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Advances in Laboratory Medicine Jun 2024Spontaneous bacterial peritonitis is a frequent severe complication in cirrhotic patients with ascites. Carbapenem antibiotics are currently the treatment of choice for...
OBJECTIVES
Spontaneous bacterial peritonitis is a frequent severe complication in cirrhotic patients with ascites. Carbapenem antibiotics are currently the treatment of choice for patients with hospital-acquired or healthcare-related infections. However, there is limited evidence available on the efficacy of ertapenem in cirrhotic patients with spontaneous bacterial peritonitis. As a result, the pharmacokynetics and pharmacodynamics of this antibiotic are still unknown. The objective of this study was to develop and validate measurement procedures based on liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to determine ertapenem concentrations in plasma and ascitic fluid.
METHODS
Samples were pretreated by acetronile protein-precipitation. Chromatographic separation is performed on a C reversed-phase Acquity-UPLC-BEH column (2.1 × 100 mm id, 1.7 µm) using a non-linear gradient of water/acetonitrile containing 0.1 % of formic acid at a flow rate of 0.4 mL/min. Ertapenem and its internal standard (ertapenem-D) are detected by tandem mass spectrometry using positive electrospray ionization and multiple reaction monitoring, and using 476.2 → 346.0/432.2 as mass transition for ertapenem and 480.2 → 350.0 for its internal standard.
RESULTS
No significant interferences or carry-over contamination were observed. Imprecisions, absolute relative bias, matrix effects and normalized recoveries were ≤14.5 %, ≤9.3 % (92.8-104.5) % and (98.8-105.8) %, respectively. Chromatographic measurement procedures were linear from (0.50-100) mg/L.
CONCLUSIONS
The measurement procedures based on UHPLC-MS/MS developed and validated in this study could be useful in pharmacokynetic and pharmacodynamic studies in subjects with liver cirrhosis who develop spontaneous bacterial peritonitis treated with ertapenem.
PubMed: 38939197
DOI: 10.1515/almed-2023-0168 -
American Journal of Reproductive... Jun 2024Endometriosis is a prevalent chronic gynecological disease linked to immune dysfunction. The protein T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3)...
PROBLEM
Endometriosis is a prevalent chronic gynecological disease linked to immune dysfunction. The protein T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) plays a crucial role in immune system balance. Malfunction of TIM-3 may result in excessive immune activation and inflammatory tissue damage. Given TIM-3's established role in the development of cancer and autoimmune diseases, we decided to study its role in women suffering from endometriosis.
STUDY METHOD
We included a total of 62 female patients, all of whom had undergone laparoscopic surgery. Of these, 47 had endometriosis and 15 did not. During surgery, we collected peritoneal fluid (PF) and peripheral blood (PB) samples from every patient for analysis using flow cytometry. To mark the samples, we used a panel of monoclonal antibodies and examined TIM-3 expression in their immune cells.
RESULTS
Endometriosis patients in PB demonstrated a significantly lower percentage of CD56+ T cells with TIM-3 expression. As endometriosis progressed through its stages, this expression lessened. This decrease was particularly notable in women with stage III/IV endometriosis. Additionally, both women diagnosed with intestinal endometriosis and those with recent endometriosis diagnoses showed a significantly reduced percentage of CD56+ T cells expressing TIM-3.
CONCLUSIONS
Patients with endometriosis exhibit diminished TIM-3 expression within circulating T cells. This warrants further investigation to discern whether it contributes to the progression of endometriosis, potentially through the amplification of autoreactive T cells and inflammation.
Topics: Humans; Endometriosis; Female; Hepatitis A Virus Cellular Receptor 2; Adult; T-Lymphocytes; Ascitic Fluid; Middle Aged
PubMed: 38924299
DOI: 10.1111/aji.13887 -
SAGE Open Medical Case Reports 2024Retroperitoneal cysts, a rare surgical phenomenon, present diagnostic challenges due to their typically asymptomatic nature. A 62-year-old male presented with a 4-month...
