To delineate Gpr109A's role and mechanisms in modulating the immune microenvironment of hepatocellular carcinoma. Employing Gpr109A-knockout mice and in vitro co-cultures of hepatocellular carcinoma cells with macrophages, this study utilized a suite of techniques, including lentiviral vectors for stable cell line establishment, Western blotting, cell scratch, CCK-8, transwell assays, flow cytometry, immunohistochemistry and phagocytosis assay to assess various cellular behaviors and interactions. Gpr109A deletion markedly reduced the oncogenic potential of H22 cells, both in vivo and when co-cultured with knockout macrophages, impairing their growth, invasion, and migration. In Gpr109A-knockout macrophages, an upregulation of MerTK and a reduction in immunosuppressive cytokine release were observed, indicating a shift towards an M2c macrophage phenotype. This shift is linked to Gpr109A's role in promoting protease overexpression and inhibiting SHP2 phosphorylation, crucial for enhancing cancer cell proliferation and invasiveness. Gpr109A significantly influences macrophage polarization to the M2c type, augmenting hepatocellular carcinoma cell aggressiveness.

Drug resistance develops frequently after colorectal carcinoma (CRC) surgery, indicating the urgent need for new therapeutic strategies. Taletrectinib (DS-6051b/AB-106), a synthetic ROS1/NTRK inhibitor which has shown meaningful antitumor activity, is currently undergoing clinical trials aimed at addressing targeted resistance. However, the anti-cancer effect of taletrectinib on CRC remains unclear. In this study, our purpose was to evaluate taletrectinib-related cytotoxicity in vitro using two CRC cell lines, as well as in vivo in a mouse tumor model. The mechanism underlying the cytotoxicity of taletrectinib was evaluated using light microscopy, scanning electron microscopy, immunofluorescence assays, an annexin V-FITC/propidium iodide detection, lactate dehydrogenase (LDH) release assays, and western blotting. We found that the viability of CRC cells decreased with increasing concentrations of taletrectinib. In addition, transcriptome sequencing indicated that HCT116 and LOVO cell lines did not carry ROS1- or NTRK-related gene fusions and that the cytotoxic effect of taletrectinib was exerted via caspase-3/gasdermin E (GSDME)-dependent pyroptosis. Moreover, the effect of taletrectinib in promoting pyroptosis was reversed by treatment with the SRC agonist, tolimidone, both in vitro and in vivo. Overall, our findings suggest that taletrectinib suppresses tumor growth by inducing GSDME-mediated pyroptosis via the SRC/AKT/mTOR signaling pathway, indicating that taletrectinib shows potential as a promising therapeutic agent against CRC.

Immunotherapy has become the first-line treatment for metastatic mismatch repair deficient (dMMR) colorectal cancer. The efficacy and safety of neoadjuvant immunotherapy for the treatment of non-metastatic dMMR colorectal cancer remain unclear. In this article, we explore the clinical effect and safety of neoadjuvant immunotherapy for non-metastatic dMMR colorectal cancer.

We collected clinical data from the databases (PubMed, Wanfang Embase, Cochrane Library, and China National Knowledge Infrastructure databases) up to November 2024. The primary outcomes of major pathological response (MPR), pathological complete response (pCR), and other outcomes were analyzed for the final results. The secondary outcomes (pCR rates for the subgroups) were also analyzed.

We included 21 articles with 628 non-metastatic dMMR colorectal cancers. A pCR was found in 320/480 (66.6%) patients [effect size (ES): 0.70, 95% CI: 0.66 to 0.74] with the fixed-effects model and little heterogeneity. A MPR was found in 388/452 (85.8%) patients (ES: 0.86, 95% CI: 0.81 to 0.91) with the fixed-effects model and little heterogeneity. In the subgroup analysis, pCR rates were similar in the T1-T3 group and T4a-T4b group in the fixed-effects model with minimal heterogeneity (OR: 0.76, 95% CI: 0.48 to 1.22). The pCR rates were similar in the colon cancer group and rectal cancer group in the fixed-effects model with minimal heterogeneity (OR: 1.41, 95% CI: 0.39 to 5.12). Similar pCR rates were found in the immune monotherapy group and immune therapy plus chemotherapy group (OR: 0.74, 95% CI: 0.26 to 2.10) with the fixed-effects model and little heterogeneity.

Neoadjuvant immunotherapy achieves high rates of pCR and MPR for non-metastatic dMMR colorectal cancer. For locally advanced T4 stage dMMR colorectal cancer, neoadjuvant immunotherapy can still achieve good pCR rates. Neoadjuvant immune monotherapy can achieve good pCRs rates, avoiding the toxic side effects caused by combined dual immunotherapy and chemo(radio)therapy. Neoadjuvant immunotherapy could be another treatment option for non-metastatic dMMR colorectal cancer.

https://www.crd.york.ac.uk/prospero/, identifier CRD42024594173.

The combination of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) with endocrine therapy (ET) has emerged as an effective alternative to neoadjuvant chemotherapy (NCT) for patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2) -negative breast cancer (BC). This single-center study retrospectively evaluated the efficacy and safety of dalpiciclib combined with an aromatase inhibitor (AI) compared to NCT.

The clinicopathological data and treatment details of patients with HR+ HER2 negative BC who underwent either neoadjuvant endocrine therapy (NET) or NCT were collected from the Fourth Hospital of Hebei Medical University. The primary endpoint of the study was the Residual Cancer Burden (RCB), while secondary endpoints included breast pathological complete response (bpCR), clinical response rates (ORR), proliferation markers, and safety profiles.

Between May 2022 and June 2023, a total of 36 patients were treated with dalpiciclib plus AI, while 137 patients received NCT for the final analysis. Prior to propensity score matching (PSM), the rates of RCB 0 were 0% in the NET group and 7.3% in the NCT group (p=0.205). The rates of bpCR were 2.8% for the NET group and 13.1% for the NCT group (p=0.142). The ORR was comparable between the two groups (p=0.397), as were the rates of BCS (p=0.608). Both treatment groups demonstrated significant reductions in Ki-67 levels, although the extent of reduction was similar (p=0.174). Notably, a Ki-67 level of ≤ 10% post-treatment was more prevalent in the NET group (p<0.0001). Only two patients in the NET group achieved a Preoperative Endocrine Prognostic Index (PEPI) 0 score. The incidence of grade 3-4 toxicities was significantly higher in the NCT group compared to the NET group (p<0.05). Following PSM, patients treated with dalpiciclib plus AI exhibited comparable clinical responses and a safety advantage relative to those receiving NCT.

This study indicates that the combination of dalpiciclib and AI elicits comparable responses and demonstrates improved safety profiles when compared to NCT in patients with HR+ HER2 negative breast tumors. Furthermore, RCB and pCR may not serve as optimal endpoints for evaluating the efficacy of CDK4/6i-based NET.

