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Objective: To investigate the specificity of Target of Myb1-Like1 (Tom1L1) expression in colorectal adenocarcinoma tissues and analyze the predictive value of Tom1L1 in the efficacy of neoadjuvant chemotherapy for patients with rectal adenocarcinoma., Methods: The cancerous tissues and paracancerous normal tissues of 102 patients diagnosed with colorectal adenocarcinoma without treatment were selected; quantitative polymerase chain reaction (qPCR), Western blot and immunohistochemistry (IHC) were adopted to validate the expression level of Tom1L1 in the two groups. Furthermore, 34 patients with locally progressive mid-low rectal adenocarcinoma, who were treated with neoadjuvant Xelox chemotherapy prior to the operation, IHC was adopted to detect the expression of Tom1L1 protein in patients before and after neoadjuvant chemotherapy and to analyze the relationship between the expression level of Tom1L1 and the sensitivity of neoadjuvant therapy., Results: The results of qPCR, Western blot and IHC showed that the expression of Tom1L1 in colorectal adenocarcinoma tissues was significantly higher than that in paracancerous normal tissues, with a statistically significant difference (P < 0.01); Neoadjuvant chemotherapy was significantly more effective in patients with low expression of Tom1L1 protein than in those with high expression of Tom1L1 protein, with a statistically significant difference (P < 0.05)., Conclusions: Tom1L1 is highly expressed in colorectal adenocarcinoma tissues; neoadjuvant Xelox chemotherapy can have an impact on Tom1L1 expression in progressive rectal cancer; patients with locally progressive mid-low rectal adenocarcinoma who have low Tom1L1 expression are more sensitive to neoadjuvant chemotherapy., Competing Interests: Declarations Ethics approval and consent to participate Informed consent and approval were obtained from all the patients and the Ethics Committee of The First Affiliated Hospital of Hebei North University (K2022058). The research was conducted in accordance with the guidelines of the Ethics Committee listed in the Ethics Statement. Patients signed informed consent regarding publishing their data and images. Consent for publication Written informed consent was obtained from the patient’s parent for publication of this case report and the accompanying images. A copy of the written consent obtained from the parent of the patient in this case report is available for review by the editorial office of this journal. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Ethnopharmacological Relevance: The flowers of Nyctanthes arbor-tristis (L.) heals mouth ulcers. Its tinctures promote gastric secretions, and improve lung expectoration when taken orally. It has traditionally been used to treats scabies and other skin problems. The leaves of NAT(L.) plant are used in Ayurvedic medicine to treat sciatica, chronic fever, rheumatism, internal worm infections, and as a laxative, diaphoretic, and diuretic. The bark used in treatment of snakebite and bronchitis. In addition to traditional uses, pharmacologically this plant has potent antimalarial, antiarthritic, anticancer and antidiabetic activity. However, the mechanistic antiproliferative potentials of NAT(L.) flower as anticancer therapeutics has not yet been explored., Aim of the Study: The current study is based on a broad range of scientific literature that highlights the nutritional and therapeutic benefits of NAT (L.). Present investigation was carried out to determine the therapeutic efficacy of NAT (L.) against breast adenocarcinoma cells and T-cell lymphoma., Materials and Methods: The ethyl-acetate extract of NAT(L.) was tested against breast cancer cells to assess the anticancer potential. To evaluate apoptosis, intracellular ROS levels and mitochondrial dynamics, fluorescence microscopy and flow cytometry were employed. Additionally, cell cycle analysis and western blotting were also performed. Furthermore, in vivo antitumor efficacy of flower extracts was investigated in T-cell lymphoma-bearing BALB/c mice model., Results: Our present study revealed that NAT (L.) exert anticancer activity against breast cancer cells effectively at IC 50 320 μg/ml while having less impact on normal cells with IC 50 more than 480 μg/ml. Fluorescence imaging showed that NAT (L.) treatment elicits a concentration-dependent rise in the occurrence of apoptotic cell deaths with altered mitochondrial dynamics and was subsequently confirmed by flow cytometry. Further, flow cytometric analysis delineates ethyl acetate flower extract exposure promotes arrest of cells in S phase of the cell cycle. The differential expression of apoptotic proteins such as Bax, Bcl-2, cleaved PARP-1, cleaved caspase 3, Cytochrome-c, p53 and VEGF A were influenced by NAT (L.) treatment. The in vivo antitumor activity study delineates that NAT(L.) therapy significantly increased the life span of T-cell lymphoma bearing mice while reducing tumor load and belly size growth pattern without causing significant other distinct side effects as evident by histopathological studies., Conclusion: Our current findings unveil that NAT(L.) ethyl acetate flower extract potentially induces mitochondrial pathway of apoptosis, promote cell cycle arrest, reduces tumor load of mice, enhances survivability and could be a promising agent against the triple negative breast cancer and lymphoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In response to the growing demand for high-value bioactive compounds, microalgae cultivation has gained a significant acceleration in recent years. Among these compounds, antioxidants have emerged as essential constituents in the food, pharmaceutical, and cosmetics industries. This study focuses on Micractinium sp. ME05, a green microalgal strain previously isolated from hot springs flora in our laboratory. Micractinium sp. cells were extracted using six different solvents, and their antioxidant capacity, as well as total phenolic, flavonoid, and carotenoid contents were evaluated. The methanolic extracts demonstrated the highest antioxidant capacity, measuring 7.72 and 93.80 µmol trolox equivalents g -1 dry weight (DW) according to the DPPH and FRAP assays, respectively. To further characterize the biochemical profile, reverse phase high-performance chromatography (RP-HPLC) was employed to quantify twelve different phenolics, including rutin, gallic acid, benzoic acid, cinnamic acid, and β-carotene, in the microalgal extracts. Notably, the acetone extracts of Micractinium sp. grown mixotrophically contained a high amount of gallic acid (469.21 ± 159.74 µg g -1  DW), while 4-hydroxy benzoic acid (403.93 ± 20.98 µg g -1  DW) was the main phenolic compound in the methanolic extracts under heterotrophic cultivation. Moreover, extracts from Micractinium sp. exhibited remarkable cytoprotective activity by effectively inhibiting hydrogen peroxide-induced oxidative stress and cell death in human breast adenocarcinoma (MCF-7) cells. In conclusion, with its diverse biochemical composition and adaptability to different growth regimens, Micractinium sp. emerges as a robust candidate for mass cultivation in nutraceutical and food applications., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: The limitations in cancer treatment and the inadequacy of classical methods have made it necessary to discover therapeutics in cancer treatment. The cytotoxicity of thymoquinone, which has quite different properties in terms of biological activities, in ovarian cancer cells, and the changes in the expression levels of apoptotic genes (p53/caspase-3 (casp-3)) were investigated., Methods: In the study, thymoquinone (5, 50, 100, 250 and 500 µM and 24, 48, 72 hours) were applied to ovarian adenocarcinoma cancer cell line (OVCAR3), at different concentrations. Cytotoxic effect of thymoquinone on OVCAR-3 cells were analyzed by MTT method, and apoptotic and pro-apoptotic gene expression levels (p53, Casp-3) of thymoquinone in cancer cells were analyzed by quantitative real-time polymerase chain reaction., Results: Thymoquinone, whose effect has been revealed in many types of cancer, was shown to significantly reduce the viability of OVCAR3 cancer cells depending on the dose and time (p < 0.05). It was also determined that Casp-3 and p53 gene expressions increased in OVCAR3 cells., Conclusions: Considering the in-vitro cytotoxic activity and apoptotic gene expressions of thymoquinone, an important treatment agent, since it is a promising agent for the future of cancer treatment, more comprehensive studies may pave the way for its clinical use.

Biomarkers associated with the progression from gastric intestinal metaplasia (GIM) to gastric adenocarcinoma (GA), i.e., GA-related GIM, could provide valuable insights into identifying patients with increased risk for GA. The aim of this study was to utilize multi-bioinformatics to reveal potential biomarkers for the GA-related GIM and predict potential drug repurposing for GA prevention in patients. The multi-bioinformatics included gene expression matrix (GEM) by microarray gene expression (MGE), ScType (a fully automated and ultra-fast cell-type identification based solely on a given scRNA-seq data), Ingenuity Pathway Analysis, PageRank centrality, GO and MSigDB enrichments, Cytoscape, Human Protein Atlas and molecular docking analysis in combination with immunohistochemistry. To identify GA-related GIM, paired surgical biopsies were collected from 16 GIM-GA patients who underwent gastrectomy, yielding 64 samples (4 biopsies per stomach x 16 patients) for MGE. Co-analysis was performed by including scRNAseq and immunohistochemistry datasets of endoscopic biopsies of 37 patients. The results of the present study showed potential biomarkers for GA-related GIM, including GEM of individual patients, individual genes (such as RBP2 and CD44), signaling pathways, network of molecules, and network of signaling pathways with key topological nodes. Accordingly, potential treatment targets with repurposed drugs were identified including epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase Src, paxillin, transcription factor Jun, breast cancer type 1 susceptibility protein, cellular tumor antigen p53, mouse double minute 2, and CD44., (© 2024. The Author(s).)

