G12C (7.4%) mutation. The ORR was 21.6% (25/116), and DCR was 76.7% (89/116). The median PFS was 8.0 months, and patients without liver metastasis had longer PFS than those with liver metastasis (9.5 months vs. 5.6 months, P &lt; 0.001). For the 45 patients without liver metastasis, the administration of metformin combined with FOLFIRI plus bevacizumab as second-line therapy resulted in significantly longer PFS than the first-line bevacizumab plus an oxaliplatin-based regimen (9.5 months vs. 7.9 months, P = 0.037). The median OS was not reached. The most common treatment-emergent adverse events (TEAEs) were neutropenia (73.7%), nausea (56.9%), anemia (54.3%) and diarrhea (49.1%). Grade 3 and above TEAEs occurred in 52 (44.8%) patients. No treatment-related mortality occurred. Conclusions: Metformin combined with FOLFIRI and bevacizumab had promising efficacy and tolerable toxicity in RAS mutant mCRC patients as second-line therapy. Further study in phase 3 trials is warranted. Clinical trial information: ChiCTR2000037943.
First-line sintilimab combined with platinum-based chemotherapy in extensive stage small cell lung cancer: A phase II study and post-hoc biomarker analysis.
Authors: ChunXia Su, Mengqing Xie, Jing Zhao, Xiangling Chu, Li Liu
Journal: Journal of Clinical Oncology (2024)

e20127 Background: Immune checkpoint inhibitors (ICIs) combined with etoposide and platinum-based chemotherapy improves prognosis of patients with extensive-stage small-cell lung cancer (ES-SCLC). However, nearly 40% of patients do not benefit from Immunochemotherapy. Herein, this phase II study of first-line immunochemotherapy was conducted aiming to investigate potential biomarkers associated with therapeutic efficacy. Methods: A multi-center, single-arm, prospective phase II trial (ChiCTR2000038354) was designed and conducted to evaluate the efficacy and safety of sintilimab combined with platinum-based chemotherapy in patients with ES-SCLC who had not previously received treatment. The primary endpoint of this study is progression-free survival (PFS), with patients being defined as disease progression according to RECIST 1.1. Pre-treatment FFPE samples were analyzed using whole exome sequencing (WES) and whole transcriptome sequencing (WTS) to investigate biomarkers. Results: A total of 44 patients were included in the study, with a median follow-up of 10 months and a median PFS of 7.57 months. 8 patients with a PFS greater than 6 months were defined as the responder group (R group) and 5 patients with a PFS less than 6 months belonged to the non-responder group (NR group). WES and WTS were performed on the pre-treatment samples of these 13 patients. WES results revealed mutation frequencies of TP53 (69%), RB1 (31%) and FAT1 (31%) aligning with prior research. Significantly, ZFHX4 mutations correlated with R group (p = 0.05). Genomic instability, as defined by Homologous Recombination Deficiency (HRD) scores, displayed higher scores in NR group than in R group (p = 0.023), which suggests potential benefits of PARP inhibition in the NR group. WTS data revealed that higher M2/M1 macrophage ratio (p = 0.028) in NR group. Additionally, the NR group demonstrated significant VEGFA overexpression. Besides, NOTCH-signaling (p = 0.034), KRAS-signaling-DN (p&lt;0.001), Angiogenesis (p&lt;0.001) and EMT (p&lt;0.001) pathway were also enriched in NR group. Conversely, M1 macrophages (p = 0.079), CD4+T cells (p = 0.093), Mast cells (p = 0.045), NK cells (p = 0.045) and neutrophils (p = 0.06) was higher in R group. Conclusions: This study highlights genomic instability as well as activation of cancer hallmarks such as angiogenesis, EMT may result the resistance to immunotherapy in ES-SCLC patients. These findings may shed light on combinational strategy overcoming therapeutic resistance. Clinical trial information: ChiCTR2000038354.
Acupuncture for rehabilitation after total knee arthroplasty: A systematic review and network meta-analysis
Authors: Wen-Xuan Li, Cai-Qin Wu, Wei Feng, Yi-Jun Zhan, Lei Yang, Heng-Jie Jia, Jian Pei, Kun-Peng Li
Journal: International Journal of Surgery (2024)

