Cancer Research Articles

Evaluation of UCP1162, a potent propargyl-linked inhibitor of dihydrofolate reductase with potential application to cancer and autoimmune disease

Cellular resistance can limit the effectiveness of antifolate drugs for the treatment of cancer and autoimmune diseases. Here we examine the biochemical and cellular effects of a propargyl linked, non-classical antifolate that shows exceptional potency and resilience in the background of methotrexate resistance, UCP1162. UCP1162 inhibited the human DHFR enzyme with affinity and kinetics comparable to methotrexate (MTX). UCP1162 also inhibited cancer cell proliferation and bound cellular DHFR at low nanomolar concentrations. Leucovorin suppressed the cellular effects of UCP1162, consistent with UCP1162 working as an antifolate. Like other antifolates, UCP1162 reduced acute inflammation in mice and inhibited FLS cell growth and motility. Single cell RNA-seq showed that MTX and UCP1162 generated overlapping gene expression changes after a 48-hour exposure. However, while leukemia cells (CCRF-CEM) resistant to MTX could be readily selected, UCP1162-resistant cells could not be obtained. Long-term exposure to UCP1162 resulted in static culture expressing stem cell genes (CD34, ABCG2, ABCB1), adaptive genes (TCN2, CDKN1A), and genes that might serve as therapeutic targets (TPBG/5T4, TNFRSF10A, ACE). These findings suggest that UCP1162 is a unique tool for studying cellular responses to long-term antifolate treatment and holds promise as a lead compound capable of overcoming some forms of antifolate resistance.

Recent Advances in Pharmaceutical Design: Unleashing the Potential of Novel Therapeutics.

Pharmaceutical design has made significant advancements in recent years, leading to the development of novel therapeutics with unprecedented efficacy and safety profiles. This review highlights the potential of these innovations to revolutionize healthcare and improve patient outcomes. The application of cutting-edge technologies like artificial intelligence, machine learning, and data mining in drug discovery and design has made it easier to find potential drug candidates. Combining big data and omics has led to the discovery of new therapeutic targets and personalized medicine strategies. Nanoparticles, liposomes, and microneedles are examples of advanced drug delivery systems that allow precise control over drug release, better bioavailability, and targeted delivery to specific tissues or cells. This improves the effectiveness of the treatment while reducing side effects. Stimuli-responsive materials and smart drug delivery systems enable drugs to be released on demand when specific internal or external signals are sent. Biologics and gene therapies are promising approaches in pharmaceutical design, offering high specificity and potency for treating various diseases like cancer, autoimmune disorders, and infectious diseases. Gene therapies hold tremendous potential for correcting genetic abnormalities, with recent breakthroughs demonstrating successful outcomes in inherited disorders and certain types of cancer. Advancements in nanotechnology and nanomedicine have paved the way for innovative diagnostic tools and therapeutics, such as nanoparticle-based imaging agents, targeted drug delivery systems, gene editing technologies, and regenerative medicine strategies. Finally, the review emphasizes the importance of regulatory considerations, ethical challenges, and future directions in pharmaceutical design. Regulatory agencies are adapting to the rapid advancements in the field, ensuring the safety and efficacy of novel therapeutics while fostering innovation. Ethical considerations regarding the use of emerging technologies, patient privacy, and access to advanced therapies also require careful attention.