This study explores the potential use of ChatGPT, an AI-based language model, in assessing herbal-drug interactions (HDi) to enhance clinical decision-making. HDi can pose significant health risks by reducing drug efficacy or causing unwanted side effects. Clinical pharmacists play a key role in identifying these HDIs, and currently, there are limited tools available for checking drug interactions. The research focuses on a case study of a rectal adenocarcinoma patient treated with capecitabine and 26 supplements, which contain a total of 80 herbal substances. ChatGPT 3.5 was asked three questions regarding potential HDIs: "Are there possible HDIs?", "What is the pharmacokinetic mechanism?", and "What is the bibliographic source of the interaction?". The results were reviewed by an oncology clinical pharmacist and compared to existing databases and independent bibliographic research. The findings highlight ChatGPT's advantage in processing large amounts of data quickly, with 16% of interactions classified as "unlikely", confirmed by the pharmacist. However, 73% of the suggested mechanisms were false positives, and 4% were categorized as "hallucinations". Additionally, most of the bibliographic sources provided by ChatGPT were outdated or unavailable. While ChatGPT proves useful for initial HDI screening, its limitations include outdated data (last updated in January 2022), lack of access to private databases, and occasional inaccuracies. Further applications of AI in this area are recommended, though expert validation remains essential in the clinical decision-making process.

Our research aims to design novel pyrimidine derivatives inspired by the common pyrimidine core found in many FDA-approved drugs. However, extensive prior research on the pyrimidine scaffold has made discovering new molecules more challenging. To overcome this obstacle, we employed a molecular hybridisation strategy, opting to hybridise tetralin and pyrimidine, recognising their potential in cancer therapeutics. The fused pyrimidine was synthesised through a base-mediated condensation of chalcone with amidine. The reaction conditions were further optimised for base, solvent, temperature and time to produce a series of 21 novel derivatives. These compounds were subsequently screened for anticancer activity against gastric adenocarcinoma cell lines using the MTT assay. Among the synthesised compounds, 2-(pyridin-3-yl)-4-(pyridin-3-yl)-5,6-dihydrobenzo[h]quinazoline 8b and 4-(2-(pyridin-3-yl)-5,6 dihydrobenzo[h]quinazolin-4-yl) phenol 5g exhibited potent anticancer activity compared to (R)-Roscovitine. Additionally, a molecular docking study was conducted to assess the reactivity of compound 5g, revealing that the presence of a phenolic hydroxyl group enables hydrogen bonding with CDKs and enhances anticancer activity. Furthermore, the efficacy of compound 5g was validated through an in vitro CDK2/cyclin A2 enzyme inhibition assay. Interestingly, the observed CDK2 inhibitory activity showed a good correlation with the corresponding value for the antiproliferative activity of the tested compounds., (© 2024 John Wiley & Sons Ltd.)

Background: Intensified systemic chemotherapy following minimally invasive surgery for patients with unresectable metastatic colorectal cancer is performed to achieve curative resection and improve quality of life. We report a case of initially unresectable rectal cancer with metastases treated with laparoscopic and thoracoscopic staged resections after triplet chemotherapy plus bevacizumab., Case: A 71-year-old man was referred to our hospital to examine the cause of constipation. A circumferential adenocarcinoma with extramural invasion and lateral lymphadenopathy was identified in the lower rectum with simultaneous metastatic liver and lung tumors. Intensified triplet chemotherapy plus bevacizumab was conducted to treat oncologically unresectable rectal cancer to avoid positive radial margins during surgical resection. Eleven cycles of chemotherapy resulted in regression of the tumors with metastases. Laparoscopic low anterior resection with lateral lymph node dissection was performed. Three months later, laparoscopic liver resection of the posterosuperior segment was performed without complications. Finally, the patient underwent thoracoscopic-assisted pulmonary segmentectomy of the right basal lobe. All resected tumors had negative surgical margins, and the patient has been surviving without adjuvant chemotherapy., Conclusion: Minimally invasive staged resection and intensified chemotherapy for the treatment of initially unresectable metastatic colorectal cancer should be performed by a skilled surgical team in coordination with a multidisciplinary team., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Metronomic chemotherapy (MCT) is a cancer therapeutic approach characterized by low dose drug chronic administration and limited or null toxicity. Obesity-induced metabolic alterations worsen cancer prognosis and influence the intestinal biochemical barrier, altering the Multidrug resistance-associated protein 2 (Mrp2) and Multidrug resistance protein-1 (Mdr-1), efflux pumps that transport chemotherapeutic drugs. Obesity and cancer are frequent co-morbidities; thus, our aim was to evaluate the effectiveness and toxicity of MCT with cyclophosphamide (Cy) in obese mice with metabolic alterations bearing a mammary adenocarcinoma. Simultaneously, the expression and activities of intestinal Mrp2 and Mdr-1 were assessed. CBi male mice, were fed with chow diet (C) or diet with 40 % of fat (HFD). After 16 weeks, metabolic alterations were confirmed by biochemical and morphological parameters. At that time-point, HFD group showed decreased expressions of Mrp2 mRNA (53 %) as well as Mdr-1a and Mdr-1b (42 % and 59 %, respectively), compared to C (P < 0.05). This result correlated with decreased intestinal Mrp2 and Mdr-1 efflux activities (64 % and 45 %, respectively), compared to C (P < 0.05). Ultimately, mice were challenged with M-406 mammary adenocarcinoma; when the tumor was palpable, mice were distributed into 4 groups. The % inhibition of tumor growth with Cy (30 mg/kg/day) in C + Cy was higher than that of HFD + Cy (P = 0.052). Besides, it was observed a 21 % diminution in body weight and leukopenia in the HFD + Cy group. Conclusion: Obesity-induced metabolic alterations impair intestinal Mrp2 and Mdr-1 functions, bringing about increments in Cy absorption, leading to toxicity; in addition, the antitumor effectiveness of MCT decreased in obese animals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. SILVINA VILLANUEVA reports financial support was provided by National Agency for the Promotion of Research Technological Development and Innovation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Fabiana Garcia reports equipment, drugs, or supplies was provided by National Council for Scientific and Technological Research. Silvina Stella Maris Villanueva reports equipment, drugs, or supplies was provided by National Agency for the Promotion of Research Technological Development and Innovation. There are no additional relationships or activities to declare. Fabiana Garcia If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Backgorund: Pancreatic adenocarcinoma remains a malignancy with a grim prognosis and scarce personalized treatment options. Pathogenic variants of DNA damage repair (DDR) genes are emerging as molecular targets, as they confer a higher sensitivity to DNA-damaging agents. This study aimed at assessing the activity of chlorambucil as salvage therapy in metastatic pancreatic cancer patients bearing a germline pathogenetic variant or variant of uncertain significance on a DDR-related gene., Methods: Platinum-pretreated metastatic pancreatic cancer patients harbouring a germline variant on a DDR gene received chlorambucil at a daily oral dose of 6 mg/m 2 for 42 every 56 days for the first cycle and for 14 every 28 days for the following cycles, until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival rate (PFS-6). Median progression-free survival (PFS) and overall survival (OS) were secondarily described., Results: Twenty patients were enrolled between December 2020 and September 2022. PFS-6 was 5%, median PFS and OS were 1.6 months and 3.0 months, respectively. Grade-3 adverse events were observed in 25% of patients, while no Grade-4 toxicity was reported., Conclusions: Single agent chlorambucil did not show sufficient signal of activity to warrant its further investigation in metastatic pancreatic cancer patients bearing a DDR-related germline alteration., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumour efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study., Methods: Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS)., Results: We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2-11.8) months (vs. 6 months in historical control, p = 0.018). The median overall survival was 16.5 (90% CI 9.8-17.5) months. Sixty-seven per cent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhoea, nausea, and vomiting)., Conclusions: Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard-of-care therapy is warranted., Clinical Trial Registration: ClinicalTrials.gov NCT04109924., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: This study reports the 2-year outcomes and biomarker analysis results of patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma who received neoadjuvant chemotherapy and immunotherapy in a phase II WuhanUHGI001 trial., Methods: Eligible patients with cT3/4aN+M0 locally advanced G/GEJ adenocarcinoma were screened, enrolled, and treated with 3 cycles of neoadjuvant tislelizumab and SOX followed by D2 gastrectomy and another 5 cycles of postoperative adjuvant SOX. The primary endpoint was major pathological response., Results: Of the 49 included patients, 24 (49.0%) achieved major pathological response and 13 (26.5%) achieved pathological complete response. During a median follow-up of 26.8 months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 69.4% and 81.2%, respectively. Grade 3-4 adverse events occurred in six patients (12.2%) during the neoadjuvant period, eight patients (17.0%) during the postoperative period, and seven patients (15.2%) during the adjuvant period. Biomarker analysis revealed that the pathological complete response showed no association with 2-year PFS and OS. Major pathological response showed a potentially strong association with improved 2-year PFS and OS rates. In addition, preoperative circulating tumor cells combined with pathological responses are helpful in prognosis assessment. In addition, our results showed that T downstaging, lymphocyte-to-monocyte ratio, and CD3+ T cells were independent factors that affect PFS. The signet ring cell component (SRCC), T downstaging, and neutrophil-to-lymphocyte ratio were independent factors affecting OS. Prognostic nomograms of PFS and OS constructed based on the multivariate Cox regression results demonstrated suitable calibration and discrimination ability., Conclusions: Neoadjuvant tislelizumab plus SOX exhibits promising efficacy and acceptable toxicity in patients with locally advanced G/GEJ adenocarcinoma. In addition, our study established a prognostic risk signature and nomograms based on clinicopathological characteristics, which can accurately predict patient outcomes and aid in personalized treatment planning., (© 2024. Society of Surgical Oncology.)

