Opioid-Free Versus Opioid-Based Anesthesia on Postoperative Pain After Thoracoscopic Surgery: The Use of Intravenous and Epidural Esketamine.

BACKGROUND: The effectiveness and safety of opioid-free anesthesia (OFA) regimens in distinct types of surgeries remain controversial. In this study, we investigated whether OFA could reduce the occurrence of chronic postoperative pain in patients receiving video-assisted thoracoscopic surgery (VATS). METHODS: We conducted a 2-center, randomized, controlled trial from September 2021 to January 2022. A total of 162 lung tumor patients scheduled to undergo VATS were randomly divided into an opioid-based anesthesia (OA) group and an OFA group. The OA group received general anesthesia combined with thoracic epidural block using morphine, while the OFA group received general anesthesia combined with thoracic epidural block using esketamine. Patient-controlled epidural analgesia (PCEA) was used after surgery (ropivacaine and morphine for the OA group versus ropivacaine and esketamine for the OFA group). The primary end point was chronic pain rates at 3 months after VATS, which were analyzed using a logistic regression model. The secondary end points were chronic pain rates at 6 months, acute pain rates at 24 hours and 48 hours postoperatively, postoperative side effects, and perioperative variables. RESULTS: The final analysis included 159 patients. Acute postoperative pain at 24 hours occurred in 0 of the 79 (0%) patients in the OA group and 10 of the 80 (17.5%) patients in the OFA group (odds ratio, 52.14; 95% confidence interval [CI], 6.47-420.10; P < .001). Acute postoperative pain at 48 hours occurred in 3 of the 79 (3.8%) patients in the OA group and 2 of the 80 (2.5%) patients in the OFA group (odds ratio, 2.07; 95% CI, 0.99-4.32; P = .053). In this study, none of the patients had moderate or severe pain in either group at 3 and 6 months postsurgically. Mild chronic postoperative pain at 3 months occurred in 27 of the 79 (34.2%) patients in the OA group and 14 of the 80 (17.5%) patients in the OFA group (odds ratio, 3.52; 95% CI, 1.49-8.31; P = .004). At 6 months, mild chronic pain still occurred in 23 of the 79 (29.1%) patients in the OA group and 9 of the 80 (11.3%) patients in the OFA group (odds ratio, 5.55; 95% CI, 2.01-15.33; P = .001). In addition, the OFA group included fewer patients with side effects, including nausea, vomiting, and pruritus, within 48 hours after surgery. CONCLUSIONS: Replacement of opioids by esketamine, intraoperatively as intravenous injection and epidural infusion and postoperatively as epidural infusion, reduces the incidence of mild chronic postoperative pain and side effects in patients after VATS.

The effect of enhanced recovery after minimally invasive esophagectomy: a randomized controlled trial.

BACKGROUND: The purpose of this randomized controlled trial was to determine if enhanced recovery after surgery (ERAS) would improve outcomes for three-stage minimally invasive esophagectomy (MIE). METHODS: Patients with esophageal cancer undergoing MIE between March 2016 and August 2018 were consecutively enrolled, and were randomly divided into 2 groups: ERAS+group that received a guideline-based ERAS protocol, and ERAS- group that received standard care. The primary endpoint was morbidity after MIE. The secondary endpoints were the length of stay (LOS) and time to ambulation after the surgery. The perioperative results including the Surgical Apgar Score (SAS) and Visualized Analgesia Score (VAS) were also collected and compared. RESULTS: A total of 60 patients in the ERAS+ group and 58 patients in the ERAS- group were included. Postoperatively, lower morbidity and pulmonary complication rate were recorded in the ERAS+ group (33.3% vs. 51.7%; p = 0.04, 16.7% vs. 32.8%; p = 0.04), while the incidence of anastomotic leakage remained comparable (11.7% vs. 15.5%; p = 0.54). There was an earlier ambulation (3 [2-3] days vs. 3 [3-4] days, p = 0.001), but comparable LOS (10 [9-11.25] days vs. 10 [9-13] days; p = 0.165) recorded in ERAS+ group. The ERAS protocol led to close scores in both SAS (7.80 ± 1.03 vs. 8.07 ± 0.89, p = 0.21) and VAS (1.74 ± 0.85 vs. 1.78 ± 1.06, p = 0.84). CONCLUSIONS: Implementation of an ERAS protocol for patients undergoing MIE resulted in earlier ambulation and lower pulmonary complications, without a change in anastomotic leakage or length of hospital stay. Further studies on minimizing leakage should be addressed in ERAS for MIE.

[Nucleic acid aptamer-based traditional Chinese medicine application:therapy,targeting and diagnosis].