FTIR monitoring of the 13-valent pneumococcal conjugate vaccine for lung cancer patients: Changes in amides vibrations correlated with biochemical assays

Lung cancer is one of the most lethal cancers. Unfortunately, respiratory tract infections are very common in lung cancer patients, delaying appropriate anticancer therapy. To increase therapy efficiency, in this study we examined the effect of 13-Valent Pneumococcal Conjugate Vaccine on the immune response in lung cancer patients, which indirectly affects the success of anticancer therapy. The study was done using biochemical tests and Fourier Transform InfraRed (FTIR) spectroscopy. For this purpose, serum from lung cancer patients aged 52 ± 9 years (III and IV clinical stage; 79 %; n = 103) before and seven as well as 30 days after vaccination was collected. Obtained results showed increasing concentrations of immunoglobulin IgG and IgG2 groups in patients after vaccination in comparison with group before vaccination. This result was confirmed by FTIR spectroscopy, where higher absorbances of amides vibrations were observed after vaccination. Interestingly, lack of differences in the amides absorbances between patients 7 and 30 days after vaccination were noticed. FTIR spectra also showed changes in the ratio between amide I and amide III as well as between amide II and amide III in the groups of patients after vaccination. From deconvolution of made I range (1600 cm−1–1700 cm−1) decrease of the ratio between α-helix and β-sheet around 0.05 was noticed in serum collected from patients after vaccination in comparison with patients before vaccination. Using Principal Component Analysis (PCA) analysis of FTIR data it was observed that serum collected from all three analyzed groups of samples was possible to differentiate. The highest accuracy in differentiation group of samples before and 7 days after vaccination was visible in amide I, while before and 30 days after vaccination using amide II. Correlation between immunoglobulin IgG and IgG2 concentrations obtained by biochemical assays and FTIR were noticed only in the group of serum collected 30 days after vaccination, which suggested that FTIR spectroscopy reflects biochemical data.

Evaluation of Treatments with Radiotherapy Alone and Radiotherapy Plus Chemo-immunotherapy in Patients with Primary Liver Cancer based on Blood Biomarkers.

It is critical to assess primary liver cancer patients likely to benefit from radiotherapy (RT) or RT plus chemo-immunotherapy. Many potential peripheral biomarkers from blood samples have been proposed for clinical application. Therefore, the aim of this study was to evaluate treatments with radiotherapy alone and radiotherapy plus chemo-immunotherapy in patients with unresectable primary liver cancer based on blood biomarkers. From January, 2017, to February, 2022, 63 unresectable primary liver cancer patients receiving radiotherapy alone (RT, n = 21) or radiotherapy plus chemo-immunotherapy (RT plus C/IT, n = 42) were included in this study. We compared the clinical outcomes and adverse effects of these two groups. Also, distant metastasis-free survival (DMFS), overall survival (OS), and progress- free survival (PFS) were retrospectively analyzed. Finally, univariable and multivariable Cox analyses were used to explore the prognostic role of blood biochemical biomarkers. In this study, 1, 2, and 3 years of OS after RT treatment were 63.9%, 27.0%, and 13.5%, and after RT plus C/IT were 68.2%, 37.0%, and 24.7%, respectively (p = 0.617). Compared with baseline, white blood cells (WBC) and lymphocytes were significantly decreased after RT (p = 0.002 and p = 0.001, respectively) or RT plus C/IT therapy (p = 0.135 and p<0.001, respectively). In multivariable Cox regression analyses, higher lymphocyte counts before RT (pre-Lymphocyte) were associated with better OS and PFS (HR=0.439, p = 0.023; HR=0.539, p = 0.053; respectively), and higher lymphocyte counts before RT (pre- Platelets) were a poor prognostic factor associated with DMFS (HR=1.013, p = 0.040). Importantly, OS and PFS were significantly better for patients (pre-Lymphocyte ≥1.10 x 109/L) (p = 0.006; p = 0.066, respectively). The DMFS was significantly better for patients (pre-platelets < 233.5 ×109/L) (p<0.001). Our evaluation of blood biomarkers before and after radiotherapy or plus chem-immunotherapy for primary liver cancer revealed a potential marker for clinics to decide on precise treatment strategies.

Early diagnostic value of ECT whole-body bone imaging combined with PINP and β-CTX for bone metastasis of lung cancer.