Background: Adjuvant chemotherapy (AC) for colorectal cancer (CRC) has led to substantial improvement in survival. Several clinical trials advocate the initiation of AC within 6-8 weeks of surgical resection based on evidence of improved survival with early initiation of AC. We aim to evaluate factors that predict initiation and completion of AC, subsequently improving survival. Methods: We identified 451 patients who underwent resection for CRC between 2014 and 2022. One hundred ten patients had stage II/III colorectal cancer who underwent resection followed by AC. Multivariable logistic regression analysis was performed to identify factors significantly predicting delay in AC >8 weeks. Secondary outcomes included chemotherapy completion rate, recurrence-free survival, and overall survival. Results: The final analysis included 110 patients. The median time to initiation of adjuvant chemotherapy (TIAC) was 6.9 weeks (IQR: 5.8-9.5). In total, 36.4% of patients had a delay >8 weeks to initiation of AC, and only 40% completed treatment. The surgical approach (open vs laparoscopic vs robotic) had no effect on the TIAC. On multivariable logistic regression analysis, preoperative albumin ≥3.5 (OR = .31; 95% CI: .12-.80) was an independent predictor of timely initiation of AC. Completion of AC was associated with a higher overall survival. Discussion: Preoperative nutritional status predicted delay in initiation of AC. Patients with a delay in AC beyond eight weeks had a lower rate of AC completions and worse survival. It is imperative to optimize this aspect of treatment as it correlates with survival., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cisplatin is crucial in management of advanced stomach adenocarcinoma, whereas development of chemotherapy resistance hinders overall efficacy of cisplatin. This work aims to explore role of CDC25B in cisplatin sensitivity in stomach adenocarcinoma and offer a possible mechanism for explaining its function. By using bioinformatics approaches, CDC25B and TEAD4 expression levels in stomach adenocarcinoma tissues and enriched pathways of CDC25B were analyzed. qRT-PCR of CDC25B and TEAD4 expression in stomach adenocarcinoma cells, CCK-8 detection of cell viability and IC 50 values, and colony formation assay on cell proliferation were performed. Cell adhesion experiment detected cell adhesion ability. Western blot detected expression of proteins related to cell adhesion, specifically Muc-1, ICAM-1, VCAM-1. Dual luciferase assay and ChIP experiment verified binding relationship between TEAD4 and CDC25B. CDC25B was upregulated in stomach adenocarcinoma tissues and cells, enriched in focal adhesion pathway. Treatment with cell adhesion inhibitors revealed that CDC25B overexpression inhibits the sensitivity of stomach adenocarcinoma to cisplatin through the cell adhesion pathway. CDC25B has an upstream transcription factor TEAD4, which targeted and bound to CDC25B and was highly expressed in stomach adenocarcinoma. Rescue experiment revealed that knocking down TEAD4 weakened suppressive impact of CDC25B overexpression on sensitivity of stomach adenocarcinoma cells to cisplatin. Transcription factor TEAD4 could activate the transcription of CDC25B through cell adhesion to drive cell invasion and reduce sensitivity of stomach adenocarcinoma to cisplatin. TEAD4 and CDC25B may become new targets for management of stomach adenocarcinoma., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The two major molecular subtypes of pancreatic adenocarcinoma reportedly have differential response to FOLFIRINOX-based therapy. To promote rapid assignment of basal versus classical subtypes, an array-based single-sample classifier assay was developed and applied to 74 formalin-fixed, paraffin-embedded biopsy or resection specimens of known subtype based on transcriptomics. The Purity Independent Subtyping of Tumors (PurIST) algorithm assigns subtype based on relative expression of 16 RNAs counted by RNA sequencing (RNAseq) versus more practical array-based NanoString nCounter Elements XT technology. Subtype calls were largely concordant between RNAseq and array methods (72/74, 97% agreement). Compared with the lengthy RNAseq protocol, the array-based assay takes just 3 working days to analyze, permitting rapid reporting of tumor subtype. In conclusion, the PurIST pancreatic cancer classifier has robust performance to classify pancreatic adenocarcinoma into basal versus classical subtypes. Clinical validation studies are underway to evaluate outcome in patients whose standard-of-care chemotherapy regimen is selected on the basis of rapid subtype assignment (NCT04683315)., Competing Interests: Disclosure Statement N.U.R. and J.J.Y. are patent holders on Purity Independent Subtyping of Tumors (PurIST) technology for subtyping pancreatic ductal adenocarcinoma (US17/601,002). GeneCentric Therapeutics, Inc., had no involvement in the current study but acquired an exclusive license from the University of North Carolina at Chapel Hill related to PurIST technology., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC., Methods: The AVENGER 500 trial (ClinicalTrials.gov identifier: NCT03504423) is a global, randomized phase III trial conducted at 74 sites across six countries to investigate the efficacy and safety of devimistat in combination with mFFX (experimental arm) compared with standard-dose FFX (control arm) in treatment-naïve patients with mPC. Treatment, administered in once-every-2-weeks cycles until disease progression or intolerable toxicity, included intravenous devimistat at 500 mg/m 2 total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS)., Results: Five hundred and twenty-eight patients were randomly assigned (266 in the experimental arm and 262 in the control arm). The median OS was 11.10 months for devimistat plus mFFX versus 11.73 months for FFX (hazard ratio [HR], 0.95 [95% CI, 0.77 to 1.18]; P = .655) and median progression-free survival was 7.8 months versus 8.0 months, respectively (HR, 0.99 [95% CI, 0.76 to 1.29]; P = .94). Grade ≥3 treatment-emergent adverse events with >10% frequency in the devimistat plus mFFX arm versus the FFX arm were neutropenia (29.0% v 34.5%), diarrhea (11.2% v 19.6%), hypokalemia (13.1% v 14.9%), anemia (13.9% v 13.6%), thrombocytopenia (11.6% v 13.6%), and fatigue (10.8% v 11.5%), respectively., Conclusion: Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.

Purpose: To investigate the effectiveness of multiparametric MRI examination in determining tumor response after neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal tumors., Methods: 46 patients with locally advanced rectal adenocarcinoma were included and were divided into two groups as complete responders and nonresponders based on Mandard score. On MRI, relative T2w signal intensity and ADC values obtained before and after treatment and tumour volumes in dynamic contrast enhanced images (DCI) were used to determine complete response to treatment., Results: There were no significant differences between mean ADC values obtained by single slice ADC and three circular ROI methods. There were significant differences between two groups in terms of Post-CRT ADC value, ΔADC and %ΔADC obtained by whole tumour volume ADC method (p < 0.05). There were significant differences between Pre-CRT and Post-CRT volume values. ΔV DCI and %ΔV DCI, ΔV ADC and T2w volume values were significantly lower in complete responders (p < 0.05). In multivariate analysis, sensitivity and specificity were calculated as 88.9% and 91.9% (AUC = 0.943) when Post-CRT mean ADC value and Post-CRT DCI volume values were used together, and sensitivity and specificity were calculated as 88.9% and 94.6% (AUC = 0.949) when ΔADC and Post-CRT DCI volume values were used together., Conclusion: Whole tumour volume mean ADC value is the most useful method to determine treatment response. Post-CRT DCI volume measurement stands out as the most useful method in assessing complete response alone. The highest diagnostic values are achieved when the post-CRT DCI volume is combined with the ADC change value of the whole tumor volume., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Based on the comparison of ramucirumab monoclonal antibody with control treatments in randomized controlled trials, this study aims to elucidate the role of ramucirumab monoclonal antibody in cancer therapy and its potential side effects, providing scientific evidence for clinical treatment., Methods: PubMed, Embase, Cochrane, and Web of Science were searched systematically to obtain the trials on ramucirumab in the treatment of gastric or gastroesophageal junction (GEJ) adenocarcinoma up to April 13, 2023. We included randomized controlled trials (RCTs) evaluating the efficacy and safety of ramucirumab as monotherapy and in combination with other chemotherapy agents as interventions for treating gastric or gastroesophageal junction (GEJ) adenocarcinoma., Results: After screening 2200 studies, we finally included 8 eligible studies (involving a total of 3,283 participants). Meta-analysis results showed that compared to the control group, ramucirumab monotherapy significantly improved overall survival (OS) (hazard ratio [HR] = 0.77, 95% confidence interval [CI] [0.67, 0.89]) and progression-free survival (PFS) (HR = 0.48, 95% CI [0.40, 0.58]). Similar results were obtained for ramucirumab combined with paclitaxel. In the treatment combining ramucirumab with paclitaxel, compared to monotherapy, three severe adverse reactions (grade ≥ 3) were observed with significantly increased risks (OR > 2). These include proteinuria (OR = 5.37, 95% CI [1.22, 23.54]), hypertension (OR = 4.02, 95% CI [2.63, 6.14]), and gastrointestinal perforation (OR = 4.64, 95% CI [1.00, 21.60]). Subgroup analysis further indicated that ramucirumab is effective in both non-East Asian and East Asian populations, with East Asian patients more prone to developing proteinuria, while having a lower incidence of hypertension. Additionally, ramucirumab demonstrated comparable efficacy between first-line and second-line treatments, with a higher incidence of proteinuria observed in second-line therapy., Conclusion: Ramucirumab significantly improves the prognosis of patients with gastric or gastroesophageal junction adenocarcinoma. When used in combination with paclitaxel, close monitoring of adverse reactions such as proteinuria (especially in East Asian populations), hypertension (especially in non-East Asian populations), and gastrointestinal perforation is essential., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy., Methods: We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments., Results: Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR., Conclusion: In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy., (© 2024. The Author(s).)

