tbuckley/cabot-search huggingface dataset:
Impact of APC mutations on prognosis and tumor microenvironment in colorectal signet ring cell carcinoma.
Authors: Yanfeng Xi, Wei Cui, Yuan Tan, Qin Zhang, Qianqian Duan, Dong-sheng Chen
Journal: Journal of Clinical Oncology (2024)

e15500 Background: Colorectal signet ring cell carcinoma (CRC-SRC) is a malignant tumour characterized by its aggressive nature and unfavourable prognosis. In spite of the fact that numerous studies have examined the molecular profile and therapeutic targets of CRC-SRC, the prognostic biomarkers for this malignancy continue to be unknown. Methods: We conducted a comprehensive analysis of multi-omics in 35 cases of CRC-SRC and 10 cases of colorectal adenocarcinomas (CRC-AC). This analysis involved various techniques, including immunohistochemistry, DNA sequencing, and RNA sequencing. Results: In CRC-SRC, despite a lower frequency of APC mutations at the genomic level (P = 0.01), they rank as the second most prevalent mutations (40%), surpassed only by TP53 mutations (65.71%). The findings revealed that 13 genes associated with immunotherapy response were found to be upregulated in CRC-AC. Additionally, the levels of CD3+, CD8+, and CD3+ &amp; CD8+ T cells were found to be similar in tumor regions in CRC-SRC. These results suggest that CRC-SRC is more likely to have an immunosuppressive tumor immune microenvironment (TiME) compared to CRC-AC. Multivariate Cox proportional hazard regression analysis (hazard ratio: 3.54, 95% confidence interval: 3.93-117.3; p-value = 0.0004), in particular, shows that the presence of APC mutations is associated with a worse prognosis. In contrast, APC-mutant cases of CRC-AC have the same overall survival (OS) rate as APC-wildtype patients in the TCGA cohort. On RNA level, APC-mutant tumors exhibited higher expression levels of VEGFA ( P = 0.028) and Mki67 (P = 0.014), which are implicated in tumour invasion and proliferation. In contrast, APC-mutant CRC-AC did not exhibit differential expression on these genes within the TCGA cohort. GSEA showed that only the E2F hallmark was significantly enriched in APC-mutant CRC-SRC patients ( P = 0.0072). On protein expression level, APC-mutant patients had a significantly lower CD3 or CD68 positive ratio in the tumour region (CD3: P = 0.035; CD68: P = 0.039). This indicated that lymphocyte infiltration is decreased in APC-mutant CRC-SRC. Conclusions: To summarize, APC mutations may have distinct functions in CRC-AC and CRC-SRC. Colorectal cancer (CRC) with APC mutations showed a more unfavourable prognosis and a distinct tumour immune microenvironment compared to CRC with normal APC. Clinical trial information: ChiCTR2300072881.
Maintenance treatment with toripalimab and anlotinib after anthracycline-based chemotherapy in patients with advanced soft tissue sarcoma (TORAN): A single-arm, phase 2 trial.
Authors: Yaotiao Deng, Jie Liu, Mei Li, Yu Jiang
Journal: Journal of Clinical Oncology (2024)

11572 Background: In patients with advanced soft tissue sarcoma (STS) who have achieved disease control after anthracycline-based chemotherapy, maintenance therapy is being explored. This study evaluated the efficacy and safety of toripalimab (a monoclonal antibody against the programmed cell death-1 receptor) combined with anlotinib (a multitargeted tyrosine kinase inhibitor) as a maintenance treatment. Methods: Patients with advanced STS who have achieved disease control after at least four cycles of first-line anthracycline-based chemotherapy were enrolled in this single-arm, phase 2 trial. Fifty patients are planned to receive treatment with toripalimab and anlotinib. The primary endpoint was progression-free survival rate at 24 weeks (PFR 24w ) during maintenance therapy. Secondary endpoints were median progression-free survival (PFS), median overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: By the cut-off date of Jan 25, 2024, 22 patients were enrolled, including patients with leiomyosarcoma (n =5), synovial sarcoma (n =3), epithelioid sarcoma (n =3), dedifferentiated liposarcoma (n =2) and other different subtypes of sarcomas (n =9). The median follow-up time was 11 months. Response has been evaluated in 18 patients. The ORR and DCR were 22.2% and 100%. The PFR 24w was 67%, the median PFS was 11.8 months, and the median OS was not reached. The grade 3 or higher adverse events were hypertension (n =4), hemorrhage (n =1), adrenal insufficiency (n =1) and hypertriglyceridemia (n =1). Conclusions: Maintenance therapy with toripalimab and anlotinib is a promising treatment option for patients with advanced STS after first-line anthracycline-based chemotherapy. Clinical trial information: ChiCTR2100054901.
