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Frontiers in Immunology 2024Research of immunotherapy for cholangiocarcinoma has yielded some results, but more clinical data are needed to prove its efficacy and safety. Moreover, there is a need...
BACKGROUND
Research of immunotherapy for cholangiocarcinoma has yielded some results, but more clinical data are needed to prove its efficacy and safety. Moreover, there is a need to identify accessible indexes for selecting patients who may benefit from such treatments.
METHODS
The medical records of 66 cholangiocarcinoma patients who underwent immunotherapy were retrospectively collected. The effectiveness of immunotherapy was assessed by tumor response, progression-free survival (PFS), and overall survival (OS), while safety was evaluated by adverse events during treatment. Univariate and multivariate Cox regression analyses were performed to identify prognostic risk factors for PFS and OS, and Kaplan-Meier curves of potential prognostic factors were drawn.
RESULTS
Overall, in this study, immunotherapy achieved an objective response rate of 24.2% and a disease control rate of 89.4% for the included patients. The median PFS was 445 days, and the median OS was 772.5 days. Of the 66 patients, 65 experienced adverse events during treatment, but none had severe consequences. Multivariate Cox analysis indicated that tumor number is a prognostic risk factor for disease progression following immunotherapy in cholangiocarcinoma patients, while tumor differentiation and the fibrosis-4 (FIB-4) index are independent risk factors for OS.
CONCLUSION
In general, immunotherapy for cholangiocarcinoma is safe, with adverse events remaining within manageable limits, and it can effectively control disease progression in most patients. The FIB-4 index may reflect the potential benefit of immunotherapy for patients with cholangiocarcinoma.
Topics: Humans; Cholangiocarcinoma; Male; Female; Middle Aged; Bile Duct Neoplasms; Aged; Prognosis; Immunotherapy; Retrospective Studies; Adult; Fibrosis; Aged, 80 and over; Risk Factors
PubMed: 38799431
DOI: 10.3389/fimmu.2024.1376590 -
BioRxiv : the Preprint Server For... May 2024Replenishment of pancreatic beta cells is a key to the cure for diabetes. Beta cells regeneration is achieved predominantly by self-replication especially in rodents,...
Replenishment of pancreatic beta cells is a key to the cure for diabetes. Beta cells regeneration is achieved predominantly by self-replication especially in rodents, but it was also shown that pancreatic duct cells can transdifferentiate into beta cells. How pancreatic duct cells undergo transdifferentiated and whether we could manipulate the transdifferentiation to replenish beta cell mass is not well understood. Using a genome-wide CRISPR screen, we discovered that loss-of-function of ALDH3B2 is sufficient to transdifferentiate human pancreatic duct cells into functional beta-like cells. The transdifferentiated cells have significant increase in beta cell marker genes expression, secrete insulin in response to glucose, and reduce blood glucose when transplanted into diabetic mice. Our study identifies a novel gene that could potentially be targeted in human pancreatic duct cells to replenish beta cell mass for diabetes therapy.
PubMed: 38798376
DOI: 10.1101/2024.05.13.593941 -
Medicina (Kaunas, Lithuania) May 2024In ampullary cancer, 5-year survival rates are 30-50%, even with optimal resection and perioperative systemic therapies. We sought to determine the important...
In ampullary cancer, 5-year survival rates are 30-50%, even with optimal resection and perioperative systemic therapies. We sought to determine the important clinicopathological features and adjuvant treatments in terms of the prognosis of patients with operable-stage ampullary carcinomas. We included 197 patients who underwent pancreaticoduodenectomy to treat ampullary carcinomas between December 2003 and May 2019. Demographics, clinical features, treatments, and outcomes/survival were analyzed. The median disease-free survival (mDFS) and median overall survival (mOS) were 40.9 vs. 63.4 months, respectively. The mDFS was significantly lower in patients with lymphovascular invasion ( < 0.001) and lymph node involvement ( = 0.027). Potential predictors of decreased OS on univariate analysis included age ≥ 50 years ( = 0.045), poor performance status ( = 0.048), weight loss ( = 0.045), T3-T4 tumors ( = 0.018), surgical margin positivity ( = 0.01), lymph node involvement ( = 0.001), lymphovascular invasion ( < 0.001), perineural invasion ( = 0.007), and poor histological grade ( = 0.042). For the multivariate analysis, only nodal status (hazard ratio [HR]1.98; 95% confidence interval [CI], 1.08-3.65; = 0.027) and surgical margin status (HR 2.61; 95% CI, 1.09-6.24; = 0.03) were associated with OS. Nodal status and a positive surgical margin were independent predictors of a poor mOS for patients with ampullary carcinomas. Additional studies are required to explore the role of adjuvant therapy in patients with ampullary carcinomas.