Background: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer have poor outcomes. Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer. Inetetamab is a novel anti-HER2 drug, and its efficacy and safety in gastric cancer have not yet been reported., Aim: To evaluate the efficacy and safety of the S-1 plus oxaliplatin (SOX) regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer., 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, disease control rate, 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, whereas it was 7.3 months in the trastuzumab group ( P = 0.046); this difference was significant. The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months ( P = 0. 33), and the objective response rate was 50% vs 42% ( P = 0.63), respectively; these differences were not significant. 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., Conclusion: In the first-line treatment of HER2-positive advanced gastric cancer, inetetamab and trastuzumab showed comparable efficacy. The inetetamab group showed superior PFS, and both groups had good safety., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Docetaxel (DTX) is a recommended treatment in patients with metastasic prostate cancer (PCa), despite its therapeutic efficacy is limited by strong systemic toxicity. However, in localized PCa, intratumoral (IT) administration of DTX could be an alternative to consider that may help to overcome the disadvantages of conventional intravenous (IV) therapy. In this context, we here present the first in vivo preclinical study of PCa therapy with nanomedicines of mesoporous silica nanoparticles (MSN) and DTX by IT injection over a xenograft mouse model bearing human prostate adenocarcinoma tumors. The efficacy and tolerability, the biodistribution and the histopathology after therapy have been investigated for the DTX nanomedicine and the free drug, and compared with the IV administration of DTX. The obtained results demonstrate that IT injection of DTX and DTX nanomedicines allows precise and selective therapy of non-metastatic PCa and minimize systemic diffusion of the drug, showing superior activity than IV route. This allows reducing the therapeutic dose by one order and widens substantially the therapeutic window for this drug. Furthermore, the use of DTX nanomedicines as IT injection promotes strong antitumor efficacy and drug accumulation at the tumor site, improving the results obtained with the free drug by the same route., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Pablo Botella Asuncion reports financial support was provided by State Agency of Research. Pablo Botella Asuncion reports financial support was provided by Government of Valencia. Pablo Botella Asuncion has patent #WO2021/099662 issued to Universitat Politècnica de Valencia-Consejo Superior de Investigaciones Cientificas. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Lung enteric-type adenocarcinoma (ETAC) is a rare subtype of non-small cell lung cancer (NSCLC), comprising approximately 0.6% of all primary lung adenocarcinomas. It is characterized by a tendency for early metastasis and a prognosis comparable to that of common lung adenocarcinoma. This case report described a patient with lung-ETAC who developed gastric metastasis. The patient underwent treatment with chemotherapy and a PD-1 inhibitor, resulting in disease remission with a progression-free survival (PFS) of 8 months. The follow-up time was 13 months. This case report was aimed to enhance understanding of the biological behavior of this rare tumor and provide insights into potential future treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Ma, Ma, Zhao, Fan and Xu.)

Introduction: Cachexia is strongly associated with digestive cancers, particularly oesogastric cancer. Mitochondria in adipose tissue are involved in the regulation of metabolism and physiopathology of cancer cachexia in animal studies. Chemotherapeutic regimens used to control tumour development could also alter mitochondrial function in adipose tissue. We hypothesise that cachexia induces an increase in adipose tissue mitochondrial energy metabolism and that chemotherapy can mitigate this. The purpose of the ChiFMeOE study is to identify adipocyte factors involved in the energy imbalance associated with the cachectic process and their response to chemotherapeutic treatments in patients with oesogastric cancer., Methods and Analysis: ChiFMeOE is a single-centre observational study that will prospectively include 60 patients referred to chemotherapy and surgery for oesophageal and gastro-oesophageal junction adenocarcinomas at the University Hospital of Clermont-Ferrand, France. Visceral and subcutaneous adipose tissue biopsies will be collected during surgery scheduled before and after neoadjuvant chemotherapy administration, as well as cachexia and nutritional assessment. The primary outcome is the maximum mitochondrial respiration rate (Vmax) measured by high-resolution respirometry. Secondary outcomes are other mitochondrial parameters (ie, enzymatic activities, proteins content and gene expression), tumour characteristics, nutritional status and body composition., Ethics and Dissemination: The study was approved by an independent institutional review board on June 2023 (Comité de protection des personnes Sud-Méditerranée V; 2023-A00582-43) and declared to the French regulatory authority for research. Written informed consent will be obtained prior to patient inclusion. The principal investigator will be notified of any changes in patient's health status requiring a modification of his management and/or treatment during the course of the protocol. Results will be published in peer-reviewed journals., Trial Registration Number: ClinicalTrials.gov, NCT05954117., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Urtica dioica L. is one of the most widely utilized medicinal plants commonly applied in the form of tea, juice, and dietary supplements. This study aimed to assess the effect of the U. dioica ethanol-water extract (UdE) and polyphenolic fraction isolated from the extract (UdF) on normal human colon epithelial cells and to evaluate their protective activity against induced oxidative stress. The cytotoxic potential against human colorectal adenocarcinoma (HT29) and the anti-inflammatory effects were also investigated. UPLC-MS-DAD analysis revealed that both extracts were abundant in caffeic acid derivatives, specifically chlorogenic and caffeoylmalic acids, and therefore, they showed significant protective and ROS scavenging effects in normal human colon epithelial cells. Moreover, they had no negative impact on cell viability and morphology in normal cells and the extracts, particularly UdF, moderately suppressed adenocarcinoma cells. Furthermore, UdF significantly decreased IL-1β levels in HT29 cells. Our research indicates that U. dioica may provide significant health advantages because of its antioxidant and anti-inflammatory effects., Competing Interests: The authors declare no conflicts of interest.

KRAS mutations are the most common oncogenic mutations in lung adenocarcinoma in Black Americans. Polyisoprenylated Cysteinyl amide Inhibitors (PCAIs) constitute a group of potential cancer therapy agents that we designed to specifically disrupt and suppress hyperactive G-protein signaling, such as that caused by mutated RAS proteins. Here we determine the effects of PCAIs on the viability, G-protein levels, downstream mediators, and apoptosis-related proteins on the KRAS-mutated, Black American-derived lung adenocarcinoma cell line, NCI-H23. Of the 17 PCAIs tested, compounds NSL-YHJ-2-27 and NSL-YHJ-2-46 showed the most potency with EC50 values of 2.7 and 3.3 μM, respectively. Western blotting was used to determine the effect of the PCAIs on the phosphorylation levels of MAPK pathway enzymes. After 48 h exposure to 5 μM of the PCAIs, NSL-YHJ-2-46, the MAPK proteins BRAF, MEK1/2, ERK1/2, and p90RSK were activated through phosphorylation by 90, 190, 150 and 120%, respectively. However, CRAF/RAF1 phosphorylation decreased by 40%, suggesting significant changes in the KRAS/MAPK signaling patterns. Furthermore, 5 μM of NSL-YHJ-2-27 depleted the singly polyisoprenylated monomeric G-proteins RAC 1/2/3 and CDC42 by 77 and 76%, respectively. The depletion of these key cytoskeletal proteins may account for the observed inhibition of cell migration and invasion, and spheroid invasion observed on exposure to NSL-YHJ-2-27 and NSL-YHJ-2-46. Treatment with 5 μM of NSL-YHJ-2-27 suppressed full-length inactive caspase 3 and 7 levels by 72 and 91%, respectively. An analysis of cells treated with the fluorescently labeled active caspase 3/7 irreversible inhibitor, CaspaTagTM Caspase-3/7 in situ reagent revealed a 124% increase in active caspase at 3 μM over controls. These findings clearly show the direct effects of the PCAIs on the RAS signaling pathway. Given the profound increases observed in RPS6KA1/p90RSK phosphorylation, future work will involve a determination whether the proapoptotic isoforms of RPS6KA1/p90RSK are phosphorylated due to the PCAIs treatments. These results support the potential use of the PCAIs as targeted therapies against cancers with KRAS mutations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gregory et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs), possess immunomodulatory properties and have shown promising outcomes when combined with anti-PD-1 antibodies. The OASIS phase II trial (NCT04503967) is designed to determine the clinical activity and safety of nivolumab (anti-PD-1) and anlotinib hydrochloride (a multi-targets TKI) as second-line or above therapy in patients with advanced gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC). From December 2020 to September 2022, 45 patients with GAC and 3 with ESCC were enrolled in this study. The pre-specified endpoints were reached, with the primary endpoint of overall response rate achieving 29.2%. For secondary objectives, disease control rate was 64.6%; median progression-free survival was 4.0 months; and median overall survival was 11.1 months with a manageable toxicity profile. The exploratory analyses unveiled that the balance of gut bacteria and the presence of a pre-existing immune signature characterized by a high percentage of CD68 + PD-L1 + PD-1 + macrophages and low pretreatment variant allele frequencies (VAF), as well as low expression of certain cytokines were significantly associated with improved clinical outcomes in patients with GAC., (© 2024. The Author(s).)