The increasing interest in acupuncture for promoting postoperative rehabilitation has encouraged its use in rehabilitation after total knee arthroplasty (TKA), but its effectiveness remains controversial. This study aims to assess the efficacy of different models of acupuncture-related therapies on pain relief, motor function, inflammation, and overall rehabilitation of the knee after TKA. Databases PubMed, Embase, Cochrane, Web of Science, Scopus, and Clinicaltrials.gov were searched to screen eligible randomized controlled trials (RCTs). All RCTs that used acupuncture/moxibustion on TKA patients were included by two researchers independently after rigorous quality evaluation, with data extracted. The statistics were performed by using R 4.2.3 and Stata 17. The network meta-analysis incorporated 28 RCTs, 21 of which were conducted in mainland China and Taiwan. Evidence of the relation of several common acupuncture/moxibustion treatments was shown by the network meta-analysis (NMA). The results of NMA showed that electroacupuncture was the preferred therapy for soothing pain symptoms (standardized mean difference=0.58, 95% CI=0.36-0.81). Auricular acupressure was the best treatment to improve the knee motor function. Electroacupuncture was superior to special acupuncture in relieving knee joint stiffness and inflammation. Acupuncture intervention, especially electroacupuncture, can effectively alleviate pain, improve motion, reduce stiffness, and decrease inflammation in post-TKA patients with no serious adverse events.
INTASYL PH-762: PD-1 intratumoral immunotherapy for cutaneous carcinoma.
Authors: Mary C Spellman, Katharine Furst, Linda Mahoney
Journal: Journal of Clinical Oncology (2024)

TPS9620 Background: Immune checkpoint-targeted antibodies directed at PD-1 or PD-L1 block co-inhibitory receptors expressed by anti-tumor T cells, breaking immune tolerance against tumor cells and generating cancer immunity. Intratumoral (IT) immunotherapy aims to use the tumor as a ‘self-vaccine’. Local immune stimulation may induce robust priming of an anti-tumor immune response and generate abscopal tumor responses, mediated by circulating activated anti-tumor immune cells. Local delivery of immunotherapy minimizes systemic exposure and off-target toxicities and may decrease tumor size and improve surgical morbidity. PH-762 is an INTASYL compound designed to precisely silence PD-1 mRNA. INTASYL is a patented, self-delivering RNAi technology platform designed to impart specific properties to small interfering RNAs. PH-762’s unique structural and chemical modifications ensure an optimized cell and tissue uptake profile with IT administration. In vitro investigations have demonstrated efficient uptake of PH-762 by human T cells, silencing of PD-1 mRNA and subsequent protein reduction. Preclinical studies have shown that IT injections of murine-targeted PH-762 (mPH-762) can silence PD-1 mRNA in T cells within the tumor and increase the secretion of IFN-γ. mPH-762 was well tolerated at the maximum administered dose and treatment with mPH-762 provided robust and statistically significant inhibition of tumor growth. Toxicokinetic studies conducted in marmoset monkeys demonstrated that PH-762, when administered intravenously at doses of up to 147 mg/kg, is well-tolerated. No cytokine-release associated cytokines were detected in the plasma of treated monkeys at this dose. Methods: This open-label Phase 1 clinical study (NCT 06014086) is designed to evaluate the safety and tolerability of neoadjuvant use of IT PH-762 in cutaneous squamous cell carcinoma, melanoma, or Merkel cell carcinoma, to determine the pharmacokinetic profile of PH-762 after IT injection, to observe pathologic and immunologic tumor responses, and to determine the recommended dose for development. Escalating dose concentrations of PH-762 (from 1.14 mg/mL through 22.00 mg/mL) are tested serially in cohorts of 3 patients each. Patients receive IT PH-762 once weekly, 4 times over a 3-week period prior to surgical excision, which occurs 5 weeks after the initial injection. Following excision of the tumor, patients are followed for approximately 11 weeks. Tumor changes are evaluated per iRECIST criteria and pathological response. Immunological response in tumor tissue and blood samples are assessed as secondary endpoints. This clinical study, enrolling patients since November 2023, will establish the basis for continued clinical development of PH-762. Clinical trial information: 06014086.
Phase IB/II first line panitumumab, irinotecan, trifluridine/tipiracil in RAS wild-type patients with metastatic colorectal cancer: PIT study.
Authors: Timothy Jay Price, Rohit Joshi, Christos Stelios Karapetis, Pam Cooper, Chris Hocking, Nimit Singhal, Amanda Rose Townsend
Journal: Journal of Clinical Oncology (2024)