Immune checkpoint inhibitors (ICIs) have significantly improved survival for patients with metastatic melanoma, yet many experienceresistance due to immunosuppressive mechanisms within the tumor immune microenvironment (TIME). Understanding how the spatial architecture of immune and inflammatory components changes across disease stages may reveal novel prognostic biomarkers and therapeutic targets.

We performed high-dimensional spatial profiling of two melanoma tissue microarrays (TMAs), representing Stage III (n = 157) and Stage IV (n = 248) metastatic tumors. Using imaging mass cytometry (IMC) and multiplex immunofluorescence (mIF), we characterized the phenotypic, functional, and spatial properties of the TIME. Cellular neighborhoods were defined by inflammatory marker expression, and spatial interactions between immune and tumor cells were quantified using nearest-neighbor functions (G-cross). Associations with survival were assessed using Cox proportional hazards models with robust variance estimation.

Stage IV tumors exhibited a distinct immune landscape, with increased CD74- and MIF-enriched inflammatory neighborhoods and reduced iNOS-associated regions compared to Stage III. Cytotoxic T lymphocytes (CTLs) and tumor cells were more prevalent in Stage IV TIME, while B cells and NK cells were depleted. Spatial analysis revealed that CTL-Th cell, NK-T cell, and B-NK cell interactions were linked to improved survival, whereas macrophage aggregation and excessive B-Th cell clustering in inflammatory regions correlated with worse outcomes. Organ-specific analyses showed that CTL infiltration near tumor cells predicted survival in gastrointestinal metastases, while NK-T cell interactions were prognostic in lymph node and skin metastases.

Our results reveal stage-specific shifts in immune composition and spatial organization within the melanoma TIME. In advanced disease, immunosuppressive neighborhoods emerge alongside changes in immune cell localization, with spatial patterns of immune coordination-particularly involving CTLs, NK cells, and B cells-strongly predicting survival. These findings highlight spatial biomarkers that may refine patient stratification and guide combination immunotherapy strategies targeting the inflammatory architecture of the TIME.

PD-1 inhibitors combined with chemotherapy have become the standard first-line treatment for advanced gastric cancer (GC), but their efficacy in young GC patients is unknown. This study aimed to evaluate the efficacy of immunotherapy in young GC patients and explore new treatment strategies for this population.

Clinicopathological data of young unresectable GC patients were collected from multiple centres. We defined young as ≤45 years. Statistical analyses were conducted with SPSS IBM for Windows version 24.0.

In total, 225 young unresectable GC patients were registered. Their clinicodemographic characteristics included female predominance (60.9%), poor differentiation (86.7%), high family history of cancer (14.2%), low HER2 expression (12.2%), PD-L1 expression (43.0%) and mismatch repair (MMR) deficiency (1.0%), and a high proportion of peritoneal metastasis (49.3%). After screening, 134 patients were included for analysis: 63 received dual chemotherapy (mFOLFOX6, XELOX, SOX and two-drug containing paclitaxel), 32 PD-1 inhibitors plus dual chemotherapy (mFOLFOX6, XELOX, SOX and two-drug containing paclitaxel), and 39 triple regimens (two-drug chemotherapy combined with apatinib or trastuzumab, or triple chemotherapy based on platinum, fluorouracil and paclitaxel). The effectiveness analysis revealed no significant difference in the disease control rate (DCR) between the dual chemotherapy group and the PD-1 inhibitor plus dual chemotherapy group (P=0.787), but triple regimens led to the best DCR (71.4% vs. 68.8% vs. 94.9%, all P<0.05). Kaplan-Meier curves showed median progression-free survival (PFS) times of the three groups of 4.7, 4.7 and 9.2 months, respectively. The median overall survival (OS) was 13.9, 11.0 and 15.9 months, respectively. Multivariate analyses showed that triple regimens were an independent prognostic factor for PFS [hazard ratio (HR) 0.430, 95% confidence interval (CI) 0.263-0.700; P=0.001]. Detailed survival analysis demonstrated that patients receiving intraperitoneal infusion of paclitaxel followed by intravenous paclitaxel combined with S-1 and apatinib oral therapy had better PFS (P=0.014) and OS (P=0.013) than those receiving other regimens.

Young patients with GC have unique clinical characteristics and are not sensitive to immunotherapy. Triple regimens, especially intraperitoneal infusion of paclitaxel followed by intravenous paclitaxel combined with S-1 and apatinib oral therapy, deserve to be studied as first-line therapies.

Previous reports have indicated that the survival rate of total mastectomy (TM) is higher than that of breast-conserving surgery (BCS). This study established survival prediction models for T1-stage locally advanced breast cancer (LABC) comparing TM and BCS, aiming to identify risk factors for overall survival (OS) associated with different surgical approaches and provide a basis for individualized treatment by clinicians. Cases of pathologically confirmed T1 LABC between 2010 and 2015 were retrieved from the Surveillance Epidemiology and End Results (SEER) database. COX regression analysis was used to analyze the relationship between LABC TM, BCS and various factors. Hazard ratio (HR) and 95% confidence interval (95%CI) were calculated to determine the possible influencing factors. Significant factors from multivariate COX regression were included into the models construct nomograms. Receiver operating characteristic curves (ROC), area under the curve of ROC (AUC), calibration curves, and the Hosmer-Lemeshow goodness-of-fit test for the calibration curves were generated. Model validation was conducted in a separate validation group. The results of COX regression analysis on survival rates for T1 LABC patients undergoing TM and BCS showed that the 5-year overall survival (OS) and breast cancer-specific survival (BCSS) were higher in the BCS group compared to the TM group. Age, race, histological grade, N stage, molecular subtype, chemotherapy, and radiation therapy (RT) were associated with 5-year OS of BCS. Similarly, age, race, pathological type, histological grade, human epidermal growth factor receptor 2 (HER2) status, N stage, molecular subtype, chemotherapy, and RT were correlated with 5-year OS of TM. Prediction nomograms were established using the aforementioned predictors, resulting in AUCs of 0.743 (for 5-year OS of BCS) and 0.718 (for 5-year OS of TM) in the modeling group. Both models were well-validated in the validation group. This study found that the survival rate of the BCS group was higher than that of the TM group, indicating that tumor size determines the survival rate of BCS to some extent. Lymph node status cannot be considered a contraindication for BCS surgery, suggesting that BCS can be considered for LABC patients with smaller tumors and more lymph node metastases. However, patients with primary tumors in N3 stage, triple-negative, and inner upper quadrant have a higher risk of death after BCS compared to other groups, so BCS should be carefully considered for these patients.

Patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) are at a heightened risk of developing brain metastases (BM). EGFR-tyrosine kinase inhibitors (TKI) are standard treatment for EGFR-mutated NSCLC. However, the necessity and optimal approach of brain radiotherapy for NSCLC patients with EGFR mutation remain inconclusive. We aimed to answer these questions by retrospectively analyzing the efficacy of radiotherapy in patients with BM from NSCLC with EGFR mutations.

Patients with EGFR- mutant NSCLC and BMs who were diagnosed between January 1, 2018 and December 31, 2022 were included. According to treatment methods those patients were divided into whole brain radiotherapy (WBRT) plus EGFR-TKI (WBRT group), stereotactic radiotherapy (SRT) plus EGFR-TKI (SRT group) and EGFR-TKI alone (TKI-only group). Propensity-score-matching (PSM) was performed to minimize the effect of possible confounding factors and to balance treatment groups.

A total of 142 patients were included in this study. The median follow-up time was 22 months (range, 3.0-43.0 months). In the PSM cohort, the median intracranial progression free survival (iPFS) was 14, 30, 12 months and the median overall survival (OS) was 27 months, not reach and 33 months in WBRT group, SRT group and TKI-only group, respectively. Compared with the other two groups, SRT group significantly improved iPFS and OS (p < 0.05). And the local progression rate of intracranial lesions in SRT group was significantly reduced (p < 0.05).

This study showed that SRT combined with TKI may improve iPFS and prolong survival in patients with EGFR mutations in BMs from NSCLC.

Osteosarcoma is a common bone tumor in adolescents, which is characterized by lipid metabolism disorders and plays a key role in tumorigenesis and disease progression. Ferroptosis is an iron-dependent form of programmed cell death associated with lipid peroxidation. This review provides an in-depth analysis of the complex relationship between lipid metabolic reprogramming and associated ferroptosis in OS from the perspective of metabolic enzymes and metabolites. We discussed the molecular basis of lipid uptake, synthesis, storage, lipolysis, and the tumor microenvironment, as well as their significance in OS development. Key enzymes such as adenosine triphosphate-citrate lyase (ACLY), acetyl-CoA synthetase 2 (ACSS2), fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD1) are overexpressed in OS and associated with poor prognosis. Based on specific changes in metabolic processes, this review highlights potential therapeutic targets in the lipid metabolism and ferroptosis pathways, and in particular the HMG-CoA reductase inhibitor simvastatin has shown potential in inducing apoptosis and inhibiting OS metastasis. Targeting these pathways provides new strategies for the treatment of OS. However, challenges such as the complexity of drug development and metabolic interactions must be overcome. A comprehensive understanding of the interplay between dysregulation of lipid metabolism and ferroptosis is essential for the development of innovative and effective therapies for OS, with the ultimate goal of improving patient outcomes.

Preclinical studies showed that cytotoxic agents and antiangiogenic agents had regulatory effects in the tumor immune microenvironment of soft tissue sarcoma (STS), and then enhance the antitumor effect of immunotherapy. This study was to investigate the efficacy and safety of immunotherapy-based therapy in metastatic STS.

We conducted a retrospective analysis in three centers where some patients received immunotherapy-based therapy consisting of immunotherapy alone or in combination with systemic agents (cytotoxic agents and/or antiangiogenic agents). The primary endpoints were median progression-free survival (mPFS) and median overall survival (mOS), and Kaplan-Meier method was used to compare survival.

A total of 79 patients were included in this study. With the median follow-up of 14.2 months, the mPFS and mOS was 7.5 months and 19.5 months, respectively. The PFS (P < 0.01) and OS (P < 0.01) were significantly better in the alveolar soft part sarcoma (ASPS) group compared to the non-ASPS group. Patients who treated in ≤2 lines had longer PFS (P < 0.01) and OS (P < 0.01) compared to those in subsequent lines. Further analysis was performed according to histopathological types, in patients with ASPS, the combination of immunotherapy-based therapy resulted in a longer PFS (P < 0.01) compared to immunotherapy in monotherapy. Similarly, the patients treated in ≤2 lines had longer PFS (P=0.03) and OS (P < 0.01) compared to in subsequent lines. In patients with non-ASPS, patients with potentially sensitive sarcomas (undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, myxofibrosarcoma, and angiosarcoma) had a longer PFS (P = 0.02) and OS (P = 0.03) compared to other subtypes. The OS (P = 0.03) for patients with potentially sensitive sarcomas treated in ≤2 lines showed a long trend compared to subsequent lines. Most adverse events reported were mild and tolerable.

The immunotherapy-based therapy showed promising activity in survival, especially in certain histological subtypes (undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, myxofibrosarcoma, and angiosarcoma), as well as in combination treatment and in early lines. Prospective researches are needed to confirm the potential benefits.

Breast cancer (BC) is a common malignant tumor in women, and cancer-related fatigue (CRF) is prevalent among breast cancer patients. Time-Acupoints-Space Acupuncture (ATAS) is an acupuncture method different from traditional acupuncture. It combines time acupoints with space acupoints, proposing a new treatment approach. This randomized controlled trial aims to evaluate whether ATAS can improve fatigue in postoperative chemotherapy patients with breast cancer.

This randomized controlled trial focuses on survivors of postoperative chemotherapy for breast cancer, primarily assessing whether ATAS can reduce fatigue in these patients. Additionally, it reports on the effects of ATAS on sleep, anxiety, depression, and inflammatory factors.

The researchers randomly assigned 90 postoperative breast cancer patients to the ATAS group (n=30), the sham acupuncture group (n=30), and the waitlist control group (n=30). The primary outcome was the Piper Fatigue Scale (PFS), and the secondary outcomes were the Insomnia Severity Index (ISI), Hospital Anxiety and Depression Scale (HADS), Interleukin-2 (IL-2), Interleukin-6 (IL-6), CD3+T, and CD4+T. Data analysis was performed using the statistical software SPSS, utilizing descriptive statistics and analytic statistics. The significance level was set at less than 0.05.

The baseline differences in PFS scores among the three groups were not statistically significant (P > 0.05). ATAS treatment is superior to sham acupuncture and the waitlist control in improving fatigue (mean difference 4.98, 95% CI 3.96 to 6.00, P<0.05). Additionally, secondary outcome analysis shows that the ATAS group has positive effects on ISI, HADS, and inflammatory factors. After the treatment ended, ISI (mean difference 15.17, 95% CI 12.28 to 18.06, P<0.05), HADS-A (mean difference 8.63, 95% CI 5.18 to 12.08, P<0.05), HADS-D (mean difference 7.80, 95% CI 4.73 to 10.87, P<0.05). IL-2(mean difference 20.18, 95% CI 11.51 to 28.85, P<0.05), IL-6(mean difference 24.56, 95% CI 7.57 to 41.55, P<0.05), CD3+T(mean difference 79.03, 95% CI 68.56 to 89.50, P<0.05), CD4+T(mean difference 42.89, 95% CI 35.14 to 50.64, P<0.05).