This research was aimed at investigating the early diagnostic value of emission computed tomograph (ECT) whole-body bone imaging combined with PINP and β-CTX for bone metastasis of lung cancer. Case data of 86 lung cancer patients were categorized into lung cancer with bone metastasis (LCWBM, 46 cases) and lung cancer without bone metastasis (LCWOBM, 40 cases) groups according to the presence or absence of bone metastasis. Patients' general information were collected. ECT whole-body bone imaging was used to detect bone metastases and the grading of the extent of disease (EOD) in both groups, and electrochemiluminescence was utilized to detect the serum levels of PINP and β-CTX. Spearman correlation analysis was employed to evaluate the correlation between EOD grading and PINP and β-CTX levels. Logistic univariate and multivariate regression was implemented to analyze the risk factors of bone metastasis of lung cancer. Receiver operating characteristic (ROC) curve was applied to analyze the diagnostic efficacy of the single test of ECT whole-body bone imaging, PINP, or β-CTX and the combination of the three tests. The differences in pathological type, clinical stage and EOD grading, the number of positive ECT cases, and the expression levels of PINP and β-CTX between the LCWBM and LCWOBM groups were statistically significant. In LCWBM patients with different EOD grading, the trends of the expression of PINP and β-CTX were grade 3 > grade 2 > grade 1 and grade 0. Further correlation analyses revealed that EOD grading showed a significant positive correlation with the PINP and β-CTX expression levels. Univariate logistic regression analysis demonstrated that adenocarcinoma, TNM stage IV, ECT positivity, and high expression of PINP and β-CTX were associated with bone metastasis of lung cancer, and multivariate logistic regression analysis indicated that ECT positivity, high expression of PINP and β-CTX were independent risk factors for bone metastasis of lung cancer. The area under the curve (AUC) of ECT, PINP, and β-CTX alone for the diagnosis of bone metastasis of lung cancer were 0.872, 0.888, and 0.874, respectively, and the AUC for the combined diagnosis of the three was 0.963, which was greater than that of any one of the individual indices, with a sensitivity of 86.96% and a specificity of 97.50% at a Youden index of 0.845. ECT whole-body bone imaging combined with PINP and β-CTX has high diagnostic value for bone metastasis of lung cancer.

Saprophytic fungus (Ganoderma sessile) restrained Treg recruitment in the tumor microenvironment by down-regulating CCL28/CCR10 pathway

Ganoderma sessile, a saprophytic fungus, is a traditional Chinese medicinal material used in Chinese folk medicine and cuisine for its potential to enhance cancer patients immunity in clinical practice. However, the underlying mechanisms of its therapeutic effects remain elusive. Therefore, we explored the edible value to determine the underlying mechanisms of GS through multiple breast cancer models. GS was found to suppress tumor growth and lung metastasis, and prolong survival after surgery. It significantly increased tumor-infiltrating CD44HiCD62LHiCD8+ TCM cells while decreasing CD4+CD25+CD127− Treg cells in both lymph nodes and tumors. The mechanism behind GS’s effects primarily involved modulation of the Hif1-a/CCL28 pathway associated with Treg recruitment. Furthermore, GS could reduce CCR10 levels on the surface of Tregs. Collectively, GS inhibits tumor growth and pulmonary metastasis by restraining Treg recruitment through downregulation of the CCL28/CCR10 pathway—a finding which highlights its potential as a natural anti-tumor immune agent warranting further exploration.