Topics: Humans; Male; Female; Middle Aged; Retrospective Studies; Aged; Ampulla of Vater; Prognosis; Common Bile Duct Neoplasms; Pancreaticoduodenectomy; Adult; Aged, 80 and over; Disease-Free Survival; Survival Analysis
PubMed: 38793001
DOI: 10.3390/medicina60050818 -
International Journal of Molecular... May 2024Long non-coding RNAs (lncRNAs) have been shown to modulate gene expression and are involved in the initiation and progression of various cancer types. Despite the wealth...
Long non-coding RNAs (lncRNAs) have been shown to modulate gene expression and are involved in the initiation and progression of various cancer types. Despite the wealth of studies describing transcriptome changes upon lncRNA knockdown, there is limited information describing lncRNA-mediated effects on regulatory elements (REs) modulating gene expression. In this study, we investigated how the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) lncRNA regulates primary target genes using time-resolved MALAT1 knockdown followed by parallel RNA-seq and ATAC-seq assays. The results revealed that MALAT1 primarily regulates specific protein-coding genes and a substantial decrease in the accessibility downstream of the gene that was associated with a decreased expression. Moreover, the presence of an NR4A1-downstream RE was demonstrated by CRISPR-i assays to define a functional MALAT1/NR4A1 axis. By analyzing TCGA data, we identified a positive correlation between NR4A1 expression and NR4A1-downstream RE accessibility in breast cancer but not in pancreatic cancer. Accordingly, this regulatory mechanism was experimentally validated in breast cancer cells (MCF7) but not in pancreatic duct epithelial carcinoma (PANC1) cells. Therefore, our results demonstrated that MALAT1 is involved in a molecular mechanism that fine-tunes NR4A1 expression by modulating the accessibility of a downstream RE in a cell type-specific manner.
Topics: RNA, Long Noncoding; Humans; Nuclear Receptor Subfamily 4, Group A, Member 1; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; MCF-7 Cells; Breast Neoplasms; Pancreatic Neoplasms; Female; Regulatory Sequences, Nucleic Acid
PubMed: 38791553
DOI: 10.3390/ijms25105515 -
Experimental and Molecular Pathology Jun 2024Little information is available concerning protein expression of the free fatty acid receptor 2 (FFAR2), especially in tumours. Therefore, the aim of the present study...
OBJECTIVE
Little information is available concerning protein expression of the free fatty acid receptor 2 (FFAR2), especially in tumours. Therefore, the aim of the present study was to comprehensively characterise the expression profile of FFAR2 in a large series of human normal and neoplastic tissues using immunohistochemistry thus providing a basis for further in-depth investigations into its potential diagnostic or therapeutic importance.
METHODS
We developed a novel rabbit polyclonal anti-FFAR2 antibody, 0524, directed against the C-terminal region of human FFAR2. Antibody specificity was confirmed via Western blot analyses and immunocytochemistry using the FFAR2-expressing cell line BON-1 and FFAR2-specific small interfering RNA as well as native and FFAR2-transfected HEK-293 cells. The antibody was then used for immunohistochemical analyses of various formalin-fixed, paraffin-embedded specimens of normal and neoplastic human tissues.
