Cervical cancer: a new era.

Cervical cancer is a major global health issue, ranking as the fourth most common cancer in women worldwide. Depending on stage, histology, and patient factors, the standard management of cervical cancer is a combination of treatment approaches, including (fertility- or non-fertility-sparing) surgery, radiotherapy, platinum-based chemotherapy, and novel systemic therapies such as bevacizumab, immune checkpoint inhibitors, and antibody-drug conjugates. While ambitious global initiatives seek to eliminate cervical cancer as a public health problem, the management of cervical cancer continues to evolve with major advances in imaging modalities, surgical approaches, identification of histopathological risk factors, radiotherapy techniques, and biomarker-driven personalized therapies. In particular, the introduction of immune checkpoint inhibitors has dramatically altered the treatment of cervical cancer, leading to significant survival benefits in both locally advanced and metastatic/recurrent settings. As the landscape of cervical cancer therapies continues to evolve, the aim of the present review is to provide a comprehensive discussion of the current state and the latest practice-changing updates in cervical cancer.

Validation of a semi-quantitative scoring system and workflow for analysis of fluorescence quantification in companion animals.

Significance: Many commercially available near-infrared (NIR) fluorescence imaging systems lack algorithms for real-time quantifiable fluorescence data. Creation of a workflow for clinical assessment and post hoc analysis may provide clinical researchers with a method for intraoperative fluorescence quantification to improve objective outcome measures. Aim: Scoring systems and verified image analysis are employed to determine the amount and intensity of fluorescence within surgical specimens both intra and postoperatively. Approach: Lymph nodes from canine cancer patients were obtained during lymph node extirpation following peritumoral injection of indocyanine green (ICG). First, a semi-quantitative assessment of surface fluorescence was evaluated. Images obtained with a NIR exoscope were analysed to determine fluorescence thresholds and measure fluorescence amount and intensity. Results: Post hoc fluorescence quantification (threshold of Hue = 165-180, Intensity = 30-255) displayed strong agreement with semi-quantitative scoring (k = 0.9734, p < 0.0001). Fluorescence intensity with either threshold of 35-255 or 45-255 were significant predictors of fluorescence and had high sensitivity and specificity (p < 0.05). Fluorescence intensity and quantification had a strong association (p < 0.001). Conclusion: The validation of the semi-quantitative scoring system by image analysis provides a method for objective in situ observation of tissue fluorescence. The utilization of thresholding for ICG fluorescence intensity allows post hoc quantification of fluorescence when not built into the imaging system.

New concept in selecting blue dye injection site effect on clinical outcome of early-stage breast cancer patients: a retrospective cohort.

BACKGROUND: Clinico-anatomical review and pilot studies demonstrated that intraparenchymal injection at any site, even those not containing the index lesion, or periareolar injections should provide concordant outcomes to peritumoral injections. METHOD: This was a single-center retrospective cohort at King Chulalongkorn Memorial Hospital. The electronic medical records of patients were characterized into conventional and new injection concept groups. The inclusion criteria were patients who had either a mastectomy or BCS along with SLNB. We excluded patients who underwent ALND, received neoadjuvant therapy, or had non-invasive breast cancer. The primary outcome was the 5-year rate of breast cancer regional recurrence. Additionally, we reported on the re-operation rate, disease-free period, distant disease-free period, mortality rate, and recurrence rates both locoregional and systemic. Recurrences were identified through clinical assessments and imaging. SURGICAL TECHNIQUE: 3 ml of 1%isosulfan blue dye was injected, with the injection site varying according to the specific concept being applied. In cases of SSM and NSM following the new concept, the blue dye was injected at non-periareolar and non-peritumoral sites. After the injection, a 10-minute interval was observed without massaging the injection site. Following this interval, an incision was made to access the SLNs, which were subsequently identified, excised, and sent for either frozen section analysis or permanent section examination. RESULT: There were no significant differences in DFS, DDFS or BCSS between the two groups (p = 0.832, 0.712, 0.157). Although the re-operation rate in the NI group was approximately half that of the CI group, this difference was not statistically significant (p = 0.355). CONCLUSION: Our study suggests that tailoring isosulfan blue dye injection site based on operation type rather than tumor location is safe and effective approach for SLN localization in early-stage breast cancer. However, this study has limitations, including being a single-center study with low recurrence and death cases. Future studies should aim to increase the sample size and follow-up period.