Comparing the efficacy of linovera spray plus hydrocortisone cream for breast cancer patients undergoing conformal radiotherapy

BackgroundBreast cancer is one of the most prevalent malignancies globally, with a significant proportion of patients undergoing radiotherapy, a crucial treatment modality that substantially reduces recurrence rates. However, radiotherapy is often complicated by dermatological adverse effects ranging from mild erythema to severe dermal burns. Despite various interventions aimed at mitigating skin toxicities, the efficacy of hyperoxygenated fatty acids (HOFA) in this context remains underexplored. ObjectiveTo evaluate the effectiveness of topical HOFA (Linovera spray) in preventing radiotherapy-induced skin reactions in breast cancer patients undergoing conformal radiotherapy. MethodsThis prospective, randomized, controlled trial enrolled post-partial mastectomy breast cancer patients indicated for conformal radiotherapy targeting lymph node levels and the supraclavicular region, with dosages of 45–50 Gy and a 60 Gy tumor bed boost. Patients with active skin diseases or sensitivity to the study spray were excluded. The intervention group applied hydrocortisone ointment and Linovera spray twice daily to the treatment site, while the control group used only hydrocortisone ointment. Skin reactions were graded using the validated Global Skin Reaction Classification and assessed during radiotherapy weeks 3 and 5. ResultsAll 60 randomized patients (intervention n = 24, control n = 28) developed radiation dermatitis. By week 5, the intervention group showed a statistically significant reduction in dermatitis severity versus controls (p = 0.04). Dermatitis grades also significantly worsened within both groups from week 3–5 (all p < 0.001). ConclusionWhile HOFA-based moisturizers did not statistically impact overall incidence or severity, marginal benefits were observed with prolonged Linovera spray plus hydrocortisone use versus hydrocortisone alone by week 5. Further research is warranted to explore HOFA's potential skin-protective effects.

Utilization and validation of dried blood spot-based metabolomics in plasma-derived diagnostic models

Metabolomics has rapidly advanced in life sciences, enhancing our understanding of physiological conditions. Plasma stands out as a predominant sample type in metabolomics studies. Dried blood spot (DBS) has been recognized as a valuable strategy due to its unique characteristics, such as minimal invasiveness, small sample volume, and easy transport. Most large cohort studies construct the diagnostic model using plasma-based metabolomics rather than DBS. However, the comparability of metabolite measurements between DBS and plasma samples, as well as the integration of DBS-based metabolomics into established plasma-derived diagnostic models, remains unclear. We collected plasma and DBS samples from the same 12 healthy controls under fasting and non-fasting conditions and performed ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolomics. We identified 277 metabolites present in both plasma and DBS samples, with 229 (82.7 %) showing a strong correlation between the two sample types. Furthermore, pre-processing datasets from plasma and DBS samples before combining them effectively diminished inconsistencies between plasma- and DBS-based metabolomics without compromising the inherent classification within the data. For the clinical application, the plasma samples were obtained from the gastric cancer patients (n = 204) and the healthy controls (n = 128) to serve as the training cohorts. Additionally, DBS samples were collected from different participants of gastric cancer (n = 19) and healthy controls (n = 12) to validate the diagnostic model. Finally, DBS-based metabolomics were integrated into established plasma-derived gastric cancer diagnostic models, yielding an area under the ROC curve (AUC) of 0.934. Overall, incorporating DBS-based metabolomics into an established plasma-derived diagnostic model holds promise, offering valuable opportunities and insights for diagnostic research and clinical practice.

Classification of colorectal cancer patients based on serum micronutrients: An exploratory investigation.

Colorectal cancer (CRC) is a growing global health challenge with a multifactorial etiology encompassing genetic susceptibility, nutrition, and inflammation in the bowel. To examine micronutrient status in CRC patients undergoing CRC resection. We performed a case-control study including 13 consecutive CRC patients and 10 healthy controls (CTRL) comparing the serum levels of 29 micronutrients, namely Copper, Zinc, Selenium, Chromium, Manganese, Carnitine, Choline, Inositol, Methylmalonic acid (MMA), Vitamin (Vit) B1, Vit B2, Vit B3, Vit B5, Vit B6, Vit C, Vit A, Vit D3, Vit E, Vit K1, Vit K2 and the amino acids Serine, Valine, Leucine, Isoleucine, Asparagine, Glutamine, Arginine, Citrulline and Cysteine. After considering the effect of age and sex, copper, arginine, and cysteine were increased, while zinc, selenium, chromium, Vit B1, Vit K1, and Vit A were decreased in CRC patients in comparison with CTRL. Zinc levels perfectly predicted the diagnosis of CRC, and were associated with lymph nodes (pN), of the pTNM staging. Copper levels in serum were strongly associated with the pathological pTNM staging of CRC. Though this is a preliminary study that needs confirmation with a larger longitudinal cohort, our results show that serum micronutrients are linked to tumor growth, likely caused by increased demand from tumor tissue associated with an aberrant cell proliferation and changes in the antioxidant function.