Nucleic acid aptamers, broad-spectrum target-specific single-stranded oligonucleotides, serve as molecules in targeted therapy, targeted delivery and disease diagnosis for the treatment of tumor or microbial infection and clinical detection. Due to the existence of components in the use of traditional Chinese medicine(TCM), the target is difficult to concentrate and the specificity of treatment is poor. The effective components of TCM are toxic components, so a highly sensitive detection method is urgently needed to reduce the toxicity problem at the same time. The combined application of TCM and modern medical treatment strategy are difficult and cannot improve the therapeutic effect. Aptamers, advantageous in biosensors, aptamer-nanoparticles for targeted drug delivery, and aptamer-siRNA chimeras, are expected to connect Chinese medicinals with nanotechnology, diagnostic technology and combined therapies. We summarized the preparation, screening, and modification techniques of nucleic acid aptamers and the biomedical applications and advantages in therapy, targeting, and diagnosis, aiming at providing a reference for the in-depth research and development in TCM.

Nab-paclitaxel promotes the cancer-immunity cycle as a potential immunomodulator.

Paclitaxel is a widely used anti-tumor chemotherapeutic drug. Solvent-based paclitaxel causes bone marrow suppression, allergic reactions, neurotoxicity and systemic toxicity, which are associated with non-specific cytotoxicity and side effects of fat-soluble solvents. Studies have explored various new nano-drug strategies of paclitaxel, including nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to improve the water solubility and safety of paclitaxel. Nab-paclitaxel is a targeted solvent-free formulation that inhibits microtubule depolymerization to anticancer. It is easily taken up by tumor and immune cells owing to the nano-scaled size and superior biocompatibility. The internalized nab-paclitaxel exhibits significant immunostimulatory activities to promote cancer-immunity cycle. The aim of this study was to explore the synergistic effect of nab-paclitaxel in tumor antigen presentation, T cell activation, reversing the immunosuppressive pattern of tumor microenvironment (TME), and the synergistic effect with cytotoxic lymphocytes (CTLs) in clearance of tumor cells. The effects of nab-paclitaxel on modulation of cancer-immunity cycle, provides potential avenues for combined therapeutic rationale to improve efficacy of immunotherapy.

Arsenic compounds: The wide application and mechanisms applied in acute promyelocytic leukemia and carcinogenic toxicology.

Arsenic (As), as well as its various compounds have been widely used for nearly 4000 years either as drugs or poisons. These compounds are valuable in the treatment of various diseases ranging from dermatosis to cancer, thereby emphasizing their important roles as therapeutic agents. The ability of As compounds, especially arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL), has fundamentally altered people's understanding of the poison, and has become a major factor in the re-emergence of Western medicine candidates to treat leukemia and other solid tumors. However, long-term exposure to As has been correlated with numerous disadvantageous influences on health, particularly carcinogenesis. Importantly, accumulating evidence suggests that biotransformation of As, as a step to eliminate As from the human body, can induce alterations at the genetic and epigenetic levels, resulting in therapeutic effects or carcinogenesis. In this article, we aimed to provide a systematic overview of the primary contributions associated with As and its compounds, as well as the detailed mechanisms applied in APL cells and carcinogenic toxicology. This review may help to understand the underlying mechanisms and safe wide clinical applications of medicinal As along with its compounds.

Drug-Metabolizing Cytochrome P450 Enzymes Have Multifarious Influences on Treatment Outcomes.

Drug metabolism is a critical process for the removal of unwanted substances from the body. In humans, approximately 80% of oxidative metabolism and almost 50% of the overall elimination of commonly used drugs can be attributed to one or more of various cytochrome P450 (CYP) enzymes from CYP families 1-3. In addition to the basic metabolic effects for elimination, CYP enzymes in vivo are capable of affecting the treatment outcomes in many cases. Drug-metabolizing CYP enzymes are mainly expressed in the liver and intestine, the two principal drug oxidation and elimination organs, where they can significantly influence the drug action, safety, and bioavailability by mediating phase I metabolism and first-pass metabolism. Furthermore, CYP-mediated local drug metabolism in the sites of action may also have the potential to impact drug response, according to the literature in recent years. This article underlines the ability of CYP enzymes to influence treatment outcomes by discussing CYP-mediated diversified drug metabolism in primary metabolic sites (liver and intestine) and typical action sites (brain and tumors) according to their expression levels and metabolic activity. Moreover, intrinsic and extrinsic factors of personal differential CYP phenotypes that contribute to interindividual variation of treatment outcomes are also reviewed to introduce the multifarious pivotal role of CYP-mediated metabolism and clearance in drug therapy.

Interaction of nobiletin with methotrexate ameliorates 7-OH methotrexate-induced nephrotoxicity through endoplasmic reticulum stress-dependent PERK/CHOP signaling pathway.