A Prospective Cohort Study on Neck Lymph Node Mapping in Oral Cancers Using Methylene Blue Dye.

In the current scenario, the management of N0 neck in early-stage oral cancer is debatable, whether or not they should undergo elective neck dissection. Most of the time these patients are either over-treated or under-treated. Sentinel lymph node (SLN) biopsy is a good option to identify occult LN in this cohort of patients for guiding neck dissection. With a focus on SLN biopsy using methylene blue dye, this study aims to evaluate its feasibility and accuracy in node-negative oral squamous cell carcinoma. A prospective observational study was conducted involving operable squamous cell carcinoma patients with clinically and radiologically node-negative neck. Methylene blue was injected in the peritumoral area and after that SLN was identified and then neck dissection was completed. Of 47 patients, SLN was identified in 82.98%, with 53.85% having more than two SLN. Common locations were in levels IB, IA and IIA. Occult metastasis was observed in 12.82% of cases, predominantly in T2 patients. Sensitivity, specificity and NPV were 50%, 100% and 88.89% respectively. The study affirms the feasibility and accuracy of methylene blue-assisted SLN biopsy in oral cancer. Despite a high detection rate, methylene blue dye alone should not be used for SLN identification in oral cavity cancer. However, it can be used as an adjunct of lymphoscintigraphy to increase the yield of the procedure. Multi-institutional trials with larger cohorts may provide valuable insights and more information for comprehensively addressing the limitations of this technique and its broader applicability in decision-making, particularly in resource-constrained countries like India where lymphoscintigraphy is not readily accessible.

Transvaginal natural orifice transluminal endoscopic surgery (VNOTES) retroperitoneal sentinel lymph node BIOPSY compared with conventional laparoscopy in patients with endometrial cancer.

INTRODUCTION: To explore the possibility of treatment with VNOTES sentinel lymph node dissection concept in patients with endometrial cancer. METHODS: Patients who underwent VNOTES sentinel lymph node biopsy with the Comba modification were compared to patients who underwent conventional laparoscopic sentinel lymph node biopsy performed by the same surgical team. A total of 38 patients who underwent sentinel lymph node biopsy + total laparoscopic hysterectomy and bilateral salpingo-oophorectomy (BSO) were compared with 19 patients who underwent VNOTES retroperitoneal sentinel lymph node biopsy + hysterectomy and BSO. Surgical steps were described. RESULTS: The average operation time, perioperative blood loss, the number of sentinel lymph nodes, presence of complications, and preoperative-postoperative hemoglobin-hematocrit differences, tumor stages, grades, largest tumor diameter, depths of invasion, and histological subtypes were similar in both the VNOTES and conventional laparoscopy groups. The postoperative pain scores were lower and the hospital stay was shorter in the VNOTES group than in the conventional laparoscopy group. No disease recurrence had been detected in either group at the time of writing. CONCLUSION: Compared to conventional laparoscopy, sentinel lymph node biopsy with the VNOTES technique provides similar surgical results and is more advantageous in terms of postoperative pain and hospital length of stay.

Chitosan-enclosed SLN improved SV-induced hepatocellular cell carcinoma death by modulation of IQGAP gene expression, JNK, and HDAC activities.

BACKGROUND: Hepatocellular carcinoma (HCC) is a global life-threatening problem and therapeutic interventions are still encountered. IQGAP genes are involved in HCC oncogenesis. The modulatory effect of statins on the expression of IQGAP genes is still unclear. This study aims to study the effect of free SV and chitosan (CS) decorated simvastatin (SV) loaded solid lipid nanoparticles (C-SV-SLNs) on HCC mortality. METHODS AND RESULTS: Plain, SV-SLN, and C-SV- SLN were prepared and characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI). The biosafety of different SLN was investigated using fresh erythrocytes, moreover, cytotoxicity was investigated using HepG2 cell lines. The effect of SLNs on IQGAPs gene expression as well as JNK, HDAC6, and HDAC8 activity was investigated using PCR and MOE-docking. The current results displayed that SV-SLNs have nanosized, negative ZP and are homogenous, CS decoration shifts the ZP of SLN into cationic ZP. Furthermore, all SLNs exhibited desirable biosafety in terms of no deleterious effect on erythrocyte integrity. SV solution and SV-SLN significantly increase the mortality of HepG2 compared to undertreated cells, however, the effect of SV-SLN is more pronounced compared to free SV. Remarkably, C-SV-SLN elicits high HepG2 cell mortality compared to free SV and SV-SLN. The treatment of HepG2 cells with SV solution, SV-SLN, or C-SV-SLN significantly upregulates the IQGAP2 gene with repression of IQGAP1 and IQGAP3 genes. MOE-docking studies revealed both SV and tenivastatin exhibit interactions with the active sites of JNK, HDAC6, and HDAC8. Moreover, tenivastatin exhibited greater interactions with magnesium and zinc compared to SV. CONCLUSIONS: This research provides novel insights into the therapeutic potential of SV, SV-SLN and C-SV-SLNs in HCC treatment, modulating critical signaling cascades involving IQGAPs, JNK, and HDAC. The development of C-SV-SLNs presents a promising strategy for effective HCC therapy.