Organ-confined pT2 ISUP4/5 vs. nonorgan confined pT3/4 ISUP2 vs. ISUP3 prostate cancer: Differences in biochemical recurrence-free survival after radical prostatectomy

BackgroundTo test for differences in organ-confined pathological tumor stage (pT) and intermediate International Society of Urological Pathologists (ISUP) grade vs. nonorgan confined pT stage and high ISUP grade and biochemical recurrence (BCR) after radical prostatectomy (RP). MethodsRelying on a tertiary-care database, prostate cancer patients undergoing RP between January 2014 and December 2021 were stratified according to their combination of pT stage and ISUP grade in RP specimens (pT2 ISUP4/5 vs. pT3/4 ISUP2 vs. pT3/4 ISUP3). As Active Surveillance is recommended in ISUP1, these patients were excluded. Moreover, patients with pT2 ISUP2/3 are known for their good prognosis and pT3/4 ISUP4/5 patients for their poor prognosis. Therefore, these patients were also excluded from analyses. Kaplan–Meier survival analyses and multivariable Cox regression models addressed BCR after RP. ResultsOf 215 RP patients, 29 (13%) exhibited pT2 ISUP4/5 vs. 122 (57%) pT3/4 ISUP2 vs. 64 (30%) pT3/4 ISUP3 pathology. In survival analyses, 3-year BCR-free survival rates were 95% in pT2 ISUP4/5 vs. 88% in pT3/4 ISUP2 vs. 65% in pT3/4 ISUP3 patients (P < 0.001). In multivariable Cox regression models addressing BCR, pT3/4 ISUP3 pathology was associated with higher BCR rate relative to pT2 ISUP4/5 pathology (hazard ratio 3.42, 95% confidence interval 1.07-10.94; P = 0.039), but not pT3/4 ISUP2 pathology (P = 0.6). ConclusionCompared to prostate cancer patients with pT2 ISUP4/5 pathology, the combination of pT3/4 ISUP3 pathology is associated with higher risk of BCR after RP. In consequence, patients with pT3/4 ISUP3 pathology should be considered for a closer postoperative follow-up.

The clinical value of ultrasound-guided sacral anesthesia in Intracavitary and/or interstitial brachytherapy for cervical Cancer

ObjectiveTo explore the effectiveness and safety of ultrasound-guided sacral anesthesia in intracavitary and/or interstitial brachytherapy for cervical cancer patients. MethodA retrospective analysis was conducted on a total of 1039 intracavitary and/or interstitial brachytherapy involving 220 patients in our department from December 7, 2020 to March 21, 2024. The study assessed the satisfaction with anesthesia, changes in vital signs, onset time of anesthesia, dosage of anesthetic drugs, duration of anesthesia, and incidence of adverse reactions. ResultThe rate of satisfaction with anesthesia was 73.8 %. There were no significant differences in patients' heart rate (HR), mean arterial pressure (MAP), systolic blood pressure (SBP), or oxygen saturation (SaO2) before and after anesthesia (P > 0.05). The onset time of anesthesia ranged from 20 to 35 min, the average dosage of anesthetic was 20 ml, and the duration of anesthesia lasted from 30 to 120 min. Serious adverse reactions included 2 cases of post-anesthesia syncope (associated with sacral cysts). The incidence of nausea was 2.2 %, and the total incidence of other adverse reactions, such as vomiting, urinary retention, bradycardia, anal discomfort, and dizziness, was less than 1 %. ConclusionUltrasound guided sacral anesthesia demonstrates significant advantages, including effective anesthesia, minimal impact on vital signs, rapid onset, prolonged maintenance, and a low incidence of adverse reactions. It is recommended for widespread application in intracavitary and/or interstitial brachytherapy for cervical cancer patients.