RESULTS
In normal tissues, FFAR2 was mainly present in distinct cell populations of the cerebral cortex, follicular cells and C cells of the thyroid, cardiomyocytes of the heart, bronchial epithelia and glands, hepatocytes and bile duct epithelia of the liver, gall bladder epithelium, exocrine and β-cells of the endocrine pancreas, glomerular mesangial cells and podocytes as well as collecting ducts of the kidney, intestinal mucosa (particularly enteroendocrine cells), prostate epithelium, seminiferous tubules of the testicles, and placental syncytiotrophoblasts. In neoplastic tissues, FFAR2 was particularly prevalent in papillary thyroid carcinomas, parathyroid adenomas, and gastric, colon, pancreatic, hepatocellular, cholangiocellular, urinary bladder, breast, cervical, and ovarian carcinomas.
CONCLUSIONS
We generated and characterised a novel rabbit polyclonal anti-human FFAR2 antibody that is well-suited for visualising FFAR2 expression in human routine pathology tissues. This antibody is also suitable for Western blot and immunocytochemistry experiments. To our knowledge, this antibody enabled the first broad FFAR2 protein expression profile in various normal and neoplastic human tissues.
Topics: Humans; Neoplasms; HEK293 Cells; Animals; Rabbits; Immunohistochemistry; Receptors, G-Protein-Coupled; Female; Male
PubMed: 38788249
DOI: 10.1016/j.yexmp.2024.104902 -
Biology May 2024The source, mRNA transcription, and synthesis of insulin in the pancreas, in addition to the bile duct and liver, in streptozotocin (STZ)-induced diabetic rats (DR) in...
Among Other Tissues, Short-Term Garlic Oral Treatment Incrementally Improves Indicants of Only Pancreatic Islets of Langerhans Histology and Insulin mRNA Transcription and Synthesis in Diabetic Rats.
BACKGROUND
The source, mRNA transcription, and synthesis of insulin in the pancreas, in addition to the bile duct and liver, in streptozotocin (STZ)-induced diabetic rats (DR) in response to garlic oral treatment are not yet clear.
OBJECTIVE
This study investigated the accumulative effects of continued garlic oral treatment on changes in the pancreas, bile duct, and liver with regards to: 1-Insulin mRNA transcription, synthesis, and concentration in relation to changes in serum insulin (SI); 2-Insulinogenic cells insulin intensity and distribution, proliferation, and morphology.
METHOD
Fasting blood glucose (FBG) and insulin concentration in serum and pancreas (PI) and sources and mRNA transcription in the pancreas, bile duct, and liver in normal rats given normal saline (NR-NS) and DR given either NS (DR-NS) or garlic extract (DR-GE) before and after 1, 4, and 8 weeks of oral treatment were examined.
RESULTS
Compared to NR-NS, DR-NS showed a significant increase in FBG and reductions in SI and PI and deterioration in islets histology, associated pancreatic insulin numerical intensities, and mRNA transcription. However, compared to DR-NS, the targeted biochemical, histological, and genetic variables of DR-GE were significantly and incrementally improved as garlic treatment continued. Insulin or its indicators were not detected either in the bile duct or the liver in DR-GE.
CONCLUSIONS
8 weeks of garlic oral treatment is enough to incrementally restore only pancreatic islets of Langerhans insulin intensity and insulinogenic cells proliferation, morphology, and distribution. These indices were associated with enhanced pancreatic insulin mRNA transcription and synthesis. Eight weeks of garlic treatment were not enough to stimulate insulinogenesis in either the bile duct or the liver.
PubMed: 38785837
DOI: 10.3390/biology13050355 -
Diseases (Basel, Switzerland) Apr 2024Pancreaticolithiasis represents a rare phenomenon, being superimposed most of the time on a form of chronic pancreatitis of multifactorial etiology. Pancreaticolithiasis...