Hydrogen sulfide (H2S) is a critical molecule that participates in various molecular, physiological, and pathophysiological processes in biological systems. Emerging evidence has revealed that H2S is implicated in the progression of colon cancer and immune escape. Against this backdrop, the present study aimed to construct a prognostic risk feature for colon adenocarcinoma (COAD) by leveraging hydrogen sulfide-related genes (HSRG). Transcriptomic data and corresponding clinical-pathological information of colon cancer were obtained from The Cancer Genome Atlas and gene expression omnibus databases. Univariate Cox regression analysis was employed to assess the prognostic relevance of HSRG. Consensus clustering was utilized to perform molecular subtyping of COAD, followed by comparison of immune cell infiltration, drug sensitivity, and immune therapy response between subtypes. Differential expression gene and gene set enrichment analyses were conducted between subtypes. Univariate, lasso, and multivariate Cox regression analyses were applied to construct a prognostic model derived from HSRG. A nomogram model for predicting COAD prognosis was constructed and evaluated. In this study, we identified 12 HSRGs that were associated with COAD prognosis. Consensus clustering analysis revealed 3 COAD molecular subtypes that exhibited significant differences in terms of prognosis, tumor immune cell infiltration, drug sensitivity, and immune therapy response. Gene set enrichment analysis demonstrated that immunoregulatory processes were significantly suppressed in the poor-prognosis subtype while Wnt-related pathways and processes were significantly upregulated. Based on the differentially expressed genes between subtypes, we constructed a risk model comprising 11 genes that effectively distinguished high-risk patients from low-risk patients with significant associations with patient survival outcomes, drug treatment, pathological staging, and T staging. The HSRG-derived risk feature was an independent prognostic factor for COAD in drug treatment and pathological staging and could be integrated into a nomogram for prognosis prediction. Calibration curve, receiver operating characteristic curve, and decision curve analysis demonstrated excellent performance of the nomogram in evaluating COAD prognosis. Our study systematically assessed the prognostic significance of HSRG in COAD, identified HSRG-based molecular subtypes and risk features, and highlighted their potential utility in predicting prognosis and treatment response., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Nucleolar and spindle-associated protein 1 (NUSAP1), a microtubule-associated protein, has been recently identified to exhibit aberrant expression patterns that correlate with malignant tumorigenesis and progression across various cancer types. However, the specific regulatory mechanisms and potential targeting therapies of NUSAP1 in lung adenocarcinoma (LUAD) remain largely elusive. In this study, by conducting bioinformatics analyses as well as in vitro and in vivo experiments, we identified that NUSAP1 was significantly upregulated in LUAD, with a notable correlation with poorer overall survival, higher scores for immunogenicity and immune infiltration, as well as increased sensitivity to conventional chemotherapeutic drugs such as paclitaxel, docetaxel and vinorelbine in LUAD. Functionally, NUSAP1 overexpression significantly promoted LUAD cell proliferation, while its knockdown markedly suppressed this process. Interestingly, our results revealed that NUSAP1 upregulation was mediated by estrogen via ERβ activation. Furthermore, we identified entinostat as a novel inhibitor of NUSAP1. Pharmacological targeting ERβ/NUSAP1 axis with fulvestrant (ERβ antagonist) or entinostat (novel NUSAP1 inhibitor) significantly reduced LUAD growth both in vitro and in vivo , which may represent effective alternative therapeutic strategies for patients with LUAD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study., Methods: Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2-IIB node positive vs III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint., Findings: Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy group and 531 patients in the placebo-chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3-34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4-86·1) in the pembrolizumab-chemoradiotherapy group and 74·8% (70·1-78·8) in the placebo-chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50-0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 371 (70%) of 530 in the placebo-chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 90 (17%) of 530 patients in the placebo-chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945., Interpretation: Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co., Competing Interests: Declaration of interests DL, YX, KH, GS, ML, PR-E, AA, JC, LR, AJPdSG, FCM, LH, HA, J-YL, VS, FZ, LG, JS, ET, KL, NC, C-LC, MB, HZ, AO, MC, EP, TU, SP, and LRD received funding to their institutions from Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD) to support the study. DL reports grants or contracts from AstraZeneca, Clovis Oncology, Pharma&, Genmab, GSK, Immunogen, MSD, Pharmamar, Novartis, Seagen, Alkermes, Incyte, Roche, and Corcept; consulting fees from AstraZeneca, Corcept, Clovis Oncology, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Novartis, Oncoinvest, Novocure, Seagen, and Sutro; speaker fees from AstraZeneca, Corcept, Genmab, GSK, Immunogen, MSD, and Seagen; travel grants from AstraZeneca, Menarini, GSK, and MSD; advisory board participation for AstraZeneca, Corcept, Clovis Oncology, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Oncoinvest, Novocure, Seagen, and Sutro; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for GCIG, MITO, and ENGOT. YX reports study funding, paid to the Peking Union Medical College Hospital, and support for attending meetings or travel from MSD. KH reports research contracts from Daiichi Sankyo, Eisai, MSD, and Takeda; advisory board fees from Chugai, Eisai, Takeda, MSD, Roche, Genmab, Sanofi, GSK, and Zymeworks; honoraria from Daiichi Sankyo, AstraZeneca, Chugai, Eisai, Genmab, MSD, Takeda, Sanofi, Kyowa Kirin, Kaken, and GSK; and travel support from Regeneron and Seagen. GS reports consulting fees from AstraZeneca, MSD, Coviden AG (a Medtronic company), Johnson & Johnson, and TESARO Bio Italy; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events from Baxter Healthcare, Olympus Europa, Intuitive Surgical, GSK, and Clovis Oncology Italy. ML reports payment for expert testimony from MSD, support for attending meetings or travel from MSD and AstraZeneca; and other financial or non-financial interests from MSD, AstraZeneca, and Roche. PR-E reports honoraria for educational events from MSD, AstraZeneca, Novartis, Asofarma, Pfizer, and Roche; support for attending ESMO and ASCO meetings from AstraZeneca, Pfizer, and Asofarma; and honoraria for advisory boards from MSD, Roche, AstraZeneca, Asofarma, BMS and Novartis. LR reports medical writing support from Merck, institutional grants from Merck, Zentalis, Karyopharn, GOG Foundation, Regeneron, ImmunoGen, Acrivon, CanariaBio, Corcept Therapeutics, and Seagen; consulting fees from AstraZeneca, Merck, GSK, Genmab, Seagen, GOG Foundation, Zentalis, ImmunoGen, Semline, Eisai, Caris, Nykode, and Clovis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Seagen and Genmab; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, from GOG Foundation. AJPdSG reports consulting fees and payment for expert testimony from Bayer, Astellas, and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for expert testimony from Astellas, AstraZeneca, Bayer, and Janssen; and participation on a data safety monitoring board or advisory board for Astellas, Bayer, and Janssen. FCM reports honoraria for presentations from MSD and BMS; support for attending meetings or travel from AstraZeneca and MSD; and advisory board participation from Janssen and MSD. J-YL reports support for the present manuscript from MSD; grants or contracts from Advenchen, Ascendis Pharma, Alkermes, AstraZeneca, Beigene, BergenBio, BMS, CanariaBio, Corcept, Cellid, CKD, Clovis Oncology, Eisai, Genmab, Genemedicine, GII, GSK, ImmunoGen, Janssen, Kelun, Merck, Mersana, MSD, Novartis, Onconic Therapeutics, ONO, Regeneron, Roche, Seagen, Sutro, Synthon, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Janssen, MSD, Roche, Takeda, and ONO; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for AstraZeneca, CanariaBio, Genmab, GII, ImmunoGen, Seagen, Merck, Sutro, Regeneron, and MSD. FZ reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, consulting fees, support for attending meetings or travel, and data safety monitoring board and advisory board participation for AstraZeneca, Daiichi, Eli-Lilly, Merck, Novartis, MSD, Pfizer, Genesis-Pharma, and Roche. LG reports institutional grants from IMV, Pfizer, Sutro Bio, Pharma, Merck Sharpe Dohme, Corcept Therapeutics, ImmunoGen, Shattuck Labs, Roche, Tesaro, K-Group, Beta Inc., GOG Foundation, GSK, AstraZeneca, OncoQuest Pharmaceuticals, Novocure, Alkermes, Espersas, and Mersana; consulting fees from Merck and GSK; payment or honoraria for lectures and presentations from Merck and GSK; support for attending meetings or travel from GSK, Merck, EndomERA, and Zentalis; and participation on advisory board meetings for GSK, Merck, Eisai, Novocure, Kora Health, Corcept, ImmunoGen, Canariabio, and Repare Therapeutics. JS reports grants or contracts from Roche, MSD, GSK, Tesaro, AstraZeneca, Eisai, Merck, and Novocure; consulting fees from Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure, MSD, Eisai, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure, BMS, Eisai, and Novartis; support for attending meetings or travel from GSK, Astra Zeneca, Roche, Novocure, Immunogen, Incyte, MSD, and Eisei; participation on a data safety monitoring board or advisory board for Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure, Bristol Myers Squibb, MSD, Merck, Bayer, and PharmaMar; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for ENGAGE, ESGO, ASCO, ESGO, GCIG, Deutsche Stiftung Eierstockkrebs, and AGO; and medical writing assistance from MSD. ET reports honoraria for presentations and meeting travel support from Elektra. KL reports study funding from MSD; grants or contracts from GSK; lecture honoraria from Eisai and AstraZeneca; participation on a data safety monitoring board for Karyopharm; participation on an advisory board for Eisai, MSD, Nykode, AstraZeneca, and GSK; and serving as deputy medical director for the Nordic Society of Gynecological Oncology Clinical Trial Unit. NC reports institutional grants from AstraZeneca and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK and MSD; payment for participation on a data safety monitoring board or advisory board for AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Mersana, MSD, Merck, Nuvation Bio, Onxerna, Pfizer, PharmaMar, Pieris, Roche, and Novocure; and non-remunerated leadership role as Chair of the Alleanza Contro il Tumore Ovarico Scientific Committee. MB reports honoraria for lectures and educational events from Roche, AstraZeneca, and GSK; and support for attending meetings from Roche, AstraZeneca, and Viatris. AO reports consulting fees from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Daïichi Sankyo, Debiopharm International, Eisai, Exelisis, F. Hoffmann-La Roche, Genmab, GSK, ImmunoGen, Itheos, MSD, Mersana Therapeutics, Myriad Genetics, Novocure, OncoXerna Therapeutics, PharmaMar, Regeneron, Sattucklabs, Seagen–Pfizer, Sutro Biopharma, TORL Therapuetics, Zentalis, and Zymeworks; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from NSGO, Peerview, Peervoice, Medscape, Asociación Colombiada de Ginecológos Oncólogos, ESO, AstraZeneca, and GSK; support for attending meetings or travel from AstraZeneca, PharmaMar, and Roche; participation on a data safety monitoring board or advisory board from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Daïichi Sankyo, Debiopharm International, Eisai, Exelisis, F Hoffmann-La Roche, Genmab, GSK, ImmunoGen, Itheos, MSD, Mersana Therapeutics, Myriad Genetics, Novocure, OncoXerna Therapeutics, PharmaMar, Regeneron, Sattucklabs, Seagen–Pfizer, Sutro Biopharma, TORL Therapuetics, Zentalis, and Zymeworks; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for Gynecologic Cancer Intergroup and European Society for Medical Oncology; and other financial or non-financial interests in Gynecologic Cancer Intergroup, European Society for Medical Oncology, American Society of Clinical Oncology, Spanish Society of Medical Oncology, and GOG Foundation. EP reports provision of study material from MSD; honoraria for lectures, presentations, and educational events from MSD, Roche, GSK, and AstraZeneca; and receipt of investigational drug for study treatment from MSD. PL, KY, ST, and SMK are current or former full-time employees of MSD and hold stock or restricted stock units in the company. SP reports research funding from Roche, MSD, GSK, Pfizer, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, MSD, Roche, Pfizer, Novartis, and GSK; and participation on a Data Safety Monitoring Board or Advisory Board for GSK, MSD, Eisai, Biontech, and AstraZeneca. LRD reports institutional grants from Merck, Genentech, Roche, AbbVie, Acrivon, Advaxis, Aduro BioTech, Alkermes, Blueprint, Constellation, Eisai, GSK, Novartis, Immunogen, Inovio, Iovance, Karyopharm, KSQ Therapeutics, Lycera, Morab, MorphoTek, Naveris, Nurix, OncoQuest, Pfizer, Syndax, Tesaro, and Zentalis; royalties or licenses from UpToDate, Wiley, and ASCO; editing for ASCO Connection; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Advance Medical, CEA Group, and Clinical Care Options; participation on a data safety monitoring board for Innovia and Aegenus (payment to institution); and roles as Secretary Treasurer for SGO (unpaid) and on the Editorial Board of the British Journal of Obstetrics and Gynaecology., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background/aim: Colorectal cancer (CRC) is one of the most widespread malignancies. One of the alternative therapeutic methods appears to be photodynamic therapy (PDT)., Materials and Methods: This study investigated the efficiency of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin zinc (ZnTPPS 4 ) and chloro-aluminum phthalocyanine disulfonate (ClAlPcS 2 ) with two commercial photosensitive compounds 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP) and tetramethylthionine chloride (methylene blue, MB) in PDT for CRC in vitro. In addition to the study of the photodynamic effect on the viability of the colorectal carcinoma cell line HT29, cellular uptake, ROS production, and DNA damage were investigated., Results: All photosensitizers showed good accumulation within HT29 cells, high efficiency in killing the cells, and a concentration-dependent increase in the production of ROS., Conclusion: PDT using ZnTPPS 4 and ClAlPcS 2 may be effective in the treatment of CRC, achieving a similar photocytotoxic effect at much lower concentrations compared to MB., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Gastric adenocarcinoma (GAC) remains a prevalent cancer worldwide and its incidence is increasing in South America. The heterogenous nature of GAC makes advances in management challenging., Areas Covered: Despite challenges, recent therapeutic targets are individualizing treatment. For localized disease with microsatellite-instability-high/deficient mismatch repair, immunotherapy is now an adopted practice. In the advanced unresectable setting, those harboring human epidermal growth factor receptor-2 (HER2) expression continue to be a separate entity., Expert Opinion: Future targets are developing. Among these include claudin 18.2 (CLDN18.2), fibroblast growth factor receptor 2b (FGFR2b), and trophoblast cell surface antigen-2 (TROP-2). FDA approval of zolbetuximab's, an anti-CLDN 18.2 monoclonal antibody, is expected soon. Additionally, bemarituzumab, ananti-FGFR2b monoclonal antibody, has shown improvements in combination with chemotherapy in those with HER2 negative GAC with FGFR2 overexpression. This combination is now being investigated in a phase 3 trial. Lastly, TROP-2 has emerged as an exciting solid tumor target and study is expected in GAC. All three of these therapeutic targets have seen an abundance of drug development in recent years, and we anticipate newer targeted agents driving therapeutic decisions in GAC in the coming years.