68Ga-Prostate-Specific Membrane Antigen PET/CT in Endometrial Cancer: A Preliminary Report.

Endometrial cancer is the most common gynecological cancer. Prostate-specific membrane antigen (PSMA) is expressed in prostate cancer cells but can be found in other cancers, such as endometrial cancer, during angiogenesis.The aim of this prospective pilot study was to evaluate the feasibility of using 68Ga-PSMA-11 PET/CT in endometrial cancer patients before surgical treatment. Seven women with a mean age of 58 ± 7.9 years were included in the study. All patients underwent standard imaging studies involving transvaginal ultrasound, ceCT scans of the chest and abdomen, and MRI as qualified for surgery. Additionally, PET/CT was performed on a Siemens Biograph scanner 60 minutes after the injection of 2 MBq/kg 68Ga-PSMA-11. Six of 7 patients had positive 68Ga-PSMA-11 PET/CT images, and histopathology confirmed endometrial cancer. One patient also exhibited uptake in the left ovary, and final histopathology revealed a hemorrhagic cyst. Lymph node involvement was further confirmed after ceCT fusion with 68Ga-PSMA-11. The consensus of histopathological staging of endometrial cancer and ceCT was 4/7, that of MR was 6/7, and that of 68Ga-PSMA-11 PET/CT was 5/7. All methods were consistent in terms of staging in 3/7 patients. The initial experience showed the possibility of using 68Ga-PSMA-11 in endometrial cancer patients. However, prospective large studies are needed to explore the real diagnostic role of radiolabelled PSMA in this field.This study was approved by the Ethical Committee of the Medical University of Warsaw (KB/2/A/2018).

Study of NALT1 and CTBP1-AS1 lncRNAs expression levels in triple-negative breast cancer patients in the Iranian population

BackgroundTriple-negative breast cancer (TNBC), an aggressive subtype with a poor prognosis, is notably difficult to treat. Emerging research highlights the significant roles of long non-coding RNAs (lncRNAs) in cancer biology. LncRNAs, such as NALT1 and CTBP1-AS1 are implicated in oncogenic processes; this study hypothesizes that NALT1 and CTBP1-AS1 are overexpressed in TNBC tissues compared to adjacent non-tumor tissues and may serve as biomarkers. Methods: One hundred pairs of tumor and adjacent non-tumor tissues were obtained from female patients with triple-negative breast cancer. After extracting RNA, cDNA synthesis was carried out for all samples. Quantitative real-time PCR (qRT-PCR) was employed to assess differential gene expression. Results: The expression of NALT1 (p-value <0.0001) and CTBP1-AS1 (p-value <0.0002) lncRNAs increased in TNBC tumor tissues in comparison to adjacent non-tumor tissues. A statistically positive correlation (ρ = 0.5844, p < 0.0001) was observed between the expression levels of NALT1 and CTBP1-AS1 in breast cancer patients. The ROC analysis indicated that NALT1 (AUC = 0.718, specificity = 61 %, sensitivity = 70 %) shows moderate potential and CTBP1-AS1 (AUC = 0.648, specificity = 65 %, sensitivity = 55 %) exhibits poor potential as a diagnostic biomarker for breast cancer. Conclusion: This study shows that NALT1 and CTBP1-AS1 lncRNAs are upregulated in TNBC tissues. Additionally, a positive correlation exists between their expression levels in breast cancer. Further research is needed to understand their mechanisms as molecular biomarkers.