An Indian real-world experience of intravenous fosnetupitant-palonosetron (IV NEPA) in preventing delayed and extended delayed CINV.
Authors: Hanmant V. Barkate, Dr. Amullya Pednekar, Pragya Shukla, Shaunak Valame, Siddhartha Nanda, Abhinandan Hanji, Naval Kishore Shakya, Arun Kumar Verma, Sagar B Bhagat, Saiprasad Patil, Sumit Bhushan
Journal: Journal of Clinical Oncology (2024)

12070 Background: Although the reports suggest 15-25% cancer patients receiving highly- and moderately emetogenic chemotherapy (HEC and MEC) experience nausea and vomiting beyond day 5, majority of clinical trials focus on delayed chemotherapy induced nausea and vomiting (CINV) only during the first 5 days of treatment. Here we present a real world observational data with fixed combination of IntraVenous (Fos)NEtupitant and Palonosetron (IV NEPA) in preventing nausea/vomiting in delayed and extended delayed phase among patients receiving HEC/MEC. Methods: An open label, single arm, multicentre, phase IV prospective trial was conducted at six centres following individual Institutional Ethics Committee approval (CTRI/2023/04/051951). Patients in acute (0-24hrs), delayed (&gt;24-120hrs), extended delayed (&gt;120-240hrs) phases and extended overall phase (0-240hrs) were assessed for complete response (CR) (no vomiting and no need of rescue medication), complete protection (CP) [CR + no significant nausea (5mm to &lt;25mm) on visual analogue scale], complete control (CC) [CR + no nausea (&lt;5mm)] and safety. Results: Among 178 patients (Males-114, Females-64), 90 (50.56%) received HEC and 88 (49.44%) received MEC regimen. Cisplatin-Paclitaxel (19.10%) and Carboplatin-Paclitaxel (35.39%) were the most common HEC and MEC regimens respectively. Overall, CR in delayed and extended delayed phases were 93.26% and 96.07% respectively. Furthermore, CP and CC in delayed and extended delayed phases were 92.13% and 96.07% and 81.46% and 90.45% respectively (Table). In general, IV NEPA was well tolerated, as only 9.55% of patients experienced adverse events with 95.83% of them being mild in nature. Headache (2.25%) and injection site reactions (1.68%) were the most common adverse effect reported. Conclusions: IV NEPA demonstrated high efficacy and good tolerability in a real world Indian setting, exhibiting response rates of &gt;92% in both delayed and extended delayed phases in patients receiving HEC/MEC regimens. Clinical trial information: CTRI/2023/04/051951. [Table: see text]
Efficacy and safety of Butantan-DV in participants aged 2–59 years through an extended follow-up: results from a double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil
Authors: Mauricio L Nogueira, Monica A T Cintra, José A Moreira, Elizabeth G Patiño, Patricia Emilia Braga, Juliana C V Tenório, Lucas Bassolli de Oliveira Alves, Vanessa Infante, Daniela Haydee Ramos Silveira, Marcus Vínicius Guimarães de Lacerda, Dhelio Batista Pereira, Allex Jardim da Fonseca, Ricardo Queiroz Gurgel, Ivo Castelo-Branco Coelho, Cor Jesus Fernandes Fontes, Ernesto T A Marques, Gustavo Adolfo Sierra Romero, Mauro Martins Teixeira, André M Siqueira, Viviane Sampaio Boaventura, Fabiano Ramos, Erivaldo Elias Júnior, José Cassio de Moraes, Stephen S Whitehead, Alejandra Esteves-Jaramillo, Tulin Shekar, Jung-Jin Lee, Julieta Macey, Sabrina Gozlan Kelner, Beth-Ann G Coller, Fernanda Castro Boulos, Esper G Kallás, Wuelton Monteiro, Joabi Nascimento, Rosilene Ruffato, Eduardo Garbin, Érica Cristina da Silva, Solange Cunha da Silva, Anna Paula Ioris, Antonia Francileuda Casarin, Volfânio Andrade, Vitor Menezes, Flávio Henrique Dourado de Macêdo, Guilherme Alves de Lima Henn, Andréa de Almeida Coêlho, Luciano Teixeira Gomes, Tiago Rodrigues Viana, Pedro de Carvalho Ferreira, Ana Maria Aguiar dos Santos, Irassandra Rooze Pereira Uchôa Cavalcanti de Aquino, Rafael Dhalia, Karla Andreia Mëtte Waldrich Tauil, Valéria Gonçalves Santos, Camilla dos Santos Mota, Helton Santiago, Lisia Esper, Ultimo Libanio, Cassia Fernanda Estofolete, Samuel Noah Scamardi, Paula Patrícia de Freitas Chama, Barbara Azevedo, Clarisse Bressan, Patricia Brasil, Aldina Barral, Antonio Bandeira, Daniela Paixão, Angela Carvalho Freitas, Pedro Henrique Fernandes Moreira de Figueiredo, Luara Teófilo Pignati, Cristina Bonorino, Larissa Sanches, Isabelli Guasso, Vanessa Terezinha Gubert, Jéssica Melo Silva da Silveira, Christiane Herold de Jesus, Sonia Regina de Almeida, Maria do Carmo Sampaio Tavares Timenetsky, Cecilia Luisa Simões Santos
Journal: The Lancet Infectious Diseases (2024)
Improving chemotherapy-induced alopecia for women receiving anthracycline plus taxane chemotherapy using the Paxman scalp cooling system at lower temperatures.