Retroperitoneal cysts, a rare surgical phenomenon, present diagnostic challenges due to their typically asymptomatic nature. A 62-year-old male presented with a 4-month history of abdominal distension and increased burping. Upon clinical examination, a soft, distended, nontender abdomen with a palpable mass extending from the epigastric region to 3 cm below the umbilicus was revealed. Imaging revealed a 14.6 cm × 15.8 cm × 16.4 cm nonenhancing retroperitoneal lesion, compressing the right ureter and causing mild right hydronephrosis. Multiple gall bladder calculi, an umbilical hernia, and lipomatous lesions associated with adrenal glands were also discovered. Laparoscopic retroperitoneal cystectomy, cholecystectomy, and umbilical hernia repair were performed. Intraoperatively, 150 ml ascitic fluid and 1200 ml cystic fluid were found. This case highlights the intricate clinical presentation of a retroperitoneal cyst, emphasizing the need for surgical exploration. Successful laparoscopic management contributes to the evolving understanding of optimal treatment strategies.
PubMed: 38911179
DOI: 10.1177/2050313X241263773 -
Cancers May 2024Bromodomain and extra-terminal (BET) domain proteins that bind to acetylated lysine residues of histones serve as the "readers" of DNA acetylation. BRD4 is the most...
BACKGROUND
Bromodomain and extra-terminal (BET) domain proteins that bind to acetylated lysine residues of histones serve as the "readers" of DNA acetylation. BRD4 is the most thoroughly studied member of the BET family and regulates the expression of key oncogenes. BRD4 gene amplification has been identified in ovarian cancer (~18-19%) according to (TCGA) analysis. BET inhibitors are novel small molecules that displace BET proteins from acetylated histones and are currently tested in Phase I/II trials. We here aim to explore the prognostic role of the BRD4 gene and protein expression in the ascitic fluid of patients with advanced FIGO III/IV high-grade serous ovarian carcinoma (HGSC).
METHODS
Ascitic fluid was obtained from 28 patients with advanced stage (FIGO III/IV) HGSC through diagnostic/therapeutic paracentesis or laparoscopy before the initiation of chemotherapy. An amount of ~200 mL of ascitic fluid was collected from each patient and peripheral blood mononuclear cells () were isolated. Each sample was evaluated for BRD4 and GAPDH gene expression through RT-qPCR and BRD4 protein levels through enzyme-linked immunosorbent assay (ELISA). The study protocol was approved by the Institutional Review Board of Alexandra University Hospital and the Committee on Ethics and Good Practice (CEGP) of the National and Kapodistrian University of Athens (NKUA).
RESULTS
Low BRD4 gene expression was associated with worse prognosis at 12 months compared to intermediate/high expression (95% CI; 1.75-30.49; = 0.008). The same association was observed at 24 months although this association was not statistically significant (95% CI; 0.96-9.2; = 0.065). Progression-free survival was shorter in patients with low BRD4 gene expression at 12 months (5.6 months; 95% CI; 2.6-8.6) compared to intermediate/high expression (9.8 months; 95% CI; 8.3-11.3) (95% CI; 1.2-16.5; = 0.03). The same association was confirmed at 24 months (6.9 months vs. 13.1 months) (95% CI; 1.1-8.6; = 0.048). There was a trend for worse prognosis in patients with high BRD4 protein levels versus intermediate/low BRD4 protein expression both at 12 months (9.8 months vs. 7.6 months; = 0.3) and at 24 months (14.2 months vs. 16.6 months; = 0.56) although not statistically significant. Again, there was a trend for shorter PFS in patients with high BRD4 protein expression although not statistically significant both at 12 months ( = 0.29) and at 24 months ( = 0.47).
CONCLUSIONS
There are contradictory data in the literature over the prognostic role of BRD4 gene expression in solid tumors. In our study, intermediate/high BRD4 gene expression was associated with a favorable prognosis in terms of overall survival and progression-free survival compared to low BRD4 gene expression.