Our preliminary findings indicate that ATAS effectively improves fatigue in postoperative chemotherapy patients with breast cancer. It also has positive effects on sleep, anxiety, depression, and inflammatory factors. These results suggest that ATAS intervention may be an effective method for alleviating fatigue in breast cancer patients.

https://www.chictr.org.cn/showproj.html?proj=21999, identifier ChiCTR17013652.

The therapeutic window of antibody drug-conjugates (ADC) remains challenging due to safety issues such as interstitial lung disease (ILD) observed with specific deruxtecan-based ADCs. To avoid ILD, we designed M9140 by conjugating the maleimide-containing hydrophilic β-glucuronide linker to exatecan and our anti-CEACAM5 (CarcinoEmbryonic Antigen-related Cell Adhesion Molecule 5) specific antibody. Following repeated iv-infusion at 3 to 30 mg/kg of M9140 every 3 weeks, the pathological findings obtained in cynomolgus monkeys were confined to gastrointestinal and hematolymphoid tissues and resembled the toxicity of exatecan. At 24 mg/kg or higher, transient reductions in neutrophil and reticulocyte counts were observed with each dosing event along with reversible anemia throughout the study. The no observed adverse effect level was 24 mg/kg and the maximum tolerated dose was 30 mg/kg. The difference in toxicity by this small dose increment was correlated with a 2.5-fold difference in plasma exatecan exposure indicating antigen-independent toxicity. As anticipated, no lung toxicity was found with M9140 in these studies that were similar in study design to those used to confirm ILD with trastuzumab-deruxtecan in monkeys. Since the non-human primate model is regarded as predictive for the ILD risk in humans, this result indicates a low risk for ILD when applying M9140 to patients. The current M9140 safety data are discussed with special focus on the absence or presence of ILD with other antibody camptothecin-conjugates, for which a hypothetical pathogenic mechanism is postulated here. The favorable nonclinical profile of M9140 warrants further investigation in patients with CEACAM5-overexpressing tumors.

This study describes treatment and retreatment patterns and outcomes in patients in France following nivolumab as a second-line or later (2L+) treatment in locally advanced or metastatic non-small cell lung cancer (LAM NSCLC).

This analysis included adults with tumor, node, metastasis stage IIIB-IV NSCLC (as defined in the 7th or 8th edition American Joint Committee on Cancer/Union for International Cancer Control) treated with nivolumab monotherapy in 2L+ using data from the retrospective Epidemiological-Strategy and Medical Economics Lung Cancer database. The inclusion period was from January 1, 2015, to September 30, 2020, with a follow-up until September 30, 2021. Analyses were stratified according to the duration of index nivolumab treatment and tumor programmed death ligand 1 expression levels.

In total, the study included 4,001 patients (68% male; mean age [standard deviation] at index date, 63.6 [9.7] years) with a median follow-up of 34.3 months. The median nivolumab duration was 2.5 months (interquartile range, 1.4-6.3). The median overall survival (OS) from nivolumab initiation was 10.2 months (95% confidence interval [CI], 9.6-10.8). The median real-world progression-free survival and time to treatment discontinuation or death (95% CI) were 2.2 (2.1-2.3) and 2.7 (2.5-2.8) months, respectively. In total, 2,985 (74.6%) patients discontinued index nivolumab treatment: 226 (7.6% of discontinuers) received a further immune checkpoint inhibitor (ICI; 12.3% of discontinuers receiving further systemic treatment), and 1,604 (53.7%) received chemotherapy and/or targeted therapy. The proportion of ICI-retreated patients was the highest among those with the longest index treatment duration (15.8% among discontinuers receiving ≥26 weeks' index nivolumab). The median OS from retreatment was longer in the resumption (ICI restart without another therapy for ≥6 weeks) compared with the rechallenge (ICI restart following non-ICI therapy) patient subgroup.

Few patients with LAM NSCLC in France received ICI retreatment following index nivolumab discontinuation, but the proportion increased with a longer duration of index nivolumab.

Measure associations between clinicopathological and immunohistochemical human Mut-L homologue 1 (hMLH1) gene, and human Mut-L homologue 2 (hMSH2) genes, variables in recurrent AMBs.

This study consisted of a research retrospective, observational case-control study consisting of 22 cases of recurrent AMB and 22 non-recurrent cases. Cases of AMB with more than one year of follow-up were included in the study. Quantitative immunohistochemical analysis was performed considering the cellular location (nuclear) of the proteins studied. The McNemar test was used to compare variables between primary and recurrent AMBs. Recurrence-free survival was analyzed by the Kaplan-Meier method and survival functions were compared according to the variables using the log-rank test.

The posterior mandible was the most affected site in the recurrent (n = 18, 81.8%) and non-recurrent groups (n = 16, 72.8%). Recurrence-free survival was 50.0 (34.5-63.6) months. The following factors were significantly associated with AMB recurrence: presence of cortical bone expansion (p = 0.01), absence of bone reconstruction (p = 0.02), conservative treatment (p = 0.02), loss of hMSH2 (p = 0.01) and hMLH1 (p = 0.04) immunoexpression, and strong Ki-67 immunoexpression (p = 0.03). The risk factors for AMB recurrence were anatomical location (OR = 3.31), locularity (OR = 1.07), cortical expansion (OR = 6.17), cortical perforation (OR = 2.10), bone resorption (OR = 1.52), tooth impaction (OR = 1.86), jaw reconstruction (OR = 6.92), and immunoexpression of hMSH2 (OR = 10.0) and hMLH1 (OR = 4.50).

Radiographic appearance, treatment modality, and immunoexpression of mismatch repair proteins can be used as predictors of AMB recurrence.

While MEK inhibitors demonstrated activity in metastatic triple negative breast cancer (mTNBC) preclinical studies, preclinical, and clinical studies implicate rapid development of resistance limiting clinical benefit. The purpose of this study was to determine response rate for Trametinib alone and in combination with Uprosertib in patients with mTNBC previously treated with chemotherapy.

This was an open-label, two-part, phase II, single-arm, multicenter study. Patients first received Trametinib monotherapy (2 mg daily; Part I) then at progression transitioned to Trametinib (1.5 mg) plus Uprosertib (50 mg; Part II).