Pancreaticolithiasis represents a rare phenomenon, being superimposed most of the time on a form of chronic pancreatitis of multifactorial etiology. Pancreaticolithiasis is a late complication of the phenomenon of chronic pancreatitis. The reverberant inflammatory process, followed by the fibrotic degeneration of the pancreatic parenchyma, and pancreatic fluid stasis at the ductal level are factors that contribute to the phenomenon of calcium precipitation. This article describes the case of a patient with a diagnosis of pancreaticolithiasis (Wirsung duct lithiasis), a phenomenon superimposed on chronic pancreatitis of ethanolic cause (Rosemont classification). It was decided to perform surgery via the classical approach with the perfection of corporeo-caudal pancreatectomy and preservation of the splenic vessels (Kimura procedure) with pancreatico-jejunal anastomosis on the Roux-en-Y loop. The aim of this study is to identify the best method of treatment for pancreaticolithiasis. To enhance the case and provide a basis for standardization, a literature review was carried out, which included a total of six articles. The results of this study highlight that, currently, the management of symptomatic pancreaticolithiasis encompasses medical therapy (enzyme replacement therapy), interventional therapy (ESWL (extracorporeal shock wave lithotripsy) ± ERCP (endoscopic retrograde cholangiopancreatography), ERCP + sphincterotomy + stent insertion, and POP (oral pancreatoscopy)), and surgical treatment. In conclusion, based on the analysis conducted in this study, the size of the calculi present determines which is the suitable therapeutic care. Unlike stones over 0.5 cm, when surgery is explicitly advised for therapeutic purposes in the absence of endoscopic techniques, stones under 0.5 cm should be treated using endoscopic procedures.
PubMed: 38785741
DOI: 10.3390/diseases12050086 -
Frontiers in Surgery 2024Heterotopic pancreas is a relatively rare condition that may be associated to clinical complaints or signs. Here, we report a case of gastric heterotopic pancreas...
Heterotopic pancreas is a relatively rare condition that may be associated to clinical complaints or signs. Here, we report a case of gastric heterotopic pancreas assictaed to ductal adenocarcinoma. Obstructive jaundice was the initial symptom prompting medical intervention. A 73-year-old male patient presented with yellow staining of the skin and sclera, and dull epigastric pain. Contrast-enhanced computed tomography showed stenosis of the extrahepatic distal bile duct and mass lesions of the antrum. The patient underwent tumor resection, distal gastrectomy (Billroth II), and common bile duct exploration. Postoperative pathological examination revealed an adenocarcinoma located in the wall of the gastric antrum. Immunohistochemical results suggested that the tumor originated from the pancreas. Heterologous pancreatic tissue and a dilated pancreatic duct were found in the tumor. These findings suggest malignant transformation of the gastric heterotopic pancreas. Of note, jaundice as clinical complaint for adenocarcinoma associated to gastric heterotopic pancreas.
PubMed: 38783861
DOI: 10.3389/fsurg.2024.1274389 -
BMC Cancer May 2024Adenocarcinoma of the ampulla of Vater (AoV) is one of the rare periampullary cancers, and due to its anatomical location, it is categorized into various histologic...
BACKGROUND
Adenocarcinoma of the ampulla of Vater (AoV) is one of the rare periampullary cancers, and due to its anatomical location, it is categorized into various histologic subtypes. Its rarity and diversity pose challenges in treatment decision-making for patients with advanced AoV carcinoma. This study investigated the efficacy and safety of the combined regimen of capecitabine and oxaliplatin (CAPOX) in a real-world clinical setting.
METHODS
This investigation encompassed patients with advanced AoV carcinoma who underwent CAPOX treatment. Histologic phenotypes were identified through a combination of histopathological analysis and protein expression markers, including MUC1, CDX2, CK20, and MUC2. The correlation between histopathological determinants and survival outcomes was explored, in addition to an evaluation of the safety profile of CAPOX therapy.
RESULTS
From January 2010 to June 2023, 42 patients received CAPOX. Of these, 14 patients (33.3%) had not received any prior palliative chemotherapy, while 28 patients (66.7%) had undergone one prior line of chemotherapy. At a median follow up of 9.0 months, the median progression-free survival (PFS) was 4.38 months (95% CI, 2.78-5.69) and the median overall survival (OS) was 9.57 months (95% CI 7.56-11.6). The objective response and disease control rates were 38.1% and 61.9%, respectively. Patients who received CAPOX as a second-line treatment had poorer PFS (HR = 2.62; 95% CI, 1.49-4.90, p = 0.003) and OS (HR = 2.82, 95% CI, 1.47-5.38, p = 0.001) compared to those who received CAPOX as a first-line chemotherapy. There were no statistically significant differences in PFS (p = 0.185) and OS (p = 0.097) between groups based on histologic subtypes. Neutropenia (14.3%) emerged as the predominant grade 3-4 toxicity. Notably, treatment cessation occurred in select instances owing to grade 3 fatigue (9.5%) and peripheral neuropathy (9.5%).