ASO Author Reflections: A Simpler Predictor of Postoperative Delirium in Elderly Gastric Cancer Patients.

ASO Author Reflections: A Simpler Predictor of Postoperative Delirium in Elderly Gastric Cancer Patients.

Incidence and risk factors of silent deep venous thromboembolism before interval debulking surgery in ovarian cancer patients, a tertiary centre experience

ObjectiveTo determine the prevalence and risk factors for the development of asymptomatic venous thromboembolism (VTE) in ovarian cancer patients who underwent interval cytoreductive surgery after finishing neoadjuvant chemotherapy. MethodsThis is a prospective observational trial. Female patients with pathologically proven ovarian cancer who received neoadjuvant chemotherapy without clinical evidence of VTE were included. ResultsA total of 107 patients were enrolled in this study. The mean age was 53.37 years, and the mean body mass index (BMI) was 34.11 kg/m2. Seven (6.5 %) patients suffered from silent VTE, as documented by bilateral Doppler ultrasound in the pre- and postoperative settings. The mean age of the patients in the VTE group was 56.17 years, and their mean body mass index was 31.71 Kg/m2. Their median serum CA125 concentration was elevated (325.6 units/ml). On the other hand, the median D-dimer level was elevated by 678 ng/ml fibrinogen equivalent units (FEUs) in the same group of patients. In the present study, comorbidities did not influence the incidence of VTE, as the 7 patients who were diagnosed with VTE did not have any comorbidities. Most of the patients who were diagnosed with serous adenocarcinoma (71.4 %) or stage IIIc disease (57.1 %) were most likely to develop VTE. ConclusionSilent VTE is more prevalent in patients with advanced-stage ovarian cancer and serous carcinomas

ASO Visual Abstract: Decision Regret in Appendiceal Cancer Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

ASO Visual Abstract: Decision Regret in Appendiceal Cancer Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

The prognostic significance of diabetes in non-small cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis

AimsStudies on the prognosis of patients with diabetes and non-small-cell lung cancer (NSCLC) in the era of immune checkpoint inhibitors (ICIs) are limited, and existing findings remain inconsistent. This meta-analysis explored the association between diabetes and survival outcomes in this population. MethodsA total of 10 non-randomized studies comparing overall survival between patients with NSCLC receiving ICIs with and without diabetes were included. A meta-analysis was performed to estimate the hazard of death or disease progression between the two groups. Another analysis was employed to explore the difference in median survival between the groups. Additionally, subgroup, meta-regression, and sensitivity analyses were conducted. ResultsPatients with diabetes exhibited a significantly higher risk of death than those without diabetes (HR = 1.28, 95 % CI = 1.14–1.44; P < 0.01). Moreover, individuals with diabetes had a median life expectancy that was 6.04 months shorter (95 % CI = −10.53 to − 1.54 months, P = 0.009) than that of individuals without diabetes. Moreover, for every 1 % increase in the proportion of patients with diabetes using metformin, a corresponding 2.2 % decrease in the HR of progression-free survival was observed (95 % CI = 1.2–3.1 %). ConclusionDiabetes compromises the effectiveness of ICI treatment in patients with NSCLC.

Intraperitoneal immunotherapy with denileukin diftitox (ONTAK) in recurrent refractory ovarian cancer

