-
Journal of Medicinal Chemistry Jul 2024Using a multigram-scalable synthesis, we obtained nine dinuclear complexes based on nonendogenous iron(I) centers and featuring variable aminocarbyne and P-ligands. One...
1,3,5-Triaza-7-phosphaadamantane and Cyclohexyl Groups Impart to Di-Iron(I) Complex Aqueous Solubility and Stability, and Prominent Anticancer Activity in Cellular and Animal Models.
Using a multigram-scalable synthesis, we obtained nine dinuclear complexes based on nonendogenous iron(I) centers and featuring variable aminocarbyne and P-ligands. One compound from the series () emerged for its strong cytotoxicity in vitro against four human cancer cell lines, surpassing the activity of cisplatin by 3-6 times in three cell lines, with an average selectivity index of 6.2 compared to noncancerous HEK293 cells. demonstrated outstanding water solubility (15 g/L) and stability in physiological-like solutions. It confirmed its superior antiproliferative activity when tested in 3D spheroids of human pancreatic cancer cells and showed a capacity to inhibit thioredoxin reductase (TrxR) similar to auranofin. In vivo treatment of murine LLC carcinoma with (8 mg kg dose) led to excellent tumor growth suppression (88%) on day 15, with no signs of systemic toxicity and only limited body weight loss.
PubMed: 38951717
DOI: 10.1021/acs.jmedchem.4c00641 -
Scientific Reports Jul 2024The NK cell is an important component of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC), also plays a significant role in PDAC development. This...
The NK cell is an important component of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC), also plays a significant role in PDAC development. This study aimed to explore the relationship between NK cell marker genes and prognosis, immune response of PDAC patients. By scRNA-seq data, we found the proportion of NK cells were significantly downregulated in PDAC and 373 NK cell marker genes were screened out. By TCGA database, we enrolled 7 NK cell marker genes to construct the signature for predicting prognosis in PDAC patients. Cox analysis identified the signature as an independent factor for pancreatic cancer. Subsequently, the predictive power of signature was validated by 6 GEO datasets and had an excellent evaluation. Our analysis of relationship between the signature and patients' immune status revealed that the signature has a strong correlation with immunocyte infiltration, inflammatory reaction, immune checkpoint inhibitors (ICIs) response. The NK cell marker genes are closely related to the prognosis and immune capacity of PDAC patients, and they have potential value as a therapeutic target.
Topics: Humans; Carcinoma, Pancreatic Ductal; Killer Cells, Natural; Prognosis; Pancreatic Neoplasms; Biomarkers, Tumor; Single-Cell Analysis; Female; Male; Gene Expression Regulation, Neoplastic; Sequence Analysis, RNA; Tumor Microenvironment; Middle Aged; Aged; Gene Expression Profiling
PubMed: 38951569
DOI: 10.1038/s41598-024-65917-1 -
Journal of Cancer Research and Clinical... Jul 2024In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy.
PATIENTS AND METHODS
The primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80% and a significance level of 5%, 196 events needed). Secondary endpoints included overall survival (OS), progression-free survival of third-line therapy and safety. The trial is registered with EudraCT Nr. 2016-004640-11.
RESULTS
The trial was terminated with 60 evaluable (37 with FOLFIRI, 23 with OFF) patients due to insufficient recruitment. PFS of second-line therapy was 2.4 (95% CI 2.3-2.6) months with FOLFIRI vs 2.4 (95% CI 2.2-2.7) months with OFF (HR: 0.80, 95% CI 0.45-1.42, P = 0.43). OS was comparable between the arms (HR: 0.95, 95% CI 0.54-1.66), P = 0.84). Only 4 out of 28 (14%) patients receiving third-line therapy achieved a disease control (partial remission or stable disease). Both second-line regimens were well tolerated without new or unexpected safety signals being observed.
CONCLUSION
The exploratory analysis of this early terminated trial suggests that FOLFIRI and OFF have similar efficacy ant toxicity as second-line therapy of PDAC after failure of gemcitabine/nab-paclitaxel. Third-line therapy regardless of regimen does not provide satisfactory efficacy in this sequential treatment algorithm.