Artificial intelligence assisted ultrasound for the non-invasive prediction of axillary lymph node metastasis in breast cancer.

PURPOSE: A practical noninvasive method is needed to identify lymph node (LN) status in breast cancer patients diagnosed with a suspicious axillary lymph node (ALN) at ultrasound but a negative clinical physical examination. To predict ALN metastasis effectively and noninvasively, we developed an artificial intelligence-assisted ultrasound system and validated it in a retrospective study. METHODS: A total of 266 patients treated with sentinel LN biopsy and ALN dissection at Peking Union Medical College & Hospital(PUMCH) between the year 2017 and 2019 were assigned to training, validation and test sets (8:1:1). A deep learning model architecture named DeepLabV3 + was used together with ResNet-101 as the backbone network to create an ultrasound image segmentation diagnosis model. Subsequently, the segmented images are classified by a Convolutional Neural Network to predict ALN metastasis. RESULTS: The area under the receiver operating characteristic curve of the model for identifying metastasis was 0.799 (95% CI: 0.514-1.000), with good end-to-end classification accuracy of 0.889 (95% CI: 0.741-1.000). Moreover, the specificity and positive predictive value of this model was 100%, providing high accuracy for clinical diagnosis. CONCLUSION: This model can be a direct and reliable tool for the evaluation of individual LN status. Our study focuses on predicting ALN metastasis by radiomic analysis, which can be used to guide further treatment planning in breast cancer.

Feasibility and Diagnostic Accuracy of Ultrastaging in the Detection of Micrometastases in Sentinel and Non-sentinel Lymph Nodes in Cervical Cancer: A Single-Center Retrospective Study With a Five-Year Follow-Up Period.

BACKGROUND: Cervical cancer is the fourth most common cause of malignant tumor-related deaths among women in developing nations. Cervical cancer has been estimated to cause 527.600 new cases and 265.700 deaths globally per year. OBJECTIVES: This study aimed to evaluate patients with cervical cancer by ultrastaging all the lymph nodes (LN), sentinel LN (SLN) and non-SLN, to increase the sensitivity of the detection of LN metastases and the diagnostic accuracy in cervical cancer with a five-year follow-up. MATERIALS AND METHODS: This is a retrospective study of 14 cervical cancer cases from 2017 to 2019 at the Municipal Emergency Clinical Hospital of Timisoara, Romania. The cases were selected based on their high risk of LN involvement but negative intraoperative pathologic LN. After re-evaluating all paraffin block biopsy samples from 29 cases, 14 cases were included in the study, which met all criteria for ultrastaging on surgical biopsy samples. RESULTS: Patients' ages included in the study ranged from 43 to 70 years (median: 57.14 years). According to the International Federation of Gynecology and Obstetrics (FIGO) staging, the majority of the patients were in stage IB: seven cases (50%). The study revealed a positive correlation between patient age and FIGO staging, with Pearson's correlation coefficient of 0.707 and a p-value of less than 0.05, indicating that older patients were more likely to be diagnosed with a higher FIGO stage. The mean follow-up was 34.5 months, and the median follow-up was 36 months (range: 6-60 months). We obtained 167 nodes, with a mean of 11.92 nodes/case. Twenty-one LN were found to be positive with the ultrastaging method. We detected 11 LN with macrometastases (MAC) (52.38%), seven with micrometastasis (MIC) (33.3%), and three with tumor cell islets (14.4%). That would be 13% of newly diagnosed ultrastaging cases as positive nodes. This ultrastaging method detected nodal MIC in eight (57.1%) out of the 14 patients, who initially tested negative for LN involvement using the routine Hematoxylin and Eosin (HE) method. The detection of micrometastases in these patients underscored the superior sensitivity of ultrastaging, which was further highlighted by the subsequent relapse of four (28.57%) out of these eight patients. The study also found no correlation between the FIGO standardization and the number of MIC found in these patients. CONCLUSIONS: Predicting cervical LN metastasis (LNM) is crucial for improving survival rates and reducing recurrence. Very few small cohort studies used an ultrastaging method to assess non-SLNs; most of them only assessed SLNs. We showed in our study that the ultrastaging method, both in the case of SLN and non-SLN, is superior compared with H&E analysis, with a 13% rate of new positive nodule diagnosis. Metastatic involvement of non-SLN was found in over 50% of all cases (8/14) according to the ultrastaging method. Additionally, our study confirms that the sensitivity of SLN ultrastaging is high for the presence of both MIC and MAC in SLN pelvic LN. As a result, we feel that ultrastaging is the most effective method for SLN analysis in patients with early-stage cervical cancer, and bilateral detection is preferable, significantly reducing false-negative results. The routine use of SLN along with ultrastaging would lead to more accurate surgical staging and better oncological follow-up of cases.