BackgroundDenileukin diftitox (ONTAK) is a diphtheria/IL-2R fusion protein able to deplete regulatory T cells in peripheral blood. Regulatory T cells in the local immune microenvironment have been shown to be associated with poor prognosis in ovarian cancer. This study examined whether denileukin diftitox (ONTAK) could be safely administered intraperitoneal in patients with advanced refractory ovarian cancer and assessed its effects on regulatory T cells and tumor associated cytokines in ascites and peripheral blood. Patients and methodsA phase I dose escalation study of intraperitoneal denileukin diftitox (ONTAK) enrolled 10 patients with advanced, refractory ovarian carcinoma at 3 doses (5 μg/kg, 15 μg/kg, and 25 μg/kg). Serial CA-125 measurements assessed clinical response. Regulatory T cells were quantified using RT-PCR and cytokine levels measured by Luminex. ResultsThe maximum tolerated dose was 15 μg/kg with a dose limiting toxicity observed in 1 out of 6 patients in the expansion group. The majority of adverse events were transient grades 1–2. One patient treated at the 25 μg/kg dose experienced cytokine storm with prolonged hospitalization. 3 patients had decreases in CA-125 after treatment but none met criteria for partial response. Treatment with denileukin diftitox (ONTAK) decreased regulatory T cells in peripheral blood and ascites. Treated patients did not show any significant changes in IL-8, TGF-β, sIL2Ra in ascites or peripheral blood. ConclusionsDenileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels.Clinical Trial Registration:ClinicalTrials.gov # NCT00357448

Almonertinib and alflutinib show novel inhibition on rare EGFR S768I mutant cells.

EGFR classical mutations respond well to EGFR tyrosine kinase inhibitors. However, it is uncertain whether currently available EGFR-TKIs are effective against rare EGFR mutations and compound mutations. Herein, the effectiveness of almonertinib and alflutinib, the third-generation tyrosine kinase inhibitors developed in China, on rare EGFR S768I mutations and compound mutations is identified. In this study, using CRISPR method, four EGFR S768I mutation cell lines were constructed, and the sensitivity of EGFR to almonertinib and alflutinib was tested, with positive controls being the 1st (gefitinib), 2nd (afatinib), and 3rd (osimertinib) generation drugs. The present results indicate that almonertinib and alflutinib can effectively inhibit cell viability and proliferation in rare EGFR S768I mutations through the ERK or AKT pathways in a time-dependent manner, by blocking the cell cycle and inhibiting apoptosis. These findings suggest that almonertinib and alflutinib may be potential therapeutic options for non-small cell lung cancer patients with the EGFR S768I mutation.

Incident cardiovascular disease risk among older Asian, Native Hawaiian and Pacific Islander liver cancer survivors

BackgroundCardiovascular disease (CVD) is a significant global health concern, particularly among Asian, Native Hawaiian, and Pacific Islander (ANHPI) communities that face unique health challenges. Liver cancer disproportionately affects ANHPI populations and has intricate associations with CVD risks due to shared pathophysiological mechanisms and metabolic disturbances. However, the specific CVD risk profile of ANHPI liver cancer patients remains poorly understood. MethodsUsing Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified and matched 1150 ANHPI and 2070 Non-Hispanic White (NHW) liver cancer patients diagnosed between 2000 and 2017. We used the Fine-Gray sub-distribution hazard model to estimate hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) for CVD risks, including ischemic heart disease (IHD), heart failure, and stroke, among ANHPI liver cancer patients compared to NHW counterparts and among ANHPI subgroups. ResultsANHPI liver cancer patients demonstrated a lower risk of IHD compared to NHW counterparts (HR, 0.65, 95 % CI, 0.50, 0.86), aligning with broader trends. Subgroup analysis revealed notable heterogeneity within ANHPI populations, with Southeast Asian (HR, 0.65, 95 % CI, 0.42, 1.00) and Chinese patients (HR, 0.53, 95 % CI, 0.33–0.83) exhibiting lower IHD risks compared to their NHW counterparts. However, Native Hawaiian and Pacific Islander liver cancer patients showed elevated risks of heart failure (HR, 3.16, 95 % CI, 1.35–7.39) and IHD (HR, 5.64, 95 % CI, 2.19–14.53) compared to their Chinese counterparts. ConclusionOur study highlights the complexity of CVD risks among ANHPI liver cancer patients. Addressing these disparities is crucial for improving cardiovascular outcomes and reducing the burden of CVD among ANHPI liver cancer patients.