Between October 2013 and January 2017, 37 patients were enrolled to Part I. Subsequently, 19 patients entered Part II. Of the 37 patients receiving Trametinib monotherapy, 2 patients achieved partial response (PR) for an ORR of 5.4% (2/37) and an additional 6/37 (16.2%) achieved stable disease (SD). The clinical benefit rate (PR+SD) for patients receiving monotherapy was 21.6% (8/37). Of the 19 patients in Part II, 3 patients achieved PR for an ORR to Part II of 15.8% (3/19) and an additional 3 achieved SD. Median progression-free survival (PFS) was 7.7 weeks for Part I and 7.8 weeks for Part II. Circulating tumor DNA (ctDNA) clearance at C2D1 of Trametinib monotherapy was associated with improved PFS and overall survival.

In patients with mTNBC, Trametinib monotherapy demonstrated limited efficacy and addition of Uprosertib was associated with numerically greater objective responses but no difference in PFS. Translational analyses suggest ctDNA clearance as a potential early biomarker of response.

The 5th Edition of the "WHO Classification of Tumours: Urinary and Male Genital Tumours" introduces several significant updates to the classification of testicular tumours. These updates include revised terminology for special germ cell tumour subtypes (neuroectodermal and neuroendocrine tumours) of the testis. Additionally, the signet-ring stromal tumour and myoid gonadal stromal tumour have been introduced as distinct entities within the sex-cord stromal tumours. Moreover, new combined sections have been created for lymphatic neoplasms and soft tissue tumours of the urinary and male genital tract.

Cancer-related fatigue (CRF) is the most common symptom experienced by cancer survivors. It is a multidimensional symptom affecting physical, emotional, and/or cognitive spheres, different from other types of fatigue. Characteristically is not alleviated by sleep or rest. CRF could have specific features in breast cancer survivors (BCS), because of sex, hormones, and distinct treatments. On the other hand, more than 25% of BCS report persistent CRF for 10 years or more after the diagnosis. The present study aims to recapitulate the knowledge about the biological mechanisms that potentially drive CRF in BCS after treatment.

To answer a broad question, a scoping review methodology was used. Data were collated from three bibliographic databases: PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Studies were selected if they had included more than 20 BCS, after finishing their treatment, fatigue was measured with a quantitative scale and biomarkers were analyzed.

The final database was composed of 1896 records. Sixty-four studies finally met the eligibility criteria. Inflammation (61%), hypothalamic-pituitary-adrenal (HPA) axis dysregulation (14%), autonomic nervous system (ANS) dysfunction (11%), and diet (9%) were the biological pathways most frequently studied. Unfortunately, results from studies about inflammation and HPA axis show many inconsistencies.

More research about the role of ANS dysfunction and diet on the pathogenesis of CRF would be warranted according to the results of the review. There are some fields such as endocannabinoid systems, mitochondrial dysfunction, gut microbiota, and oxidative stress that have been insufficiently explored.

To widen the scope of future research in the physiopathology of CRF, it is necessary to identify mechanisms that would be potentially involved and have been insufficiently explored. Because of the high prevalence of CRF in BCS and the tremendous impact that fatigue has in their quality of life, it is essential to improve the efficacy of the treatments through a good knowledge of the biological basis of CRF.

Male breast cancer (MBC) is a rare entity which often arises in elderly people. Aim of this review is to evaluate the principal issues related to MBC in elderly, because the therapeutic management of disease is not only related to the biological behavior of the tumor, but also to the comorbidities and frailty of older population. A scoping literature review was performed on Pubmed and Cochrane Database using the following keywords: therapeutic management/ male/ breast cancer/ elderly patients. Papers published before 2000, not edited in English or French language, or not related to the main topic, were excluded. Only articles related to therapeutic issues in MBC and including more than 10 elderly (≥ 65 years) patients were selected for the qualitative outcome analysis.

36 papers regarding surgery, radiotherapy, systemic therapy, racial disparities and therapeutic management in retrospective series of MBC in elderly were examined in details. MBC has a different biological behavior and a poorer prognosis than female, especially in cases with positive nodes at diagnosis. Elderly MBC patients have often larger tumors in more advanced stages at the time of diagnosis compared with younger patients. In spite of the advanced tumors at presentation, older patients present often cancers with more favorable biological characteristics, but they receive less guideline-concordant curative treatments (as adequate lymph node staging or adjuvant radiation therapy) compared to women. Moreover, racial differences in treatment of older MBC were observed. Therapeutic management of MBC in elderly patients is a subject rarely addressed in literature. Our review highlighted differences in the treatment and in guidelines-concordance for elderly MBC patients. Adequate geriatric assessment and use of therapeutic schemes adapted to age and comorbidities can avoid under/overtreatment, contributing to a better standard of care in this frail population.

The diagnostic performance of liquid biopsy-based biomarkers for HCC was comprehensively compared in this network meta-analysis (NMA).

A thorough literature search was conducted to identify all comparative studies from January 1, 2000, to January 11, 2024. The QUADAS-2 tool was utilized to appraise the quality of studies involving diagnostic performance. R (v4.3.3) and an ANOVA model-based NMA were used to assess the diagnostic accuracy of each biomarker.

This study included 82 studies comprising a total of 15,024 patients.CircRNA demonstrated significantly superior performance in distinguishing HCC from healthy populations (superiority index: 3.550 (95% CI [0.143-3])) compared to other diagnostic biomarkers for HCC. "mRNA exhibited significantly superior performance in distinguishing HCC from liver disease patients (superiority index:10.621 (95% CI [7-11])) compared to other diagnostic biomarkers for HCC. Further subgroup analysis of the top-ranking liquid biopsy-based diagnostic biomarkers revealed that hsa_circ_000224 (superiority index: 3.091 (95% CI[0.143-9]) ranked remarkably higher in distinguishing HCC from both healthy populations and liver disease patients. Subgroup analysis of mRNA demonstrated that KIAA0101 mRNA (superiority index: 2.434 (95% CI [0.2-5]) ranked remarkably higher in distinguishing HCC from healthy populations and liver disease patients, respectively.

The results of this meta-analysis show that circRNA and mRNA are the first choice for HCC diagnosis. Subsequent analysis of circRNA and mRNA highlighted hsa_circ_000224, hsa_circ_0003998, KIAA0101 mRNA and GPC-3mRNA as the optimal diagnostic biomarkers for distinguishing HCC from healthy populations and liver disease patients, respectively. Well-structured prospective studies are crucial to comprehensively validate these findings.

https://www.crd.york.ac.uk/PROSPERO/,identifier CRD42024521299.

Adding pembrolizumab, an anti-PD-1 antibody approved for treatment of head and neck squamous cell carcinoma (HNSCC) to neoadjuvant (induction-) chemotherapy utilizing docetaxel and cisplatin (TP) followed by radiotherapy may improve outcome in larynx organ-preservation (LOP) that is investigated in the European Larynx-Organ preservation Study (ELOS). As biomarkers for response to TP and pembrolizumab +TP are missing but may include cytokines, this work aims on determining cytokines potentially linked to outcome as prognostic markers sufficient to predict and/or monitor response to successful LOP.