Introduction: The role and impact of preoperative chemotherapy (PC) in pancreatic adenocarcinoma are questions under active investigation. Here we investigate the rate of failure to rescue (FTR) and surgical outcomes in patients undergoing pancreatectomy, with PC within 90 days (d) prior to surgery and without PC., Materials and Methods: The National Surgical Quality Improvement Program Targeted Dataset for Pancreatectomy (2014-2020) was queried to identify patients who underwent pancreatectomy for malignant non-neuroendocrine pancreatic tumors. The cohort was divided into those who underwent PC within 90 d and those without. Propensity score analysis was employed to match patients 1:1 based on age, sex, body mass index, hypertension, smoking status, ascites, diabetes, and American Society of Anesthesiology (ASA) score. The primary outcome of interest was FTR, defined as mortality following a major complication (Clavien-Dindo Class III-V)., Results: After propensity score matching, 7895 patients with PC were matched to 7895 patients without PC. PC patients exhibited a significantly lower rate of FTR (P = 0.002) despite having higher ASA scores. This benefit was most pronounced in the pancreaticoduodenectomy subgroup (P < 0.009). PC patients demonstrated a lower rate of overall complications compared to those without PC (P < 0.001). Overall, the PC group was more likely to require vascular resection (P < 0.001)., Conclusions: Patients who received chemotherapy within 90 d prior to surgery experienced a lower rate of FTR and overall complications despite higher ASA scores and incidence of vascular resection. This suggests that, when appropriate, the receipt of PC does not negatively impact surgical outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality and is projected to be the second leading cause of cancer-related deaths by 2030. Mutations in KRAS are found in the vast majority of PDAC cases and plays an important role in the development of the disease. KRAS drives tumor cell proliferation and survival through activating the MAPK pathway to drive cell cycle progression and to lead to MYC-driven cellular programs. Moreover, activated KRAS promotes a protumorigenic microenvironment through forming a desmoplastic stroma and by impairing antitumor immunity. Secretion of granulocyte-macrophage colony-stimulating factor and recruitment of myeloid-derived suppressor cells and protumorigenic macrophages results in an immunosuppressive environment while secretion of secrete sonic hedgehog and TGFβ drive fibroblastic features characteristic of PDAC. Recent development of several small molecules to directly target KRAS marks an important milestone in precision medicine. Many molecules show promise in preclinical models of PDAC and in early phase clinical trials. In this review, we discuss the underlying cell intrinsic and extrinsic roles of KRAS in PDAC tumorigenesis, the pharmacologic development of KRAS inhibition, and therapeutic strategies to target KRAS in PDAC., (©2024 American Association for Cancer Research.)