The Incidence of Breast Cancer Lymph Node Involvement in Trinidad and Tobago.

Objective This study aims to investigate breast cancer lymph node involvement in a West Indian population while correlating it with various histological parameters and evaluating the role of the sentinel lymph node biopsy. Method This is a retrospective study where histology reports for all breast cancer-related biopsies from 2018 to 2021, totaling 813 samples, were obtained. Histological parameters from these reports were extracted into a spreadsheet and analyzed using Statistical Product and Service Solutions (SPSS, version 28.0; IBM SPSS Statistics for Windows, Armonk, NY) software for TNM staging and axillary and sentinel lymph node dissections, among other fields found in histology reports. Results In 44.8% of cases, patients present at the T2 stage with associated lymph node spread. Each T stage had more lymph nodes involved than uninvolved for tumors sized T2 and higher. Inversely, for tumors staged under T2, there were generally more uninvolved lymph nodes than involved ones. Larger tumors were found to have advanced N staging, especially in the T3 category, where a significantly higher proportion of cases were found to have N2 and N3 staging compared to the other T stages. This trend is also seen in M staging, where larger tumors metastasize more than smaller tumors (40% for T4a, 0% for T1). Despite significant lymph node involvement being observed, sentinel lymph node biopsies were usually negative. Conclusion More patients in this population present with lymph node involvement than without. Larger breast cancer tumors are associated with greater lymph node involvement, particularly at T2 and higher stages. Sentinel lymph node biopsies can be omitted in smaller breast cancer tumors up to 2 cm in size, and the local recurrence rate is low despite a false-negative rate of around 10% in upfront sentinel lymph node biopsy.

Lipid-Based Nanocarrier by Targeting with LHRH Peptide: A Promising Approach for Prostate Cancer Radio-Imaging and Therapy.

Prostate cancer is a prevalently detected malignancy with a dismal prognosis. Luteinizing-hormone-releasing-hormone (LHRH) receptors are overexpressed in such cancer cells, to which the LHRH-decapeptide can specifically bind. A lipid-polyethylene glycol-conjugated new LHRH-decapeptide analogue (D-P-HLH) was synthesized and characterized. D-P-HLH-coated and anticancer drug doxorubicin (DX)-loaded solid lipid nanoparticles (F-DX-SLN) were formulated by the cold homogenization technique and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, differential scanning calorimetry, dynamic light scattering, electron microscopy, entrapment efficiency, and drug-release profile studies. F-DX-SLN allows site-specific DX delivery by reducing the side effects of chemotherapy. Cancer cells could precisely take up F-DX-SLN by targeting specific receptors, boosting the cytotoxicity at the tumor site. The efficacy of F-DX-SLN on PC3/SKBR3 cells by the MTT assay revealed that F-DX-SLN was more cytotoxic than DX and/or DX-SLN. Flow cytometry and confocal microscopic studies further support F-DX-SLNs' increased intracellular absorption capability in targeting LHRH overexpressed cancer cells. F-DX-SLN ensured high apoptotic potential, noticeably larger mitochondrial transmembrane depolarization action, as well as the activation of caspases, a longer half-life, and greater plasma concentration. F-DX-SLN/DX-SLN was radiolabeled with technetium-99m; scintigraphic imaging studies established its tumor selectivity in PC3 tumor-bearing nude mice. The efficacy of the formulations in cancer treatment, in vivo therapeutic efficacy tests, and histopathological studies were also conducted. Results clearly indicate that F-DX-SLN exhibits sustained and superior targeted administration of anticancer drugs, thus opening up the possibility of a drug delivery system with precise control and targeting effects. F-DX-SLN could also provide a nanotheranostic approach with improved efficacy for prostate cancer therapy.