Collagenase IV digests were generated from 47 histopathological confirmed HNSCC tumor samples and seeded in 96-well plates containing pembrolizumab, docetaxel, cisplatin either solely or in binary or ternary combination. According to the FLAVINO protocol, supernatants were collected after 3 days, adherent cells fixed using ethanol, air-dried and pan-cytokeratin positive epithelial cells counted using fluorescence microscopy. The cytokines IL-6, IL-8, IFN-γ, IP-10, MCP-1, TNF-α, and VEGF in the supernatant were quantified by sandwich ELISA.

The mode of interaction between pembrolizumab and TP was assessed and correlated to outcome (overall, disease-specific and progression-free survival of patients). Suppression of MCP-1, IFN-γ and IL-6 production by pembrolizumab + TP exceeding the suppressive effect of TP was detected in the majority of samples and linked to improved survival. Multivariate Cox proportional hazard regression modeling revealed MCP-1, IFN-γ and IL-6 as independent outcome predictors.

Comparing response to TP vs. pembrolizumab vs. TP + pembrolizumab may allow for identification of patients with superior outcome independent from treatment applied.

Cancer vaccines, crucial in the immunotherapeutic landscape, are bifurcated into preventive and therapeutic types, both integral to combating oncogenesis. Preventive cancer vaccines, like those against HPV and HBV, reduce the incidence of virus-associated cancers, while therapeutic cancer vaccines aim to activate dendritic cells and cytotoxic T lymphocytes for durable anti-tumor immunity. Recent advancements in vaccine platforms, such as synthetic peptides, mRNA, DNA, cellular, and nano-vaccines, have enhanced antigen presentation and immune activation. Despite the US Food and Drug Administration approval for several vaccines, the full therapeutic potential remains unrealized due to challenges such as antigen selection, tumor-mediated immunosuppression, and optimization of delivery systems. This review provides a comprehensive analysis of the aims and implications of preventive and therapeutic cancer vaccine, the innovative discovery of neoantigens enhancing vaccine specificity, and the latest strides in vaccine delivery platforms. It also critically evaluates the role of adjuvants in enhancing immunogenicity and mitigating the immunosuppressive tumor microenvironment. The review further examines the synergistic potential of combining cancer vaccines with other therapies, such as chemotherapy, radiotherapy, and immune checkpoint inhibitors, to improve therapeutic outcomes. Overcoming barriers such as effective antigen identification, immunosuppressive microenvironments, and adverse effects is critical for advancing vaccine development. By addressing these challenges, cancer vaccines can offer significant improvements in patient outcomes and broaden the scope of personalized cancer immunotherapy.

Iris melanoma is a rare malignant tumor of melanocytic origin. Oncogenic viruses, whose invasion of the cell alters proliferation regulation mechanisms, play an important role in tumor development and progression.

To identify clinical, morphometric, and pathomorphological correlations with infectious status in patients with iris melanoma and to determine predictors of unfavorable prognosis.

Sixteen patients with iris melanoma were examined. Anterior segment optical coherence tomography (AS-OCT) was performed using the RS-3000 Advance system (Nidek, Japan) with OCT-Angiography software. The specific humoral response to herpesviruses was assessed by detecting IgG and IgM antibodies in blood serum via enzyme-linked immunosorbent assay (ELISA) using an automated immunoassay analyzer LAZURITE (Dynex Technologies Inc., USA). Statistical analysis employed Spearman's rank correlation coefficient (rs).

Iris melanoma was predominantly observed in female patients (n=11) of advanced age (n=8). Biomicroscopy revealed 10 pigmented, 1 hypopigmented, and 5 non-pigmented tumors. The mean prominence on OCT was 1461.7±740.5 μm, the basal diameter was 3409.6±1822.8 μm, and the volume was 4.7±3.7 mm3. Ciliary body involvement was detected in 10 patients. Iris melanomas were classified as epithelioid-cell (n=1), spindle-cell (n=12), and mixed-cell (n=3) types. Extrabulbar growth was noted in three patients. Serological markers of viral reactivation were identified: herpes simplex virus type 1 (n=11) and type 2 (n=5), and cytomegalovirus (n=3).

Direct correlations (rs=0.5-0.8) were identified between the presence of serological markers of herpesvirus reactivation and unfavorable prognostic features, including advanced age, maximum tumor basal diameter, ciliary body involvement, dense pigmentation, and extrabulbar growth. The mean follow-up period was 18.5±2.97 months, and all patients were alive, with no evidence of recurrence.

The findings of this study demonstrated a correlation between herpesvirus reactivation and unfavorable prognostic features of iris melanoma. Further research is needed to deepen the understanding of the role of herpesviruses in the pathogenesis of iris melanoma and to develop personalized approaches to prevention and treatment.

Immunotherapy is one of the research hotspots in colorectal cancer field in recent years. The colorectal cancer patients with mismatch repair-deficient (dMMR) or high microsatellite instability (MSI-H) are the primary beneficiaries of immunotherapy. However, the vast majority of colorectal cancers are mismatch repair proficient (pMMR) or microsatellite stability (MSS), and their immune microenvironment is characterized by "cold tumors" that are generally insensitive to single immunotherapy based on immune checkpoint inhibitors (ICIs). Studies have shown that some pMMR/MSS colorectal cancer patients regulate the immune microenvironment by combining other treatments, such as multi-target tyrosine kinase inhibitors, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, chemotherapy, radiotherapy, anti-epithelial growth factor receptor (EGFR) monoclonal antibodies, and mitogen-activated protein kinase (MAPK) signaling pathway inhibitors and oncolytic viruses, etc. to transform "cold tumor" into "hot tumor", thereby improving the response to immunotherapy. In addition, screening for potential prognostic biomarkers can also enrich the population benefiting from immunotherapy for microsatellite stable colorectal cancer. Therefore, in pMMR or MSS metastatic colorectal cancer (mCRC), the optimization of immunotherapy regimens and the search for effective efficacy prediction biomarkers are currently important research directions. In this paper, we review the progress of efficacy of immunotherapy (mainly ICIs) in pMMR /MSS mCRC, challenges and potential markers, in order to provide research ideas for the development of immunotherapy for mCRC.

Circulating proteins secreted by tumors are an important source of cancer biomarkers. This study aims to investigate the changes in the content of tumor immune-related circulating proteins in peripheral blood from patients with colorectal cancer (CRC).

Olink's proximity extension assay was used to detect the levels of 92 tumor immune-related circulating proteins in peripheral blood from CRC patients. An enzyme-linked immunosorbent assay was performed to detect the levels of six proteins. Elastic network regression was used to establish the model, and the performance of the model was verified by multiple iterations of cross-validation.