Topics: Humans; Pancreatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Male; Fluorouracil; Female; Middle Aged; Leucovorin; Aged; Oxaliplatin; Irinotecan; Adult; Camptothecin; Progression-Free Survival; Cross-Over Studies
PubMed: 38951245
DOI: 10.1007/s00432-024-05827-x -
Zhonghua Nei Ke Za Zhi Jul 2024
Review
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Intestinal Neoplasms; Stomach Neoplasms
PubMed: 38951086
DOI: 10.3760/cma.j.cn112138-20231229-00415 -
Modern Pathology : An Official Journal... Jun 2024Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a recently recognized pancreatic tumor. Here, we aimed to determine the most essential features with... (Review)
Review
Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a recently recognized pancreatic tumor. Here, we aimed to determine the most essential features with the systematic review tool. PubMed, SCOPUS, and Embase were searched for studies reporting data on pancreatic IOPN. The clinicopathological, immunohistochemical, and molecular data were extracted and summarized. Then, a comparative analysis of the molecular alterations of IOPN with those of pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm from reference cohorts (including The Cancer Genome Atlas) was conducted. The key findings from 414 IOPNs were as follows: 1) Clinicopathological Features: Male-to-female ratio was 1,5:1. Pancreatic head was the most common site (131/237, 55.3%), but a diffuse tumor extension involving more than one pancreatic segment was described in about 1/5 of cases (49/237, 20.6%). The mean size was 45.5 mm. An associated invasive carcinoma was present in 50% of cases (168/336). In those cases, most tumors were pT1/pT2 and pN0 (>80%), and vascular invasion was uncommon (20.6%). Regarding survival, more than 90% of patients were alive after surgical resection. 2) Immunohistochemical and Molecular Features: The most expressed mucins were MUC5AC (110/112, 98.2%) and MUC6 (78/84, 92.8%). Compared with pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, and GNAS were less altered in IOPN (p<0.01). Moreover, fusions involving PRKACA or PRKACB genes were detected in all of 68 cases examined, with PRKACB::ATP1B1 as the most common (27/68 cases, 39.7%). These genomic events emerged as an entity-defining molecular alteration of IOPN (p<0.01). Thus, such fusions represent a promising biomarker for diagnostic purposes. Recent evidence also suggests their role in influencing the acquisition of oncocytic morphology. IOPN is a distinct pancreatic neoplasm with specific clinicopathological and molecular features. Considering the clinical/prognostic implications, its recognition is essential for pathologists and, ultimately, patients' management.
PubMed: 38950698
DOI: 10.1016/j.modpat.2024.100554 -
Acta Medica Portuguesa Jul 2024
Topics: Humans; Pancreatic Neoplasms; Pancreatectomy; Time Factors; Operative Time
PubMed: 38950613
DOI: 10.20344/amp.21621 -
Molecular Imaging and Radionuclide... Jun 2024We present the case of a patient with newly diagnosed high-risk prostate cancer. The patient underwent nephrectomy for renal cell carcinoma (RCC) in 2009. The...
We present the case of a patient with newly diagnosed high-risk prostate cancer. The patient underwent nephrectomy for renal cell carcinoma (RCC) in 2009. The prostate-specific membrane antigen (PSMA) scan revealed a primary tumor with seminal vessel involvement, PSMA-positive regional lymph nodes, several nodular lung lesions with mild PSMA uptake, PSMA-positive mediastinal lymph nodes, and a PSMA-positive mass in the pancreatic head. Ultrasound-guided biopsy was performed for the pancreatic lesions revealing metastasis from a RCC. Simultaneous treatment for prostate cancer and metastatic RCC was initiated. To separate metastatic sites for both primaries, we attempted to use fluorodeoxyglucose positron emission tomography/computed tomography, which was moderately positive for the pancreatic mass but not for the other locations. RCC is a Ga PSMA-positive tumor; the synchronous combination of RCC with prostate cancer can be confusing and requires more complex clinical interpretation.
PubMed: 38949477
DOI: 10.4274/mirt.galenos.2023.90582 -
Liver International : Official Journal... Jul 2024We examined the impact of a co-diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) on patient outcomes.
BACKGROUND AND AIMS
We examined the impact of a co-diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) on patient outcomes.
METHODS
Using TriNetX, a global federated research network (n = 114 million), we undertook two retrospective cohort studies, using time-to-event analysis. Analysis 1 compared MASLD with T2D to MASLD alone; analysis 2 compared T2D with MASLD to T2D alone. Propensity score matching using greedy nearest neighbour (calliper .1) balanced the cohorts (1:1) for significant covariates. Primary outcomes were cardiovascular, liver, diabetes-related, and cancer events over 5 years.
RESULTS
Analysis 1 (n = 95 275): a co-diagnosis of T2D significantly increased the risk of ischaemic heart disease (IHD) (HR 1.39; CI: 1.34, 1.44), ischaemic stroke (HR 1.45; CI: 1.35, 1.56), heart failure (HR 1.42; CI: 1.36, 1.49), atrial fibrillation (HR 1.09; CI: 1.03, 1.16), hepatocellular carcinoma (HR 1.96; CI: 1.69, 2.27), pancreatic cancer (HR 1.25; CI: 1.06, 1.48) and liver-related complications over 5 years from MASLD diagnosis. Analysis 2 (n = 15 208): a co-diagnosis of MASLD significantly increased risk of all-cause mortality (HR 1.11; CI: 1.02, 1.22), IHD (HR 1.181; CI: 1.08, 1.29), hepatocellular (HR 50.31; CI: 6.94, 364.72), pancreatic (HR 1.78; CI: 1.12, 2.84), breast (HR 1.43; CI: 1.09, 1.88) and renal cancer (HR 2.01; CI: 1.24, 3.26), and diabetic neuropathy (HR 1.17; CI: 1.09, 1.27) over 5 years from metformin initiation.