Authors: Shari Beth Goldfarb, Alanna Jamner, Nicolas Toumbacaris, Allison Gordon, Yuan Chen, Nadia Abdo, Analisa Dacunto, Victoria Susana Blinder, Monica N. Fornier, Cassandra Chang, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2024)

12143 Background: Chemotherapy-induced alopecia (CIA) not only impacts physical appearance but may also be detrimental to patient’s psychological well-being. To address CIA, patients often use scalp cooling devices such as the FDA-approved Paxman Scalp Cooling System (PSCS), currently approved at -5°C. This study explores the potential benefits of lower temperatures, -7.5°C and -10°C, to improve the efficacy of PSCS in minimizing CIA. Methods: This prospective study analyzed data from 33 women with stage I-III breast cancer receiving anthracycline and taxane chemo at MSKCC from 12/2019–10/2022. Photography, trichoscopy, and toxicity checks were conducted at baseline, weeks 4, 8 (primary endpoint), end of treatment (EOT), and 24 weeks post-chemotherapy. 23 patients reached week 8, while 10 withdrew prior due to lack of efficacy (5/10), change in treatment (3/10), or anxiety (2/10). Successful hair preservation (HP) was defined as CTCAE v4 grade 0 or 1 alopecia. Results: At baseline, all patients had grade 0 alopecia. At week 4, 81% achieved successful HP (17/21), and at week 8, over half maintained it (53%; 9/17). The majority had HP at EOT (69%; 11/16). At 24 weeks post-chemotherapy, all patients demonstrated continued HP (100%; 11/11) and all evaluated patients at 18 months post-treatment had grade 0 alopecia (100%,4/4). Among women with baseline photographs and trichoscopy (n=25), median average hair count at baseline was 154.0 per cm² and width 70.2 per cm². By week 4 (n=21), the median average hair count decreased by 20.0%, and width decreased by 8.0% compared to baseline. By week 8 (n=17), average count improved by 15% compared to week 4 (-3% from baseline) and average width decreased by 6% (-7.5% baseline). At EOT hair count decreased 37.8% and width decreased by 11.6% compared to baseline (n=16). At 24 weeks post-EOT there was a 13% increase in median average hair count with no measurable change in width compared to baseline (n=12). No patients (0%; 0/33) reported dose-limiting toxicities (DLTs) at -7.5°C (n=7) or -10°C (n=26). Conclusions: Patients successfully tolerated scalp cooling at lower temperatures, with no reported dose-limiting toxicities and successful HP. This study indicates higher HP rate at EOT (69%; 11/16) compared to studies using PSCS at -5°C. Post-EOT data shows successful hair regrowth with a higher average hair count than pre-treatment. A larger sample size is needed to assess the additional benefit of lower temperatures on HP and regrowth. Clinical trial information: NCT.[Table: see text]
A first-in-human study of IK-595, an oral MEK/RAF molecular glue, in patients with RAS- or RAF-altered advanced solid tumors.