Drug-induced nephrotoxicity is a frequent adverse event that contributes to acute kidney injury with tubular and/or glomerular lesions. Methotrexate (MTX) is a folate analog used against a myriad of malignancies and autoimmune diseases. Unfortunately, ambiguous renal toxicology limits its safe clinical usage. Based on our previous studies, 7-OH MTX as an overlooked oxidative metabolite of MTX was proposed to be the main culprit responsible for nephrotoxicity, while nobiletin, a naturally occurring polymethoxylated flavonoid screened from our prepared total phenolic extracts of Citrus aurantium L. (TPE-CA), was employed as a therapeutic agent for drug-drug interactions. According to the present study, nobiletin can ameliorate the renal accumulation of 7-OH MTX through the interaction with aldehyde oxidase. RNA-seq analysis revealed that 7-OH MTX was mainly related to protein processing in endoplasmic reticulum (ER) stress, with the PERK/CHOP pathway selected as the most significant for metabolic nephrotoxicity. Meanwhile, the cross-linked proteins and conducted signals were investigated by western blotting and further verified by GSK inhibition analyses. These results indicated that nobiletin protected renal function from MTX-induced nephrotoxicity by modulating metabolism and ameliorated the metabolic toxicity of 7-OH MTX on ER stress-induced PERK/CHOP conduction by maintaining Ca2+ homeostasis and reducing the production of reactive oxygen species.

pH-Responsive Fluorescence Enhanced Nanogel for Targeted Delivery of AUR and CDDP Against Breast Cancer.

INTRODUCTION: Auraptene (AUR), a natural bioactive prenyloxy coumarin, is a highly pleiotropic molecule that can bind to the MT1 receptor and can effectively reduce the proliferation and migration of breast cancer cells. Cisplatin (CDDP), as the first synthetic platinum-based anticancer drug, is widely used in the clinic due to its definite mechanism and therapeutic effect on diverse tumors. However, both of AUR and CDDP exhibit some disadvantages when used alone, including poor solubility, low bioavailability, lack of selectivity and systemic toxicity when they are used singly. METHODS: Therefore, the biodegradable materials hyaluronic acid (HA) and ß-cyclodextrin derivative (mono-(6-amino-mono-6-deoxy)-ß-CD, CD) were employed as carriers to load AUR and CDDP to form nanogel (CDDPHA-CD@AUR) capable of dual-targeted delivery and synergistic therapy for breast cancer and cell imaging. RESULTS: With the help of the CDDP-crosslinked CD-loaded structure, the newly synthesized nanogel exhibited excellent physiological stability and fluorescence effects. The release of AUR and CDDP was affected by the pH value, which was beneficial to the selective release in the tumor microenvironment. Cell experiments in vitro demonstrated that the nanogel could be selectively internalized by MCF-7 cells and exhibited low cytotoxicity to HK-2 cells. Antitumor experiments in vivo showed that the nanogel have better antitumor effects and lower systemic toxicity. CONCLUSION: Based on these, the nanogel loaded with AUR and CDDP have the potential for targeted delivery against breast cancer.

A review on the wide range applications of hyaluronic acid as a promising rejuvenating biomacromolecule in the treatments of bone related diseases.

Hyaluronic acid (HA) is a multifunctional high molecular weight polysaccharide produced by synoviocytes, fibroblasts, and chondrocytes, and is naturally found in many tissues and fluids, and more abundantly in articular cartilage and synovial fluid. Naturally occurring HA is thought to participate in many biological processes, such as regulation of cell adhesion and cell motility, manipulation of cell differentiation and proliferation, and providing mechanical properties to tissues (Girish and Kemparaju, 2007). Due to its excellent physicochemical properties such as high viscosity, elasticity, biodegradability, biocompatibility, nontoxicity, and nonimmunogenicity, HA based formulations have a wide range of applications and serves as a promising rejuvenating biomacromolecule in biomedical applications. In recent decades, HA is currently a popular topic, and has been widely used in bone related diseases for its remarkable efficacy in articular cartilage lubrication, analgesia, anti-inflammation, immunomodulatory, chondroprotection, anti-cancer and etc. Moreover, the safety and tolerability of HA based formulations have also been well-documented for treatment of various types of bone related diseases (Chen et al., 2018). This review gives a deep understanding on the special benefits and provides a mechanism-based rationale for the use of HA in bone related diseases conditions with special reference to osteoarthritis (OA), rheumatoid arthritis (RA), bone metastatic cancers.

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers.

Multidrug resistance (MDR) is the dominant challenge in the failure of chemotherapy in cancers. Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that spreads intracellular signal cascades and regulates a variety of cellular processes. PI3Ks are considered significant causes of chemoresistance in cancer therapy. Protein kinase B (AKT) is also a significant downstream effecter of PI3K signaling, and it modulates several pathways, including inhibition of apoptosis, stimulation of cell growth, and modulation of cellular metabolism. This review highlights the aberrant activation of PI3K/AKT as a key link that modulates MDR. We summarize the regulation of numerous major targets correlated with the PI3K/AKT pathway, which is further related to MDR, including the expression of apoptosis-related protein, ABC transport and glycogen synthase kinase-3 beta (GSK-3ß), synergism with nuclear factor kappa beta (NF-κB) and mammalian target of rapamycin (mTOR), and the regulation of glycolysis.