PubMed: 38893083
DOI: 10.3390/cancers16111962 -
Frontiers in Immunology 2024Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and peritoneal dissemination is one major cause for this poor prognosis. Exosomes have...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and peritoneal dissemination is one major cause for this poor prognosis. Exosomes have emerged as promising biomarkers for gastrointestinal cancers and can be found in all kinds of bodily fluids, also in peritoneal fluid (PF). This is a unique sample due to its closeness to gastrointestinal malignancies. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been identified as a potential biomarker in human cancers and represents a promising target for an immunotherapy approach, which could be considered for future treatment strategies. Here we prospectively analyzed the exosomal surface protein ROR1 (exo-ROR1) in PF in localized PDAC patients (PER-) on the one hand and peritoneal disseminated tumor stages (PER+) on the other hand followed by the correlation of exo-ROR1 with clinical-pathological parameters.
METHODS
Exosomes were isolated from PF and plasma samples of non-cancerous (NC) (n = 15), chronic pancreatitis (CP) (n = 4), localized PDAC (PER-) (n = 18) and peritoneal disseminated PDAC (PER+) (n = 9) patients and the surface protein ROR1 was detected via FACS analysis. Additionally, soluble ROR1 in PF was analyzed. ROR1 expression in tissue was investigated using western blots (WB), qPCR, and immunohistochemistry (IHC). Exosome isolation was proven by Nano Tracking Analysis (NTA), WB, Transmission electron microscopy (TEM), and BCA protein assay. The results were correlated with clinical data and survival analysis was performed.
RESULTS
PDAC (PER+) patients have the highest exo-ROR1 values in PF and can be discriminated from NC (p <0.0001), PDAC (PER-) (p <0.0001), and CP (p = 0.0112). PDAC (PER-) can be discriminated from NC (p = 0.0003). In plasma, exo-ROR1 is not able to distinguish between the groups. While there is no expression of ROR1 in the exocrine pancreatic tissue, PDAC and peritoneal metastasis show expression of ROR1. High exo-ROR1 expression in PF is associated with lower overall survival (p = 0.0482).
CONCLUSION
With exo-ROR1 in PF we found a promising diagnostic and prognostic biomarker possibly discriminating between NC, PDAC (PER-) and PDAC (PER+) and might shed light on future diagnostic and therapeutic concepts in PDAC.
Topics: Humans; Receptor Tyrosine Kinase-like Orphan Receptors; Exosomes; Male; Ascitic Fluid; Pancreatic Neoplasms; Female; Carcinoma, Pancreatic Ductal; Middle Aged; Biomarkers, Tumor; Prognosis; Aged; Peritoneal Neoplasms; Adult; Prospective Studies
PubMed: 38846943
DOI: 10.3389/fimmu.2024.1253072 -
Cureus May 2024Ascites can manifest as a result of many conditions, with cirrhosis being the most common cause in the United States. Here, we present a case of lymphocytic ascites, a...
Ascites can manifest as a result of many conditions, with cirrhosis being the most common cause in the United States. Here, we present a case of lymphocytic ascites, a less common variant that occurred due to infection with Chlamydia trachomatis. This was a 37-year-old female with a history of substance and sexual abuse who presented with the chief complaints of abdominal pain, abdominal distension, and weight gain. She was febrile on admission with a distended, tender abdomen. The more common cardiac, renal, and hepatic causes were ruled out with extensive workup. Diagnosis and therapeutic paracentesis were done with fluid analysis significant for lymphocyte predominance and absence of malignant cells. Multi-modal imaging had ruled out suspicious malignant masses but CT abdomen/pelvis did show complex large volume ascites. Urine chlamydia and gonorrhea polymerase chain reaction (PCR) had resulted positive for chlamydia, leading us to start Doxycycline. Other infectious workups were negative, but ascitic fluid chlamydia NAAT was positive. Though initially worsening, the patient started showing significant clinical improvement after starting doxycycline, with the resolution of ascites and associated symptoms. This case report intends to bring to attention the importance of testing for chlamydia infection in cases of lymphocytic ascites, especially in sexually active females.