Preparation and characterization of novel nanostructured lipid carriers (NLC) and solid lipid nanoparticles (SLN) containing coenzyme Q10 as potent antioxidants and antityrosinase agents.

We developed novel and optimal Q10-NLC/SLN formulations as antioxidant and anti-tyrosinase agents. The formulations were analyzed for particle size, morphology, entrapment efficiency (EE %), and long-term stability. The in vitro drug release and in vivo skin penetration were evaluated using dialysis bag diffusion and Sprague Dawley (SD) rats, respectively. Cytotoxicity and protecting effects were assessed by AlamarBlue® assay, ROS level by DCFH-DA, and tyrosinase activity by l-DOPA assay, measuring the absorbance at 470 nm. The selected formulations had optimal surface characterizations, including Z-average size, PDI, and Zeta potential ranging from 125 to 207 nm, 0.09-0.22, and -7 to -24, respectively. They also exhibited physiochemical stability for up to 6 months and EE% above 80 %. The lipids ratio and co-Q10 amount as variable factors significantly affected particle size and zeta potential but were insignificant on PDI. The in vitro release diagram showed that Q10-NLC/SLN revealed a fast release during the first 8 h and prolonged release afterward. The in vivo skin permeation revealed a higher accumulative uptake of co-Q10 in the skin for Q10-NLC/SLN compared to Q10 emulsions. Both selected Q10-NLC and Q10-SLN could reduce intracellular ROS after exposure to H2O2. The Q10-NLC was found to be more potent for inhibiting the tyrosinase activity compared to O10-SLN. The results suggest that the new formulations are promising carriers for topical delivery of co-Q10 as an anti-aging and skin-whitening agent.

Combination of Etoposide and quercetin-loaded solid lipid nanoparticles Potentiates apoptotic effects on MDA-MB-231 breast cancer cells.

Background: Breast cancer is a major global cancer, for which radiation and chemotherapy are the main treatments. Natural remedies are being studied to reduce the side effects. Etoposide (ETO), a chemo-drug, and quercetin (QC), a phytochemical, are considered potential factors for adaptation to conventional treatments. Objectives: The anticancer effect of the synergy between ETO and Quercetin-loaded solid lipid nanoparticles (QC-SLNs), was investigated in MDA-MB-231 cells. Methods: We developed QC-SLNs for efficient cellular delivery, characterizing their morphology, particle size, and zeta potential. We assessed the cytotoxicity of QC-SLNs and ETO on breast cancer cells via the MTT assay. Effects on apoptosis intensity in MDA-MB-231 cells have been detected utilizing annexin V-FITC, PI, and caspase activities. Real-time PCR assessed Bax gene and Bcl-2 gene fold change expression, while Western blot analysis determined p53 and p21 protein levels. Results: Spherical, negatively charged QC-SLNs, when combined with ETO, significantly enhanced inhibition of MDA-MB-231 cell proliferation compared to ETO or QC-SLNs alone. The combined treatment also notably increased the apoptosis pathway. QC-SLNs + ETO increased the Bax/Bcl-2 gene ratio, elevated p53 and p21 proteins, and activated caspase 3 and 9 enzymes. These results indicate the potential for QC-SLNs + ETO as a strategy for breast cancer treatment, potentially overcoming ETO-resistant breast cancer chemoresistance. Conclusion: These results suggest that QC-SLN has the potential to have a substantial impact on the breast cancer cure by improving the efficacy of ETO. This enhancement could potentially help overcome chemoresistance observed in ETO-resistant breast cancer.

Evaluating the added value of synthetic magnetic resonance imaging in predicting sentinel lymph node status in breast cancer.