Aims: The aim of the study is to report the clinical and pharmacological observations from a pregnant patient treated with erlotinib in the second and third trimesters of pregnancy., Methods: Maternal and neonatal blood levels and safety of erlotinib and its metabolites were evaluated. Child development was monitored for 6 years., Results: A 31-year-old woman with stage IV lung adenocarcinoma with EGFR exon19 deletion began treatment with erlotinib 150 mg/day at 17 weeks of gestation. Although foetal growth retardation and oligohydramnios were observed at several times during the pregnancy, treatment was continued due to the severity of the maternal presentation, with ongoing foetal monitoring. The foetus seemed to tolerate and recover well without specific interventions. A healthy baby boy was delivered at 37 weeks gestation. The child grew and developed without any obvious issues. At last follow-up, at age 6 years, he was attending school at a grade appropriate for his age without health or developmental problems. Blood levels of erlotinib were 397-856 ng/mL at 18-37 weeks of gestation and 1190 ng/mL at 8 weeks postpartum. The blood concentration ratios of OSI-413-to-erlotinib ranged from 0.167 to 0.253 at 18-37 weeks of gestation, excluding 24 weeks, and 0.131 at 8 weeks postpartum. The maternal-to-foetal transfer rate of erlotinib, OSI-420 and OSI-413 were 24.5, 34.8 and 20.3%, respectively., Conclusion: Erlotinib use during the second and third trimester of pregnancy did not seem to cause any untoward effects on the developing foetus, or any long-lasting effects that could be detected during 6 years of follow-up of the child., (© 2024 British Pharmacological Society.)

PURPOSETo assess whether the integration of PD-1 inhibitor with total neoadjuvant therapy (iTNT) can lead to an improvement in complete responses (CRs) and favors a watch-and-wait (WW) strategy in patients with proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC).PATIENTS AND METHODSWe conducted a prospective, multicenter, randomized, open-label, phase II trial using a pick-the-winner design. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomly assigned to group A for short-course radiotherapy (SCRT) followed by six cycles of consolidation immunochemotherapy with capecitabine and oxaliplatin and toripalimab or to group B for two cycles of induction immunochemotherapy followed by SCRT and the rest four doses. Either total mesorectal excision or WW was applied on the basis of tumor response. The primary end point was CR which included pathological CR (pCR) after surgery and clinical CR (cCR) if WW was applicable, with hypothesis of an increased CR of 40% after iTNT compared with historical data of 25% after conventional TNT.RESULTSOf the 130 patients enrolled, 121 pMMR/MSS patients were evaluable (62 in group A and 59 in group B). At a median follow-up of 19 months, CR was achieved at 56.5% in group A and 54.2% in group B. Both groups fulfilled the predefined statistical hypothesis ( P < .001). Both groups reported a pCR rate of 50%. Respectively, 15 patients in each group underwent WW and remained disease free. The most frequent grade 3 to 4 toxicities were thrombocytopenia and neutropenia. Patients in group A had higher rate of cCR (43.5% v 35.6%) at restaging and lower rate of grade 3 to 4 thrombocytopenia (24.2% v 33.9%) during neoadjuvant treatment.CONCLUSIONThe iTNT regimens remarkably improved CR rates in pMMR/MSS LARC compared with historical benchmark with acceptable toxicity. Up-front SCRT followed by immunochemotherapy was selected for future definitive study.

MYC has been identified to profoundly influence a wide range of pathologic processes in cancers. However, the prognostic value of MYC-related genes in pancreatic adenocarcinoma (PAAD) remains unclarified. Gene expression data and clinical information of PAAD patients were obtained from The Cancer Genome Atlas (TCGA) database (training set). Validation sets included GSE57495, GSE62452, and ICGC-PACA databases. LASSO regression analysis was used to develop a risk signature for survival prediction. Single-cell sequencing data from GSE154778 and CRA001160 datasets were analyzed. Functional studies were conducted using siRNA targeting RHOF and ITGB6 in PANC-1 cells. High MYC expression was found to be significantly associated with a poor prognosis in patients with PAAD. Additionally, we identified seven genes (ADGRG6, LINC00941, RHOF, SERPINB5, INSYN2B, ITGB6, and DEPDC1) that exhibited a strong correlation with both MYC expression and patient survival. They were then utilized to establish a risk model (MYCsig), which showed robust predictive ability. Furthermore, MYCsig demonstrated a positive correlation with the expression of HLA genes and immune checkpoints, as well as the chemotherapy response of PAAD. RHOF and ITGB6, expressed mainly in malignant cells, were identified as key oncogenes regulating chemosensitivity through EMT. Downregulation of RHOF and ITGB6 reduced cell proliferation and invasion in PANC-1 cells. The developed MYCsig demonstrates its potential in enhancing the management of patients with PAAD by facilitating risk assessment and predicting response to adjuvant chemotherapy. Additionally, our study identifies RHOF and ITGB6 as novel oncogenes linked to EMT and chemoresistance in PAAD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Disclosure The authors have no conflicts of interest to disclose.

Background: Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a programmed cell death protein 1 monoclonal antibody) has shown potential clinical activity for locally advanced rectal cancer (LARC) in a phase II trial. This study aimed to further confirm the efficacy and safety of SCRT followed by CAPOX and camrelizumab compared to long-course chemoradiotherapy (LCRT) followed by CAPOX alone as neoadjuvant treatment for LARC., Patients and Methods: In this randomized, phase III trial, patients with T3-4/N+ rectal adenocarcinoma were randomly assigned (1 : 1) to receive SCRT or long-course chemoradiotherapy (LCRT), followed by two cycles of camrelizumab and CAPOX or CAPOX alone, respectively. After surgery, each arm underwent either six cycles of camrelizumab and CAPOX, followed by up to 17 doses of camrelizumab, or six cycles of CAPOX. The primary endpoint was pathological complete response (pCR) rate (ypT0N0) assessed by a blinded independent review committee. Key secondary endpoints tested hierarchically were 3-year event-free survival (EFS) rate and overall survival (OS)., Results: Between July 2021 and March 2023, the intention-to-treat population comprised 113 patients in the experimental arm and 118 patients in the control arm, with surgery carried out in 92% and 83.9%, respectively. At data cut-off (11 July 2023), the pCR rates were 39.8% [95% confidence interval (CI) 30.7% to 49.5%] in the experimental arm compared to 15.3% (95% CI 9.3% to 23.0%) in the control arm (difference, 24.6%; odds ratio, 3.7; 95% CI 2.0-6.9; P < 0.001). In each arm, surgical complication rates were 40.0% and 40.8%, and grade ≥3 treatment-related adverse events were 29.2% and 27.2%. Three-year EFS rate and OS continue to mature., Conclusions: In LARC patients, neoadjuvant SCRT followed by camrelizumab plus CAPOX demonstrated a significantly higher pCR rate than LCRT followed by CAPOX, with a well-tolerated safety profile. SCRT followed by camrelizumab and chemotherapy can be recommended as a neoadjuvant treatment modality for these patients., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The clinico-oncological outcomes of precursor epithelial subtypes of adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) are limited to small cohort studies. Differences in recurrence patterns and response to adjuvant chemotherapy between A-IPMN subtypes are unknown., Methods: Clincopathological features, recurrence patterns and long-term outcomes of patients undergoing pancreatic resection (2010-2020) for A-IPMN were reported from 18 academic pancreatic centres worldwide. Precursor epithelial subtype groups were compared using uni- and multivariate analysis., Results: In total, 297 patients were included (median age, 70 years; male, 78.9%), including 54 (18.2%) gastric, 111 (37.3%) pancreatobiliary, 80 (26.9%) intestinal and 52 (17.5%) mixed subtypes. Gastric, pancreaticobiliary and mixed subtypes had comparable clinicopathological features, yet the outcomes were significantly less favourable than the intestinal subtype. The median time to recurrence in gastric, pancreatobiliary, intestinal and mixed subtypes were 32, 30, 61 and 33 months. Gastric and pancreatobiliary subtypes had worse overall recurrence (p = 0.048 and p = 0.049, respectively) compared with the intestinal subtype but gastric and pancreatobiliary subtypes had comparable outcomes. Adjuvant chemotherapy was associated with improved survival in the pancreatobiliary subtype (p = 0.049) but not gastric (p = 0.992), intestinal (p = 0.852) or mixed subtypes (p = 0.723). In multivariate survival analysis, adjuvant chemotherapy was associated with a lower likelihood of death in pancreatobiliary subtype, albeit with borderline significance [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.31-1.01; p = 0.058]., Conclusions: Gastric, pancreatobiliary and mixed subtypes have comparable recurrence and survival outcomes, which are inferior to the more indolent intestinal subtype. Pancreatobiliary subtype may respond to adjuvant chemotherapy and further research is warranted to determine the most appropriate adjuvant chemotherapy regimens for each subtype., (© 2024. The Author(s).)