Authors: Nehal J. Lakhani, Alexander I. Spira, Anthony W. Tolcher, Trupti Lingaraj, Marissa Timothy, Wilmin Bartolini, Nerymar Ortiz-Otero, Katherine Kacena, Sergio Santillana
Journal: Journal of Clinical Oncology (2024)

TPS3185 Background: Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. MEK is a clinically validated cancer target and despite FDA approval of several MEK inhibitors, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas mostly due to early emergence of resistance and low therapeutic indices. IK-595, a potent novel MEK-RAF molecular glue, is being developed to overcome these limitations. IK-595 traps MEK in an inactive complex with all RAF isoforms and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors, in addition to kinase independent CRAF activity. IK-595 exhibits potent single agent activity in a wide range of in vivo cancer models harboring various RAS/RAF alterations, including, but not limited to, lung, pancreatic, colorectal cancer (CRC), melanoma, and AML. The preclinical pharmacokinetic profile of IK-595 also enables flexible dosing schedules resulting in a broader therapeutic window. Methods: This is a phase 1, first-in-human, open-label, multicenter study to evaluate IK-595 as monotherapy in patients with RAS- or RAF-altered advanced solid tumors for whom there are no other further treatment options known to confer clinical benefit. Dose escalation uses a Bayesian Optimal Interval Design (BOIN) in patients with advanced and unresectable, or metastatic solid tumors with confirmed RAS/RAF gene alterations. Backfilling of cleared dose levels with key target indications will initiate upon achievement of efficacious plasma exposures. Dose expansion will occur in genetically defined cohorts, for example NRAS-mutant CRC and malignant melanoma, as well as BRAF non-V600 and KRAS mutant tumors using a Simon 2-stage adaptive design. IK-595 will initially be administered on an intermittent dosing schedule in 30-day cycles. Additional dosing schedules may be explored. Primary objectives of the study are to evaluate safety and tolerability of IK-595 and to determine the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD). Secondary objectives include evaluation of preliminary antitumor activity by RECIST 1.1, pharmacokinetic (PK) parameters, and pharmacodynamic effects of IK-595 on pERK in paired tumor biopsies. Key exploratory endpoints include changes in pERK in peripheral blood cells, changes in pERK target genes in tumor biopsies, and assessment of candidate baseline response biomarkers. The study began in December 2023 and enrollment in Cohort 1 was completed with no DLTs; dose escalation continues to enroll. Clinical trial information: NCT.
Overview of the role of purinergic signaling and insights into its role in cancer therapy
Authors: Francesco Di Virgilio, Valentina Vultaggio-Poma, Mario Tarantini, Anna Lisa Giuliani
Journal: Pharmacology & Therapeutics (2024)

Innovation of cancer therapy has received a dramatic acceleration over the last fifteen years thanks to the introduction of the novel immune checkpoint inhibitors (ICI). On the other hand, the conspicuous scientific knowledge accumulated in purinergic signaling since the early seventies is finally being transferred to the clinic. Several Phase I/II clinical trials are currently underway to investigate the effect of drugs interfering with purinergic signaling as stand-alone or combination therapy in cancer. This is supporting the novel concept of "purinergic immune checkpoint" (PIC) in cancer therapy. In the present review we will address a) the basic pharmacology and cell biology of the purinergic system; b) principles of its pathophysiology in human diseases; c) implications for cell death, cell proliferation and cancer; d) novel molecular tools to investigate nucleotide homeostasis in the extracellular environment; e) recent developments in the pharmacology of P1, P2 receptors and related ecto-enzymes; f) P1 and P2 ligands as novel diagnostic tools; g) current issues in PIC-based anti-cancer therapy. This review will provide an appraisal of the current status of purinergic signaling in cancer and will help identify future avenues of development.
Early clues in the battle against advanced gastric cancer: How plasma ctDNA signals the effectiveness of PD-1 inhibitors with chemotherapy.
Authors: Rongqi Jiang, Hao Wu, Enqing Meng, Ping Li, Xu Cheng
Journal: Journal of Clinical Oncology (2024)

3042 Background: Combination therapy with Programmed Death 1 (PD-1) inhibitors and chemotherapy has shown efficacy in improving survival in advanced gastric cancer, but not all patients derive benefit. We aimed to explore whether early dynamic changes in circulating tumor DNA (ctDNA) can serve as predictors of treatment response and long-term survival in patients receiving first-line PD-1 inhibitors combined with chemotherapy. Methods: This is a prospective, single-center trial in which all patients are adults with advanced or metastatic GC/GEJC confirmed by pathology or imaging. 30 eligible patients will receive PD-1 mab (sintilimab/nivolumab (NIVO) Q3W) and chemotherapy (SOX/XELOX Q3W) regardless of programmed death ligand-1 status. Blood samples were collected before treatment and after two treatment cycles for ctDNA analysis. Plasma ctDNA was isolated for evaluating variant allele frequencies (VAF) of somatic mutations in 47 cancer-related genes using next-generation sequencing (NGS), ctDNA response was defined as clearance of maximum VAF (maxVAF) compared to baseline. CT scans were performed after every two cycles and will be categorized as responding (complete response plus partial response) or non-responding (progress disease plus stable disease) according to RECIST v1.1. Overall survival was calculated from the date of first PD-1 mab infusion to the time of death or censored at most recent follow-up; progression‐free survival was calculated from the date of first PD-1 mab infusion to the time of death or first documented progression, whichever came first, or censored at most recent follow-up. Results: In thirty advanced gastric cancer patients, the dynamic changes in maxVAF demonstrated a significant association with patients attaining either complete response (CR) or partial response (PR) to treatment (P=0.0021), but showed no correlation with stable disease (SD) or progress disease (PD). A substantial agreement was observed between ctDNA response and the best tumor shrinkage rate (Cohen's kappa=0.69). The objective response rate (ORR) among ctDNA responders was 85%, markedly higher compared to the 22% observed in non-responders (P=0.0073). Additionally, patients with ctDNA response had a significantly longer progression‐free survival (PFS) compared to patients without ctDNA response (median PFS 15.6 months vs 6.0 months; HR, 0.18; 95% CI, 0.06 to 0.61; p=0.003), overall survival (OS) was also significantly longer among ctDNA responders (median OS not reach[NR] vs 9.0 months; HR, 0.10; 95% CI, 0.01 to 0.88; p=0.011). Conclusions: ctDNA response serves as a potential biomarker for assessing treatment efficacy and long-term outcomes in advanced gastric cancer patients treated with first-line PD-1 inhibitors and chemotherapy. Clinical trial information: ChiCTR2200065366.