Background: The noninvasive prediction of sentinel lymph node (SLN) metastasis using quantitative magnetic resonance imaging (MRI), particularly with synthetic MRI (syMRI), is an emerging field. This study aimed to explore the potential added benefits of syMRI over conventional MRI and diffusion-weighted imaging (DWI) in predicting metastases in SLNs. Methods: This retrospective study consecutively enrolled 101 patients who were diagnosed with breast cancer (BC) and underwent SLN biopsy from December 2022 to October 2023 at the Affiliated Hospital of Jiangnan University. These patients underwent preoperative MRI including conventional MRI, DWI, and syMRI and were categorized into two groups according to the postoperative pathological results: those with and without metastatic SLNs. MRI morphological features, DWI, and syMRI-derived quantitative parameters of breast tumors were statistically compared between these two groups. Binary logistic regression was used to separately develop predictive models for determining the presence of SLN involvement, with variables that exhibited significant differences being incorporated. The performance of each model was evaluated through receiver operating characteristic (ROC) curve analysis, including the area under the curve (AUC), sensitivity, and specificity. Results: Compared to the group of 54 patients with BC but no metastatic SLNs, the group of 47 patients with BC and metastatic SLNs had a significantly larger maximum axis diameter [metastatic SLNs: median 2.40 cm, interquartile range (IQR) 1.50-3.00 cm; no metastatic SLNs: median 1.80 cm, IQR 1.37-2.50 cm; P=0.03], a higher proton density (PD) (78.44±11.92 vs. 69.20±10.63 pu; P<0.001), and a lower apparent diffusion coefficient (ADC) (metastatic SLNs: median 0.91×10-3 mm2/s, IQR 0.79-1.01 mm2/s; no metastatic SLNs: median 1.02×10-3 mm2/s, IQR 0.92-1.12 mm2/s; P=0.001). Moreover, the prediction model with maximum axis diameter and ADC yielded an AUC of 0.71 [95% confidence interval (CI): 0.618-0.802], with a sensitivity of 78.72% and a specificity of 51.85%; After addition of syMRI-derived PD to the prediction model, the AUC increased significantly to 0.86 (AUC: 0.86 vs. 0.71; 95% CI: 0.778-0.922; P=0.002), with a sensitivity of 80.85% and a specificity of 81.50%. Conclusions: Combined with conventional MRI and DWI, syMRI can offer additional value in enhancing the predictive performance of determining SLN status before surgery in patients with BC.

Spexin Diminishes Atrial Fibrillation Vulnerability by Acting on Galanin Receptor 2.

BACKGROUND: G protein-coupled receptors play a critical role in atrial fibrillation (AF). Spexin is a novel ligand of galanin receptors (GALRs). In this study, we investigated the regulation of spexin and GALRs on AF and the underlying mechanisms. METHODS: Global spexin knockout (SPX-KO) and cardiomyocyte-specific GALRs knockout (GALR-cKO) mice underwent burst pacing electrical stimulation. Optical mapping was used to determine atrial conduction velocity and action potential duration. Atrial myocyte action potential duration and inward rectifying K+ current (IK1) were recorded using whole-cell patch clamps. Isolated cardiomyocytes were stained with Fluo-3/AM dye, and intracellular Ca2+ handling was examined by CCD camera. A mouse model of AF was established by Ang-II (angiotensin II) infusion. RESULTS: Spexin plasma levels in patients with AF were lower than those in subjects without AF, and knockout of spexin increased AF susceptibility in mice. In the atrium of SPX-KO mice, potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) and sarcolipin (SLN) were upregulated; meanwhile, IK1 current was increased and Ca2+ handling was impaired in isolated atrial myocytes of SPX-KO mice. GALR2-cKO mice, but not GALR1-cKO and GALR3-cKO mice, had a higher incidence of AF, which was associated with higher IK1 current and intracellular Ca2+ overload. The phosphorylation level of CREB (cyclic AMP responsive element binding protein 1) was upregulated in atrial tissues of SPX-KO and GALR2-cKO mice. Chromatin immunoprecipitation confirmed the recruitment of p-CREB to the proximal promoter regions of KCNJ2 and SLN. Finally, spexin treatment suppressed CREB signaling, decreased IK1 current and decreased intracellular Ca2+ overload, which thus reduced the inducibility of AF in Ang-II-infused mice. CONCLUSIONS: Spexin reduces atrial fibrillation susceptibility by inhibiting CREB phosphorylation and thus downregulating KCNJ2 and SLN transcription by GALR2 receptor. The spexin/GALR2/CREB signaling pathway represents a novel therapeutic avenue in the development of agents against atrial fibrillation.

Delivery of Chlorambucil to the Brain Using Surface Modified Solid Lipid Nanoparticles.