Although gemcitabine (GEM) is the first‑line drug for advanced pancreatic adenocarcinoma (PAAD), the development of GEM resistance severely limits the effectiveness of this chemotherapy. This study investigated the mechanisms of ecotropic viral integration site 2 A (EVI2A) for resistance to GEM and immune evasion in PAAD. GEM resistance-related biomarkers were predicted using GEO datasets, and GEM-resistant PAAD cells were generated. EVI2A was found expressed highly in GEM-resistant PAAD cells. Gain-of-function analyses revealed that EVI2A encouraged the proliferation and motility of GEM-resistant cells and prevented apoptosis. In addition, EVI2A reduced T cell effector activation. SMYD2 was overexpressed in GEM-resistant cells, and SMYD2 enhanced H3K36me2 modification of EVI2A, thereby promoting EVI2A expression. SMYD2 reduced the sensitivity of GEM-resistant cells, which was reversed by EVI2A knockdown. SMYD2 increased the amount of M2 macrophages (co-cultured with PAAD cells) and decreased T cell effector activation (co-cultured with macrophage supernatant), and the number of M2 macrophages was decreased and T cell effectors were activated following EVI2A knockdown. Our findings indicate that EVI2A, manipulated by the SMYD2-H3K36me2 epigenetic axis, promoted GEM resistance and M2 macrophage-mediated immune evasion in PAAD. Therefore, EVI2A might represent a therapeutic target for overcoming GEM resistance and immunosuppressive environment in PAAD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Leukocytoclastic vasculitis (LCV) is a vasculitic inflammation against blood vessels. Various anticancer therapies can cause vasculitis, but capecitabine-induced LCV is an unusual entity. Here, we describe an LCV case associated with neoadjuvant capecitabine use for locally advanced rectal cancer (LARC)., Case Report: A 70-year-old man presented with rectal bleeding. A colonoscopic biopsy revealed rectal adenocarcinoma and he was diagnosed with LARC after imaging studies. Capecitabine plus radiation therapy was started as a neoadjuvant treatment., Management and Outcome: Seven days after the first capecitabine dose, the patient was admitted with a rash. The LCV diagnosis was histopathologically proven. Capecitabine was withheld. After the patient's rash began to regress under corticosteroid pressure, capecitabine was started at a lower dose. His treatment was completed successfully with oral corticosteroids plus low-dose capecitabine., Discussion: We aimed to point out a rare and unusual adverse effect of a frequently used drug in oncologic practice., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Prostate cancer (PCa) is the leading cause of cancer‑related death among men worldwide. PCa often develops resistance to standard androgen deprivation therapy and androgen receptor (AR) pathway inhibitors, such as enzalutamide (ENZ). Therefore, there is an urgent need to develop novel therapeutic strategies for this disease. The efficacy of ADA‑308 was evaluated through in vitro assessments of AR activity and cell proliferation, alongside in vivo studies. ADA‑308 has emerged as a promising candidate, demonstrating potent inhibition of AR‑sensitive adenocarcinoma as well as ENZ‑resistant PCa cell lines. The results of the study revealed that ADA‑308 effectively blocked AR activity, including its nuclear localization, and inhibited cell proliferation in vitro . Furthermore, ADA‑308 demonstrated notable efficacy in vivo , with a robust antitumor response in ENZ‑resistant models. These findings establish the role of ADA‑308 as a potent AR inhibitor that overcomes resistance to AR‑targeted therapies and highlights its potential as a novel therapeutic approach in advanced PCa management.

Background: Whether or not the addition of immunotherapy to current standard-of-care treatments can improve efficacy in proficient mismatch repair (pMMR)/microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), the predominant type of mCRC, is unclear., Methods: This randomized, double-blind, phase 2 part of a phase 2/3 trial was conducted at 23 hospitals across China (ClinicalTrials.gov: NCT04547166). Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomly assigned 1:1 to receive every-3-weeks intravenous serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (serplulimab group) or placebo (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (placebo group). The primary endpoint was independent radiology review committee (IRRC)-assessed progression-free survival (PFS). Secondary endpoints included other efficacy endpoints and safety., Findings: Between July 16, 2021, and January 20, 2022, 114 patients were enrolled and randomly assigned to the serplulimab (n = 57) or placebo (n = 57) group. All patients had stage IV CRC, and 95.7% of the patients with available microsatellite instability (MSI) status were MSS. With a median follow-up duration of 17.7 months, median PFS was prolonged in the serplulimab group (17.2 vs. 10.7 months; hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.31-1.14). Although the median overall survival (OS) was not reached for either group, a trend of an OS benefit was observed for the serplulimab group (HR, 0.77; 95% CI, 0.41-1.45). 36 (65.5%) and 32 (56.1%) patients in the serplulimab and placebo groups had grade ≥3 treatment-related adverse events, respectively., Conclusions: Serplulimab plus HLX04 and XELOX exhibits promising efficacy and is safe and tolerable in patients with treatment-naive mCRC., Funding: This work was funded by Shanghai Henlius Biotech, Inc., Competing Interests: Declaration of interests Y.K., H.Y., J.L., Q.W., and J. Zhu are employees of Shanghai Henlius Biotech, Inc. R.-H.X. reported participating on advisory boards for Astellas, MSD, AstraZeneca, Hengrui, BeiGene, Innovent, Hutchison, Junshi, Qilu, CPPC, and Keymed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Prostate cancer (PC) is one of the most commonly diagnosed tumours among men. Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone acetate (AbA) and enzalutamide (ENZ), are currently used in the management of metastatic castration-resistant PC (mCRPC). However, the treatment is challenging due to the lack of prognostic biomarkers. Meanwhile, single-nucleotide polymorphisms (SNPs) have emerged as potential prognostic indicators of mCRPC. Thus, this study evaluated the impact of relevant SNPs on the treatment outcomes of 123 mCRPC patients enrolled in a hospital-based cohort study. The CYP17A1 rs2486758 C allele was associated with a 50% reduction in the risk of developing castration resistance (hazard ratio (HR) = 0.55; p = 0.003). Among patients without metastasis at tumour diagnosis and under AbA, a marginal association between YBX1 rs10493112 and progression-free survival was detected (log-rank test, p = 0.056). In the same subgroup, significant associations of HSD3B1 rs1047303 (CC/CA vs. AA; HR = 3.41; p = 0.025), YBX1 rs12030724 (AT vs. AA; HR = 3.54; p = 0.039) and YBX1 rs10493112 (log-rank test, p = 0.041; CC vs. AA/AC; HR = 3.22; p = 0.053) with overall survival were also observed, which were confirmed by multivariate Cox analyses. Although validation with larger cohorts is required, these findings suggest that SNPs could enhance the prognosis assessment of mCRPC patients, leading to a more personalised treatment.

Colorectal cancer (CRC) is one of the top 10 most common cancers worldwide and caused approximately 10 million deaths in 2022. CRC mortality has increased by 10% since 2020 and 52.000 deaths will occur in 2024, highlighting the limitations of current treatments due to ineffectiveness, toxicity, or non-adherence. The widely used chemotherapeutic agent, 5-fluorouracil (5-FU), is associated with several adverse effects, including renal, cardiac, and hepatic toxicity; mucositis; and resistance. Taurine (TAU), an essential β-amino acid with potent antioxidant, antimutagenic, and anti-inflammatory properties, has demonstrated protective effects against tissue toxicity from chemotherapeutic agents like doxorubicin and cisplatin. Taurine deficiency is linked to aging and cancers such as breast and colon cancer. This study hypothesized that TAU may mitigate the adverse effects of 5-fluorouracil (5-FU). Carcinogenesis was chemically induced in rats using 1,2-dimethylhydrazine (DMH). Following five months of cancer progression, taurine (100 mg/kg) was administered orally for 8 days, and colon tissues were analyzed. The results showed 80% of adenocarcinoma (AC) in DMH-induced control animals. Notably, the efficacy of 5-FU showed 70% AC and TAU 50% while, in the 5-FU + TAU group, no adenocarcinoma was observed. No differences were observed in the inflammatory infiltrate or the expression of genes such as K-ras, p53, and Ki-67 among the cancer-induced groups whereas APC/β-catenin expression was increased in the 5FU + TAU-treated group. The mitotic index and dysplasia were increased in the induced 5-FU group and when associated with TAU, the levels returned to normal. These data suggest that 5-FU exhibits a synergic anticancer effect when combined with taurine.