CONCLUSIONS
This study confirmed the therapeutic efficacy and safety of CAPOX in a real-world setting, consistent with prior phase II trial results. While CAPOX proved feasible for advanced AoV carcinoma regardless of histologic subtype, its reduced effectiveness in second-line settings necessitates further research to determine its optimal palliative use.
Topics: Humans; Capecitabine; Male; Oxaliplatin; Ampulla of Vater; Female; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Aged; Adenocarcinoma; Adult; Common Bile Duct Neoplasms; Retrospective Studies; Progression-Free Survival; Treatment Outcome
PubMed: 38783256
DOI: 10.1186/s12885-024-12398-0 -
BMC Cancer May 2024Tumor morphology, immune function, inflammatory levels, and nutritional status play critical roles in the progression of intrahepatic cholangiocarcinoma (ICC). This...
BACKGROUND
Tumor morphology, immune function, inflammatory levels, and nutritional status play critical roles in the progression of intrahepatic cholangiocarcinoma (ICC). This multicenter study aimed to investigate the association between markers related to tumor morphology, immune function, inflammatory levels, and nutritional status with the prognosis of ICC patients. Additionally, a novel tumor morphology immune inflammatory nutritional score (TIIN score), integrating these factors was constructed.
METHODS
A retrospective analysis was performed on 418 patients who underwent radical surgical resection and had postoperative pathological confirmation of ICC between January 2016 and January 2020 at three medical centers. The cohort was divided into a training set (n = 272) and a validation set (n = 146). The prognostic significance of 16 relevant markers was assessed, and the TIIN score was derived using LASSO regression. Subsequently, the TIIN-nomogram models for OS and RFS were developed based on the TIIN score and the results of multivariate analysis. The predictive performance of the TIIN-nomogram models was evaluated using ROC survival curves, calibration curves, and clinical decision curve analysis (DCA).
RESULTS
The TIIN score, derived from albumin-to-alkaline phosphatase ratio (AAPR), albumin-globulin ratio (AGR), monocyte-to-lymphocyte ratio (MLR), and tumor burden score (TBS), effectively categorized patients into high-risk and low-risk groups using the optimal cutoff value. Compared to individual metrics, the TIIN score demonstrated superior predictive value for both OS and RFS. Furthermore, the TIIN score exhibited strong associations with clinical indicators including obstructive jaundice, CEA, CA19-9, Child-pugh grade, perineural invasion, and 8th edition AJCC N stage. Univariate and multivariate analysis confirmed the TIIN score as an independent risk factor for postoperative OS and RFS in ICC patients (p < 0.05). Notably, the TIIN-nomogram models for OS and RFS, constructed based on the multivariate analysis and incorporating the TIIN score, demonstrated excellent predictive ability for postoperative survival in ICC patients.
CONCLUSION
The development and validation of the TIIN score, a comprehensive composite index incorporating tumor morphology, immune function, inflammatory level, and nutritional status, significantly contribute to the prognostic assessment of ICC patients. Furthermore, the successful application of the TIIN-nomogram prediction model underscores its potential as a valuable tool in guiding individualized treatment strategies for ICC patients. These findings emphasize the importance of personalized approaches in improving the clinical management and outcomes of ICC.
Topics: Humans; Cholangiocarcinoma; Male; Female; Retrospective Studies; Bile Duct Neoplasms; Middle Aged; Nutritional Status; Prognosis; Aged; Nomograms; Inflammation; Biomarkers, Tumor; Alkaline Phosphatase; Tumor Burden; Nutrition Assessment; Serum Albumin; ROC Curve; Monocytes
PubMed: 38783240
DOI: 10.1186/s12885-024-12375-7