The delivery of drugs to the brain in the therapy of diseases of the central nervous system (CNS) remains a continuing challenge because of the lack of delivery systems that can cross the blood-brain barrier (BBB). Therefore, there is a need to develop an innovative delivery method for the treatment of CNS diseases. Thus, we have investigated the interaction of γ-aminobutyric acid (GABA) and S-(-)-γ-amino-α-hydroxybutyric acid (GAHBA) with the GABA receptor by performing a docking study. Both GABA and GAHBA show comparable binding affinities toward the receptor. In this study, we developed surface-modified solid lipid nanoparticles (SLNs) using GAHBA-derived lipids that can cross the BBB. CLB-loaded SLNs were characterized by a number of methods including differential scanning calorimetry, dynamic light scattering, UV-vis spectroscopy, and transmission electron microscopy. The blank and CLB-loaded SLN suspensions were found to exhibit good storage stability. Also, the SLNs showed a higher encapsulation efficiency for CLB drugs. In vitro release kinetics of CLB at physiological temperature was also investigated. The results of the in vitro cell cytotoxicity assay and flow cytometry studies in the human glioma U87MG cell line and human prostate cancer PC3 cell line suggested a higher efficacy of the GAHBA-modified CLB-loaded SLNs in U87MG cells. The transcription level of GABA receptor expression in the target organ and cell line was analyzed by a reverse transcription polymerase chain reaction study. The in vivo biodistribution and brain uptake in C57BL6 mice and SPECT/CT imaging in Wistar rats investigated using 99mTc-labeled SLN and autoradiography suggest that the SLNs have an increasing brain uptake. We have demonstrated the delivery of the anticancer drug chlorambucil (CLB) to glioma.

A prospective study evaluating an optimized sentinel node algorithm in early stage cervical cancer: The PROSACC-study.

OBJECTIVE: A single center prospective non-randomized study to assess a systematically developed anatomically-based sentinel lymph node (SLN) algorithm in cervical cancer. METHODS: Consecutive women with FIGO 2009 stage 1A2-2A1 cervical cancer undergoing robotic radical hysterectomy/trachelectomy between September 2014 and January 2023 had cervically injected Indocyanine Green (ICG) as a tracer for detection of pelvic SLN. An anatomically based surgical algorithm was adhered to; defining SLNs as the juxtauterine mapped nodes within the upper and lower paracervical lymphatic pathways including separate removal of the parauterine lymphovascular tissue (PULT). A completion pelvic lymphadenectomy was performed. Ultrastaging and immunohistochemistry was performed on SLNs, including the PULT. RESULTS: 181 women were included for analysis. Median histologic tumor size was 14.0 mm (range 2-80 mm). The bilateral mapping rate was 98.3%. As per protocol an interim analysis rejected H0 and inclusion stopped at 29 node positive women, all identified by at least one metastatic ICG-defined SLN. One woman awaiting histology at study-closure was node positive and included in the analysis. Sensitivity was 100% (95% CI, 88.4%-100%) and NPV 100% (95% CI, 97.6%-100%). In node positive women, the proximal obturator position harbored 46.1% of all SLN metastases representing the only position in 40% and 10% had isolated metastases in the PULT. CONCLUSIONS: Strictly adhering to an anatomically based SLN-algorithm including identification of parallell lymphatics within major pathways, partilularly the obturator compartment, assessment of the PULT, restricting nodal dissection to the removal of SLNs accurately identifies pelvic nodal metastatic disease in early-stage cervical cancer.

Staff radiation doses during Sentinel Lymph Node procedure of breast cancer from injection to surgeon.

The Sentinel Lymph Node (SLN) or Sentinel Lymph Node Biopsy (SLNB) technique involves various professionals from different departments in clinical settings to manage breast cancer patients properly. Tracing the nodular involvement of breast cancer patients requires radiation source Tc99m labeled with colloidal albumin to be injected at the tumor site. The patient becomes a radiation source for a sufficient time, which concerns the Nuclear Medicine (NM) and surgical staff. The study aims to provide the radiation doses of staff in the NM department during the SLN scintigraphy procedure and obtain an empirical model for calculating the radiation doses to staff in the surgical department from that particular patient. Radiation doses in SLN technique for breast cancer patients are minimal, and a sufficient number of SLN biopsy procedures can be performed by hospital staff within the category of non-radiation workers.

Endometrial cancer with positive sentinel lymph nodes: pathologic characteristics of metastases as predictors of extent of lymphatic dissemination and prognosis.