The best serum protein signature that was composed of six proteins (IL7, CXCL12, IL10, IL15, CXCL1, and MCP-3) was selected. The area under the curve value of this signature was 0.9924 in the training set and 0.8992 in the total set. IL7 and IL15 levels were significantly higher in the ≥4 cm tumor volume group than in the <4 cm tumor volume group (P = 0.0113 and P = 0.004, respectively). MCP-3 levels were significantly higher in the distant metastasis group than in the non-distant metastasis group (P =0.0465). There was a significant difference in MCP-3 levels among different tumor, node, metastasis stages (P = 0.0496). CXCL1 levels were positively correlated with the absolute count of basophils (R = 0.3220, P = 0.0273), and IL10 levels were positively correlated with the absolute count of neutrophils (R = 0.38737, P = 0.0078). CXCL1, IL7, and IL15 were independent prognostic factors of CRC (hazard ratio [HR] = 0.62, P = 0.006; HR = 0.57, P = 0.006; and HR = 0.64, P = 0.011, respectively).

The best serum protein signature model (IL7, CXCL12, IL10, IL15, CXCL1, and MCP-3) was able to distinguish CRC patients from healthy controls. These proteins were also involved in the occurrence and development of CRC.

This study aims to review and summarize the ultrasound characteristics of alveolar soft part sarcoma (ASPS) in children.

We retrospectively analyzed 20 pediatric ASPS cases confirmed by surgery or biopsy at our hospital between January 2014 and January 2024. Clinical data, including age, sex, symptoms, and tumor location, were collected. Ultrasound reports and images were reviewed to extract data on tumor size, boundaries, echogenicity, and vascularity.

The study included 20 children with ASPS. The tumors were located in the trunk and limbs (50%), as well as in the head and neck (50%). Compared with tumors in the trunk and limbs, head and neck tumors were smaller in size, had more pronounced symptoms, and had a lower incidence of metastasis. Ultrasound features predominantly included hypoechoic masses with clear boundaries, heterogeneous echogenicity, and rich internal and surrounding vascularity, often with tortuous and dilated blood vessels. Eight patients had distant metastases at diagnosis, seven of which involved the lungs. There was a moderate correlation between tumor size and the risk of distant metastasis (r = 0.64).

Understanding the clinical and ultrasound characteristics of pediatric ASPS can facilitate earlier and more accurate diagnosis.

Immunotherapy is a rapidly evolving field, with many models attempting to describe its impact on the immune system, especially when paired with radiotherapy. Tumor response to this combination involves a complex spatiotemporal dynamic which makes either clinical or pre-clinical in vivo investigation across the resulting extensive solution space extremely difficult. In this review, several in silico models of the interaction between radiotherapy, immunotherapy, and the patient's immune system are examined. The study included only mathematical models published in English that investigated the effects of radiotherapy on the immune system, or the effect of immuno-radiotherapy with immune checkpoint inhibitors. The findings indicate that treatment efficacy was predicted to improve when both radiotherapy and immunotherapy were administered, compared to radiotherapy or immunotherapy alone. However, the models do not agree on the optimal schedule and fractionation of radiotherapy and immunotherapy. This corresponds to relevant clinical trials, which report an improved treatment efficacy with combination therapy, however, the optimal scheduling varies between clinical trials. This discrepancy between the models can be attributed to the variation in model approach and the specific cancer types modeled, making the determination of the optimum general treatment schedule and model challenging. Further research needs to be conducted with similar data sets to evaluate the best model and treatment schedule for a specific cancer type and stage.

Akt1, as an important member of the Akt family, plays a controlled role in cancer cell growth and survival. Inhibition of Akt1 activity can promote cancer cell apoptosis and inhibit tumor growth. Therefore, in this investigation, a multilayer virtual screening approach, including receptor-ligand interaction-based pharmacophore, 3D-QSAR, molecular docking, and deep learning methods, was utilized to construct a virtual screening platform for Akt1 inhibitors. 17 representative compounds with different scaffolds were identified as potential Akt1 inhibitors from three databases. Among these 17 compounds, the Hit9 exhibited the best inhibitory activity against Akt1 with inhibition rate of 33.08% at concentration of 1 μM. The molecular dynamics simulations revealed that Hit9 and Akt1 could form a compact and stable complex. Moreover, Hit9 interacted with some key residues by hydrophobic, electrostatic, and hydrogen bonding interactions and induced substantial conformation changes in the hinge region of the Akt1 active site. The average binding free energies for the Akt1-CQU, Akt1-Ipatasertib, and Akt1-Hit9 systems were - 34.44, - 63.37, and - 39.14 kJ mol-1, respectively. In summary, the results obtained in this investigation suggested that Hit9 with novel scaffold may be a promising lead compound for developing new Akt1 inhibitor for treatment of various cancers with Akt1 overexpressed.

The immune system serves as a fundamental defender against the initiation and progression of cancer. Failure of the immune system augments immunosuppressive action that leading to cancer manifestation. This immunosuppressive effect causes from significant alterations in immune checkpoint expression associated with tumoral progression. The tumor microenvironment promotes immune escape mechanisms that further amplifying immunosuppressive actions. Notably, substantial targeting of immune checkpoints has been pragmatic in the advancement of cancer research. This study highlights a comprehensive review of emerging druggable targets aimed at modulating immune checkpoint co-inhibitory as well as co-stimulatory molecules in response to immune system activation. This modulation has prompted to the development of newer therapeutic insights, eventually inducing immunogenic cell death through immunomodulatory actions. The study emphasizes the role of immune checkpoints in immunogenic regulation of cancer pathogenesis and explores potential therapeutic avenues in cancer immunotherapy.Modulation of Immunosuppressive and Immunostimulatory pathways of immune checkpoints in cancer immunotherapy.

Many human cancers have been associated with the deregulation of the mesenchymal-epithelial transition factor tyrosine kinase (MET) receptor, a promising drug target for anticancer drug discovery. Herein, we report the discovery of a novel structure of potent chalcone-based derivatives type II c-Met inhibitors which are comparable to Foretinib (IC50 = 14 nM) as a potent reference drug. Based on our design strategy, we also expected an anti-tubulin activity for the compounds. However, the weak inhibitory effects on microtubules were confirmed by cell cycle analyses implicated that the observed cytotoxicity against HeLa cells probably was not derived from tubulin inhibition. Compounds 14q and 14k with IC50 values of 24 nM and 45 nM, respectively, demonstrated favorable inhibition of MET kinase activity, and desirable bonding interactions in the ligand-MET enzyme complex stability in molecular docking studies.

IAH0968 is an afucosylated anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody which improved the activity of antibody-dependent cellular cytotoxicity (ADCC) and superior anti-tumor efficacy.