PubMed: 38846180
DOI: 10.7759/cureus.59760 -
Journal of Surgical Case Reports Jun 2024Neuroendocrine carcinomas (NECs) of the gallbladder are very rare and aggressive tumors with poor prognosis. Most of them are poorly differentiated and belong to the...
Neuroendocrine carcinomas (NECs) of the gallbladder are very rare and aggressive tumors with poor prognosis. Most of them are poorly differentiated and belong to the small cell type. We report a case of a 59-year-old woman who presented with abdominal pain and distension. Contrast-enhanced computed tomography revealed a large heterogeneous mass in the liver, adjacent to the gallbladder, and omental nodules. CA 19-9 level was elevated and ascitic fluid cytology was suspicious for malignancy. Percutaneous biopsy of the liver mass confirmed the diagnosis of small cell NEC of the gallbladder. The patient was considered inoperable and planned for chemotherapy, but she died 20 days after admission. This case illustrates the diagnostic challenges and the dismal outcome of small cell NEC of the gallbladder. Early detection and multimodal treatment are essential for improving the survival of these patients.
PubMed: 38832057
DOI: 10.1093/jscr/rjae386 -
Journal of Family Medicine and Primary... Apr 2024Portal hypertension commonly occurs due to liver cirrhosis, and esophageal varices (EV) is one of the major complications associated with it. The most common cause of...
BACKGROUND
Portal hypertension commonly occurs due to liver cirrhosis, and esophageal varices (EV) is one of the major complications associated with it. The most common cause of death in liver cirrhosis is EV bleeding. Hence, GE screening for EV is required, which is an invasive procedure. Regular use of endoscopy results in low compliance due to cost and discomfort for patients. Hence, identifying non-invasive markers that could grade EV provides a useful screening tool for family physicians and primary health centers (PHCs) by referring the patient to higher centers for definitive treatment, which could reduce mortality due to variceal bleeding in cirrhotic patients.
AIMS
To assess non-invasive predictors of grade EV in patients diagnosed with liver cirrhosis.
SETTINGS AND DESIGN
Cross-sectional study.
METHODS AND MATERIAL
A total of 109 patients with liver cirrhosis underwent clinical and biochemical evaluation, USG abdomen with spleen bipolar diameter, ascitic fluid analysis, and upper GE with a grade of EV are recorded.
STATISTICAL ANALYSIS USED
SPSS software with Student -test, Chi-square -test, analysis of variance, receiver operator characteristic (ROC) curves, and Spearman correlation with 95% CI is used. <0.05 is considered significant.
RESULTS
Aminotransferase to Platelet count Ratio Index (APRI) score >1.815, PC/SD ≤909, and SAAG >1.1g/dl showed EV in liver cirrhosis ( < 0.05). The order of prediction with ROC curves shows APRI score > PC/SD > SAAG. In grading EV, APRI scores of 1.9-2.5 and >2.5 showed small and large EV, respectively ( < 0.05).
CONCLUSIONS
APRI score may be used in PHC as an early intervention to grade EV and refer the patient to higher centers for definitive treatment. This would prevent the progression of varices to rupture and reduce mortality due to variceal bleeds in liver cirrhosis patients.
PubMed: 38827661
DOI: 10.4103/jfmpc.jfmpc_792_23 -
Biomedicine & Pharmacotherapy =... Jul 2024Peritoneal metastases (PM) commonly occur in colorectal cancer patients. Systemic chemotherapy yields poor outcomes for these patients. It is hypothesised that...
BACKGROUND
Peritoneal metastases (PM) commonly occur in colorectal cancer patients. Systemic chemotherapy yields poor outcomes for these patients. It is hypothesised that traditional systemic chemotherapy is not very effective for this patient population. This study investigates to what extent systemic anti-cancer therapy crosses the peritoneal barrier.