OBJECTIVES: To assess predictors of extensive lymph node dissemination and non-vaginal recurrence in patients with endometrial cancer with positive sentinel lymph nodes (SLNs). METHODS: Patients with endometrial cancer who underwent primary surgery with SLN mapping and had at least one positive node between October 2013 and May 2019 were included. Positive SLNs were reviewed, and cases were classified according to the location of the metastasis (extracapsular vs intracapsular), and the size of the largest SLN metastasis (isolated tumor cells, micrometastasis, macrometastasis). Associations were assessed based on fitting logistic regression models and Cox proportional hazards models. RESULTS: A total of 103 patients met the inclusion criteria: including 36 (34.9%) with isolated tumor cells, 27 (26.2%) with micrometastasis, and 40 (38.8%) with macrometastasis. Notably, 71.4% of patients exhibiting extracapsular SLN metastases had multiple positive SLNs (p=0.008). Extracapsular invasion (adjusted odds ratio (aOR) 5.81, 95% CI 1.4 to 23.6) and age (aOR=1.8, 95% CI 1.1 to 3.0) emerged as independent predictors of multiple positive SLNs. Among the 38 patients who underwent a backup pelvic lymphadenectomy, 18 (47.4%) presented with positive pelvic non-SLNs, a phenomenon more prevalent in patients with macrometastasis (p=0.004).Independent predictors of non-vaginal recurrence included SLN macrometastasis (adjusted hazard ratio (aHR) 3.3, 95% CI 1.3 to 8.3), non-endometrioid histology (aHR=3.7, 95% CI 1.5 to 9.3), and cervical stromal invasion (aHR=5.5, 95% CI 2.0 to 14.9). Among the 34 patients with isolated tumor cells and endometrioid histology, 3 (9%) experienced a recurrence, all of whom had not received any adjuvant chemotherapy or external beam radiotherapy. CONCLUSION: Patients with positive SLN macrometastasis are independently associated with extensive lymphatic dissemination and distant recurrences. The risk of multiple positive SLNs increases with the extracapsular location of the SLN metastasis and with age. Independent uterine pathologic predictors of non-vaginal recurrence are non-endometrioid histology and cervical stromal invasion.

The value of the improved percutaneous and intravenous contrast-enhanced ultrasound diagnostic classification in sentinel lymph nodes of breast cancer.

Background: Metastatic burden of sentinel lymph node (SLN) in breast cancer patient is the basis for the decision to choose SLN biopsy or axillary lymph node dissection (ALND). However, the diagnostic performance of the previous percutaneous contrast-enhanced ultrasound (P-CEUS) and intravenous contrast-enhanced ultrasound (IV-CEUS) pattern were not satisfied. This study aimed to establish new classification based on structural characteristics for P-CEUS and IV-CEUS of SLN in breast cancer and evaluate the diagnostic efficacy. Methods: This retrospective study included consecutive breast cancer patients who had not received neoadjuvant therapy in the First Affiliated Hospital of Sun Yat-sen University between June 2019 and December 2021. Conventional ultrasound, P-CEUS and IV-CEUS were performed. The new classification methods for P-CEUS and IV-CEUS of SLN were established based on structural characteristics of SLN. Pathology was considered as the gold standard, the diagnostic efficacy of P-CEUS, IV-CEUS and combined contrast-enhanced ultrasound in SLNs was analyzed. Results: The detection rate of SLN by P-CEUS in 368 patients was 95.42%. The P-CEUS pattern of SLNs was divided into six types. The IV-CEUS sequence was divided into three types. The IV-CEUS mode was divided into four types. Among the 438 SLNs detected by P-CEUS, 105 (23.97%) were malignant and 333 (76.03%) were benign. Among the previously classified P-CEUS, P-CEUS, IV-CEUS and combined contrast-enhanced ultrasound, the latter had the highest diagnostic efficacy (P<0.05), with sensitivity, specificity, positive predictive value, negative predictive value, accuracy and area under curve (AUC) of 81.90% (86/105), 97.30% (324/333), 90.53% (86/95), 94.46% (324/343), 93.61% (410/438) and 0.896 (0.864-0.923), respectively. Conclusions: The new classification of the P-CEUS and IV-CEUS features of SLNs was performed based on structural characteristics of lymph nodes. Compared with the previously classified P-CEUS, the new classification method has higher diagnostic performance. The combination of new classified P-CEUS and IV-CEUS is helpful to further improve the diagnostic performance of SLNs.