To determine the maximum tolerated dose (MTD) with dose-limiting toxicity (DLT), a single institution, phase Ia/Ib study was undertaken, using 3 + 3 design. The primary endpoints were safety, tolerability and preliminary clinical activity. Eighteen patients were evaluable for safety and fifteen patients were suitable for efficacy analysis. Dose escalations were 6 mg/kg (N = 2), 10 mg/kg (N = 7), 15 mg/kg (N = 5), and tolerable up to 20 mg/kg (N = 4).

Only one DLT was found at dosage 10 mg/kg, and no MTD was reached. The most common Grade 3 treatment-related adverse events (TRAEs) were hypokalemia (5.6%), supraventricular tachycardia (5.6%), interval extension of QTC (5.6%), and infusion reaction (5.6%). Grade 4 TRAE was arrhythmia (5.6%). No serious TRAE or Grade 5 was reported. 22.2% of patients had a TRAE leading to dose adjustment and 16.7% of patients had a TRAE resulting in discontinuation of IAH0968. After a median follow-up of 9.7 months (range, 3.7 - 22.0), the objective response rate (ORR) was 13.3% (2/15), the disease control rate (DCR) was 53.3% (8/15), and median progression-free survival (mPFS) was 4.2 months (95% CI: 1.4 - 7.7), and the median duration of disease control (DDC) was 6.3 months (95% CI: 2.9-not reached), with 4/15 responses ongoing.

In HER2-positive heavily pretreated metastatic patients, IAH0968 demonstrated promising clinical activity with durable responses and tolerable safety profiles.

ClinicalTrials.gov, identifier NCT04934514.

The development of tumors and their metastasis relies heavily on the process of angiogenesis. When the volume of a tumor expands, the resulting internal hypoxic conditions trigger the body to enhance the production of various angiogenic factors. These include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor-α (TGF-α), all of which work together to stimulate the activation of endothelial cells and catalyze angiogenesis. Antiangiogenic therapy (AAT) aims to normalize tumor blood vessels by inhibiting these angiogenic signals. In this review, we will explore the molecular mechanisms of angiogenesis within the tumor microenvironment, discuss traditional antiangiogenic drugs along with their limitations, examine new antiangiogenic drugs and the advantages of combination therapy, and consider future research directions in the field of antiangiogenic drugs. This comprehensive overview aims to provide insights that may aid in the development of more effective anti-tumor treatments.

Xanthoparmelia conspersa is rich in specific secondary metabolites but an unexplored lichen species. This work determined the chemical composition and biological activities (anti-microbial, anti-protozoal, and cytotoxic) of its methanolic and hexane extracts. Additionally, we evaluated the potential of these extracts in modulating cancer signaling pathways in HeLa cells. The phytochemical analysis revealed that usnic acid was the predominant constituent in the hexane extract, while stictic acid was in the methanolic one. Among tested cell lines (VERO, FaDu, SCC-25, HeLa), cytotoxic selectivity was detected for X. conspersa hexane extract against the FaDu (SI 7.36) and HeLa (SI 2.19) cells. A noticeably better anti-microbial potential was found for hexane extract, however, the overall anti-microbial activity was relatively weak (28, 21, and 20% inhibition of Candida glabrata, Cryptococcus neoformans, and Escherichia coli, respectively). On the contrary, the anti-parasitic action of hexane extract was significant, with an IC50 value of 2.64 µg/mL against Leishmania donovani - amastigote and 7.18 µg/mL against Trypanosoma brucei. The detailed evaluation of the cancer-related signaling pathways in HeLa cells, done by two distinct methodologies (luciferase reporter tests), revealed that especially the hexane extract and usnic acid exhibited selective inhibition of Stat3, Smad, NF-κB, cMYC, and Notch pathways.

Drug resistance poses a significant obstacle to the success of anti-cancer therapy in head and neck cancers (HNCs). We aim to develop a platform for visualizing and analyzing molecular expression alterations associated with HNC drug resistance. Through data mining, we convened differentially expressed molecules and context-specific signaling events involved in drug resistance. The driver genes, interaction networks and transcriptional regulations were explored using bioinformatics approaches. A total of 2364 differentially expressed molecules were identified in 78 distinct drug-resistant cells against 14 anti-cancer drugs, comprising 1131 mRNAs, 746 proteins, 62 lncRNAs, 257 miRNAs, 1 circRNA, and 166 post-translational modifications. Among these, 255 molecules were considerably, the signature driver genes of HNC drug resistance. Further, we also developed a landscape of signaling pathways and their cross-talk with diverse signaling modules involved in drug resistance. Additionally, a publicly-accessible database named "HNCDrugResDb" was designed with browse, query, and pathway explorer options to fetch and enrich molecular alterations and signaling pathways altered in drug resistance. HNCDrugResDb is also enabled with a Drug Resistance Analysis tool as an initial platform to infer the likelihood of resistance based on the expression pattern of driver genes. HNCDrugResDb is anticipated to have substantial implications for future advancements in drug discovery and optimization of personalized medicine approaches.

Currently, several randomized controlled trials (RCTs) have been conducted to investigate the efficacy of combining immune checkpoint inhibitors (ICIs) with chemotherapy as a first-line treatment for advanced or recurrent endometrial cancer; however, the optimal treatment strategy remains undetermined.

A comprehensive search of online databases was conducted to identify RCTs published until December 31, 2023. Network meta-analysis was performed to evaluate PFS, OS, TRAEs, irAEs, and the ranking of different treatment regimens.

A total of 2702 patients from five RCTs (six reports) were included in the analysis. The combination therapy of ICIs significantly prolonged PFS (HR = 0.69, 95%CI 0.63-0.76, p < 0.0001) and OS (HR = 0.73, 95%CI 0.63-0.85, p < 0.0001) in the overall population. Among the different ICIs combinations evaluated, Durva-Olap-CP exhibited superior efficacy for both PFS and OS outcomes. In the pMMR population, both Durva-Olap-CP and Pembro-CP significantly reduced the risk of disease progression or death compared to Avelu-CP and Atezo-CP treatments; however, no significant differences were observed among various ICI combination therapies in patients with dMMR. In the dMMR population, Dostar-CP demonstrates a 42.2% probability of achieving first rank in terms of PFS, whereas in the pMMR population, Pembro-CP exhibits a 60% likelihood of securing the top position. Importantly, the toxicity associated with ICIs combination therapy was manageable and well-tolerated.

The combination of ICIs and chemotherapy as first-line treatment for advanced or recurrent endometrial cancer has demonstrated superior survival outcomes compared to chemotherapy alone. Durva-Olap-CP exhibited the most favorable PFS and OS benefits in the overall population. In patients with dMMR, Dostar-CP showed the greatest improvement in PFS, while Pembro-CP demonstrated the most pronounced PFS benefit in patients with pMMR.