METHODS
In a Phase I study, eighteen patients received systemic oxaliplatin, 5-FU, and bevacizumab. Plasma and peritoneal fluid samples were collected to measure drug concentrations. A non-compartmental analysis determined the Area Under the Curve (AUC) for oxaliplatin and 5-FU in both matrices. Intraperitoneal (IP) and intravenous (IV) exposure ratios were calculated, along with the bevacizumab concentration IP/IV ratio. The relationship between tumour load and IP/IV ratios and the correlation between the IP/IV ratios of different treatments were assessed statistically.
RESULTS
A total of 438 5-FU samples and 578 oxaliplatin samples were analysed in plasma and peritoneal fluid. Bevacizumab was quantified with 17 measurements in plasma and 15 measurements IP. Median IP/IV ratios were 0.143, 0.352 and 0.085 for 5-FU, oxaliplatin and bevacizumab, respectively. Oxaliplatin exhibited a longer IP half-life than 5-FU. A correlation was found between oxaliplatin and bevacizumab IP/IV ratios (R=0.69, p=0.01). No statistical correlations were found between the other investigated drugs.
CONCLUSIONS
Our findings indicate that only a small percentage of systemically administered anti-cancer treatment reaches the IP cavity, questioning their efficacy against PM. This strengthens the hypothesis for repeated intraperitoneal chemotherapy to reach adequate anti-cancer drug levels.
Topics: Humans; Bevacizumab; Colorectal Neoplasms; Peritoneal Neoplasms; Fluorouracil; Oxaliplatin; Male; Middle Aged; Female; Aged; Antineoplastic Combined Chemotherapy Protocols; Adult; Ascitic Fluid; Area Under Curve; Injections, Intraperitoneal
PubMed: 38810398
DOI: 10.1016/j.biopha.2024.116820 -
Advances in Experimental Medicine and... 2024Mitochondrial dysfunctions are significantly implicated in cancer initiation, progression, and metastasis, which have been shown for several cancers including ovarian... (Review)
Review
Mitochondrial dysfunctions are significantly implicated in cancer initiation, progression, and metastasis, which have been shown for several cancers including ovarian cancer.An increase in mitochondrial dysfunction is also associated with drug resistance along with cancer progression, which in part is related to its specific microenvironment that is characterized by ascites, low glucose levels, and hypoxia that causes ovarian cancer cells to switch to mitochondrial respiration to enable their survival. Peritoneal ascitic fluid accumulation is a specific feature of ovarian cancer, and it is a major cause of its metastatic spread that also presents challenges for effective treatment. Among the treatment difficulties for ovarian cancer is the mutation rate and frequency of mtDNA in ovarian cancer tissue that can affect the efficiency of chemotherapeutic drugs. The varied and multiple mutations of different types enable metabolic reprogramming, cancer cell proliferation, and drug resistance.New specific information on mechanisms underlying several of the mitochondrial dysfunctions has led to proposing various mitochondrial determinants as targets for ovarian cancer therapy, which include targeting specific mitochondrial proteins and phosphoproteins as well as reactive oxygen species (ROS) that accumulate abnormally in cancer cells. Because of the genetically and histologically heterogeneous nature of the disease, combination therapy approaches will be necessary to combat the disease and achieve progress in effective treatment of ovarian cancer. This chapter will address (1) mitochondrial vulnerabilities underlying dysfunction and disease; (2) mitochondrial dysfunction in ovarian cancer; (3) present treatment difficulties for ovarian cancer and new potential treatment strategies to target ovarian cancer mitochondrial metabolism; and (4) biobehavioral factors influencing ovarian cancer development.
Topics: Humans; Ovarian Neoplasms; Female; Mitochondria; Cell Proliferation; Reactive Oxygen Species; Neoplasm Metastasis; Tumor Microenvironment; Animals; DNA, Mitochondrial; Drug Resistance, Neoplasm
PubMed: 38805128
DOI: 10.1007/978-3-031-58311-7_7