Neoadjuvant therapy of camrelizumab combined with chemotherapy in patients (pts) with resectable esophageal squamous cell cancer (ESCC): A single-center, single-arm, exploratory clinical trial.
Authors: Ji chen Yang, Wenjie Jiao, Feng Hua, Xiaoming Zhao, Wenfeng Yang
Journal: Journal of Clinical Oncology (2024)

e16095 Background: The study aimed to evaluate the efficacy and safety of neoadjuvant therapy of camrelizumab, combined with chemotherapy in resectable ESCC pts and explore factors related to efficacy. Methods: Patient with resectable ESCC, staged as cT1b-cT2N+ or cT3-cT4aNany were enrolled. Eligible pts received camrelizumab (200 mg, d1) combined with nab-paclitaxel (200 mg/m 2 , d1) and nedaplatin (75 mg/m 2 , administered on an average of two days) and S-1 (50mg/m 2 , bid, d1-14) for 2 or 3 cycles (21 days per cycle) before surgery. The primary endpoints were pathological complete response (pCR) rate. Results: From Aug 25, 2022, to Nov 17, 2023, a total of 53 pts were enrolled in this study and completed 2 or 3-cycle neoadjuvant therapy. Median age was 58(54-63), 47 males and 6 females, The primary site was upper segment in 3 pts, middle segment in 27 pts, and lower segment in 23 pts, The clinical T staging was T2 in 2 pts, T3 in 49 pts, and T4 in 2 pts. The clinical N staging was N0 in 8 pts, N1 in 28 pts, N2 in 16 pts, and N3 in 1 pt. The physical condition score was 0 for 16 pts, and 1 for 27 pts. 37 pts underwent surgery and R0 recetion was achieved in 37 (100%) pts. pCR(ypT0N0) was identified in 9(24.3%) and 3(8.1%) pts had conplete response of primary tumor but residual didease in lymph nodes alone (ypT0N+), the MPR was was identified in 5(13.5%) pts. Of pts who underwent surgery, 25(67.6%) received 3-cycle and 12(32.4%) received 2-cycle neoadjuvant therapy, the pCR rate was 32% and 8.3%,respectively. According to tumor regression grade, 12 (11(44%) in 3-cycle and 1(8.3%) in 2-cycle) pts had TRG0, 5(4(16%) in 3-cycle and 1(8.3%) in 2-cycle) TRG1, 15 (9(36%) in 3-cycle and 6(50%) in 2-cycle) TRG2, and 4 (all 4(33.3%) in 2-cycle) TRG3. Also we found there was no relationship between the NK cells, B cells, total T lymphocytes, Th cells, Tc/Ts cells, CD4+/CD8+ratio and the pCR and MPR rate. The most common AEs were anemia (71.7%)、 lymphocyte count decreased (67.9%)、white blood cell count decreased (52.8%) and neutrophil count decreased (52.8%). Most AEs were grade 1-2. No grade 4/5 AEs occurred. Conclusions: The short-term efficacy and safety of camrelizumab combined with three drugs chemotherapy were similar to previous research combined with two drugs.The efficacy of three-cycle regimen seems to be significantly better than the two-cycle regimen, which may indicate that the two-cycle neoadjuvant therapy is still insufficient, and confirmatory results need to be verified through large-scale clinical studies. Clinical trial information: ChiCTR2300068185.