e15532 Background: Trifluridine/tipiracil (TT) is an oral fluoropyrimidine (FP) currently used in later line therapy. Preclinical data have demonstrated synergistic activity when panitumumab (Pmab) or irinotecan (Ir) are combined with TT supporting use in combination schedules in early line protocols. PIT was a phase IB/II study determining the maximum tolerated dose (MTD), safety and tolerability of substituting FP with TT, combined with Pmab and Ir in RAS wild-type mCRC. Methods: Phase IB 3+3 design dose escalation study (Dose level 1: TT 20mg/m2 oral BD, Ir 150mg/m2 IV, Pmab 6mg/m2). Primary objective was MTD of the combination in RAS WT mCRC patients, either 1 st or 2nd line. Treatment was administered in 14-day cycles. Pmab and Ir were administered intravenously on day 1 with TT dosed orally, bid, days 1-5. Once MTD was established the phase II expansion study was to enrol 50 previously untreated mCRC patients. Primary endpoint was modified to toxicity. Results: The study closed due to slow recruitment. 14 patients were enrolled from 6/18 to 10/21. Med follow up 23 months. Med age 59 yrs (range 37-74yrs). 60% were male. One patient each was BRAF MT and right sided. ECOG 0/1 50%/50%. Thirteen patients had PIT as first line, 57% had prior adjuvant therapy. There was one DLT in first 3 patients however based on additional toxicity data (Clin Cancer Res. 2020 Apr 1:1555) a decision was made to not dose escalate beyond level 1 and commence phase II. Overall Gd 3 toxicity: Acne/rash 46%, Diarrhoea 31%, Fatigue 8%, neutropenia 15%, hypomagnesaemia 23%. One patient had Gd 4 neutropenia and there was one treatment related death (neutropenic sepsis). 12 patients had evaluable disease, 58% PR, 42% SD. Survival: Med PFS 14.1 mths, Med OS 40.6mths and 12 mth OS 64%. Conclusions: The MTD was deemed TT 20mg/m2, irinotecan 150mg/m2 and panitumumab 6mg/kg. Toxicity was manageable however significant grade 3 diarrhoea and rash was seen. There was one toxic death contributed to therapy. Small numbers do make interpretation difficult however there is a signal of activity. The slow recruitment illustrates difficulty in exploring novel combinations in early lines and potentially the reluctance to consider first line anti-EGFR therapy. Clinical trial information: ACTRN12617001190392.
Racial Equity, Diversity and Inclusion in Bioethics: Recommendations from the Association of Bioethics Program Directors Presidential Task Force
Authors: Sandra Soo-Jin Lee, Alexis Walker, Shawneequa L. Callier, Faith E. Fletcher, Charlene Galarneau, Nanibaa’ Garrison, Jennifer E. James, Renee McLeod-Sordjan, Ubaka Ogbogu, Nneka Sederstrom, Patrick T. Smith, Clarence H. Braddock, Christine Mitchell
Journal: The American Journal of Bioethics (2024)

Recent calls to address racism in bioethics reflect a sense of urgency to mitigate the lethal effects of a lack of action. While the field was catalyzed largely in response to pivotal events deeply rooted in racism and other structures of oppression embedded in research and health care, it has failed to center racial justice in its scholarship, pedagogy, advocacy, and practice, and neglected to integrate anti-racism as a central consideration. Academic bioethics programs play a key role in determining the field's norms and practices, including methodologies, funding priorities, and professional networks that bear on equity, inclusion, and epistemic justice. This article describes recommendations from the Racial Equity, Diversity, and Inclusion (REDI) Task Force commissioned by the Association of Bioethics Program Directors to prioritize and strengthen anti-racist practices in bioethics programmatic endeavors and to evaluate and develop specific goals to advance REDI.