CONCLUSIONS
T2D significantly potentiates the risk of cardiovascular, malignancy and liver-related outcomes in people with MASLD. The effect of MASLD on people with T2D, although less dramatic, still potentiated risk of death, IHD, malignancy and peripheral neuropathy.
PubMed: 38949295
DOI: 10.1111/liv.16016 -
Lancet Regional Health. Americas Jul 2024This study determined the impact of pre-operative abdominal MRI on all-cause mortality for patients with resected PDAC.
BACKGROUND
This study determined the impact of pre-operative abdominal MRI on all-cause mortality for patients with resected PDAC.
METHODS
All adult (≥18 years) PDAC patients who underwent pancreatectomy between January 2011 and December 2022 in Ontario, Canada, were identified for this population-based cohort study (ICD-O-3 codes: C250, C251, C252, C253, C257, C258). Patient demographics, comorbidities, PDAC stage, medical and surgical management, and survival data were sourced from multiple linked provincial administrative databases at ICES. All-cause mortality was compared between patients with and without a pre-operative abdominal MRI after controlling for multiple covariates.
FINDINGS
A cohort of 4579 patients consisted of 2432 men (53.1%) and 2147 women (46.9%) with a mean age of 65.2 years (standard deviation: 11.2 years); 2998 (65.5%) died while 1581 (34.5%) survived. Median follow-up duration post-resection was 22.4 months (interquartile range: 10.8-48.8 months), and median survival post-pancreatectomy was 25.9 months (95% confidence interval [95% CI]: 24.8, 27.5). Patients who underwent a pre-operative abdominal MRI had a median survival of 33.1 months (95% CI: 30.7, 37.2) compared to 21.1 months (95% CI: 19.8, 22.6) for all others. A total of 2354/4579 (51.4%) patients underwent a pre-operative abdominal MRI, which was associated with a 17.2% (95% CI: 11.0, 23.1) decrease in the rate of all-cause mortality, with an adjusted hazard ratio (aHR) of 0.828 (95% CI: 0.769, 0.890).
INTERPRETATION
Pre-operative abdominal MRI was associated with improved overall survival for PDAC patients who underwent pancreatectomy, possibly due to better detection of liver metastases than CT.
FUNDING
Northern Ontario Academic Medicine Association (NOAMA) Clinical Innovation Fund.
PubMed: 38948322
DOI: 10.1016/j.lana.2024.100809 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To explore the relationship between baseline clinical characteristics and hematological parameters of patients undergoing radical resection for pancreatic ductal...
OBJECTIVE
To explore the relationship between baseline clinical characteristics and hematological parameters of patients undergoing radical resection for pancreatic ductal adenocarcinoma (PDAC) and their prognosis, and to provide references for stratifying the patients' clinical risks.
METHODS
We retrospectively collected clinical data from 445 patients who underwent radical surgical treatment for PDAC at West China Hospital, Sichuan University between January 2010 and February 2019. Then, we conducted retrospective clinical analysis with the collected data. Data on patients' basic clinical characteristics, routine blood test results, and tumor indicators were collected to explore their effects on the postoperative overall survival (OS) of PDAC patients. Cox proportional hazards regression was used to identify factors affecting OS. Statistical analysis was performed using the SPSS 23.0 software package.
RESULTS
The postoperative median overall survival (mOS) was 17.0 months (95% CI: 15.0-19.0). The 1, 2, 3, 4, and 5-year survival rates of the patients included in the study were 60.6%, 33.4%, 19.1%, 12.7%, and 9.6%, respectively. The multivariate Cox proportional hazards model analysis demonstrated that a number of factors independently affect postoperative survival in PDAC patients. These factors include tumor location (hazards ratio [HR]=1.574, 95% CI: 1.233-2.011), degree of tumor cell differentiation (HR=0.687, 95% CI: 0.542-0.870), presence of neural invasion (HR=0.686, 95% CI: 0.538-0.876), TNM staging (HR=1.572, 95% CI: 1.252-1.974), postoperative adjuvant therapy (HR=1.799, 95% CI: 1.390-2.328), preoperative drinking history (HR=0.744, 95% CI: 0.588-0.943), and high serum CA199 levels prior to the surgery (HR=0.742, 95% CI: 0.563-0.977).
CONCLUSION
In PDAC patients, having tumors located in the head of the pancreas, moderate and high degrees of differentiated, being free from local neurovascular invasion, being in TNM stage Ⅰ, undergoing postoperative adjuvant therapy, no history of alcohol consumption prior to the surgery, and preoperative serum CA199 being less than or equal to 37 U/mL are significantly associated with a better prognosis.
Topics: Humans; Pancreatic Neoplasms; Retrospective Studies; Prognosis; Male; Female; Carcinoma, Pancreatic Ductal; Survival Rate; Proportional Hazards Models; Middle Aged; China; Aged
PubMed: 38948268
DOI: 10.12182/20240560604