AuNPs as an important inorganic nanoparticle applied in drug carrier systems.

Gold nanoparticles (AuNPs), as a kind of inorganic nanoparticle, have been gradually recognized as one of the most promising nanomaterials, which is attributed to their unique optical, electronic, sensing and biochemical characteristics. Due to such unique characteristics, AuNPs have been widely applied in biomedical fields such as diagnosis, biosensing and drug delivery. Except for their use in cancer treatment alone with their photothermal ablation of solid tumours, when used with anticancer drugs, AuNPs can exert a dual role in treating cancer. With the advantages of protecting drugs from degradation and leakage in the physiological environment, tuneable modification in size, surface and shape, and biocompatibility, AuNPs can be used as promising drug carriers in anticancer drug design. However, there are still many aspects that need to be improved during the usage of drug carriers in pharmacology including the following aspects: prolongation in the plasma, enhancement in targeting accumulation, improvement in cellular uptake and the control of intracellular release. AuNPs are important drug carriers.

pH- and enzyme-triggered drug release as an important process in the design of anti-tumor drug delivery systems.

It is necessary to design a reasonable drug delivery system(DDS) for targeted release to overcome the potential toxicity and poor selectivity of anti-tumor drug. How a drug is released from a DDS is a critical issue that determines whether the DDS is designed successfully. We all know that the microenvironment of tumors is quite different from normal tissues, such as its acidic environment, different expression levels of some enzymes, etc. These features are widely used in the design of DDSs and play an important role in the drug release process in vivo. Numerous DDSs have been designed and synthesized. This article attention to how drugs are released from DDSs. We summarizes and classify the characteristic enzymes and chemical bonds used in the drug release process by browsing a large number of papers, and describes how they are applied in DDSs with specific examples. By understanding these acid-sensitive chemical bonds and over-expressed enzymes in tumors, different DDSs can be designed for different drug structures to solve specific problems of anti-tumor drugs.

Unusual case of primary spontaneous hemopneumothorax in a young man with atypical tension pneumothorax: a case report.

BACKGROUND: Spontaneous life-threatening hemopneumothorax is an atypical but treatable entity of unexpected circulatory collapse in young patients, affecting 0.5-11.6% of patients with primary spontaneous pneumothorax. Spontaneous pneumothorax is a well-documented disorder with a classic clinical presentation of acute onset chest pain and shortness of breath. This disorder might be complicated by the development of hemopneumothorax or tension pneumothorax. CASE PRESENTATION: A 23-year-old Asian man was referred to the emergency room of Xiamen Chang Gung Memorial Hospital with a 1-day history of right-sided chest pain that had been aggravated for 1 hour. A physical examination revealed a young man who was awake and alert but in mild to moderate painful distress. His vital parameters were relatively stable at first. The examining physician noted slight tenderness along the right posterolateral chest wall along the eighth and tenth ribs. Primary spontaneous pneumothorax was considered, and a standing chest X-ray confirmed the diagnosis. A right thoracostomy tube was immediately placed under sterile conditions, and he was referred to the respiratory service. While in the respiratory department, approximately 420 mL of blood was drained from the thoracostomy tube over 15 minutes. Our patient developed obvious hemodynamic instability with hypovolemic shock and was subsequently admitted to the cardiothoracic surgical ward after fluid resuscitation. During the ensuing 4 hours after admission, 750 mL of blood was drained through the thoracostomy tube. A bedside chest X-ray was requested after he was temporarily hemodynamically stabilized. Primary spontaneous hemopneumothorax associated with right tension pneumothorax was considered based on the radiological impression and clinical signs. An emergency limited posterolateral thoracotomy was performed. A standing chest X-ray performed on day 6 of admission after the removal of the thoracostomy tube showed a complete re-expansion of his right lung. He remained stable and was discharged within 1 week. CONCLUSIONS: The successful treatment of a large spontaneous hemopneumothorax depends on early recognition, proactive intervention, and early consideration by a cardiothoracic surgeon. Once the diagnosis is confirmed, early thoracotomy should be considered. Such an aggressive surgery not only leads to shorter hospitalization but also confers better long-term outcomes.

Successful treatment following early recognition of a case of Fournier's scrotal gangrene after a perianal abscess debridement: a case report.

BACKGROUND: Fournier's gangrene is an acute surgical emergency characterized by high mortality rates ranging from approximately 13% to 45%. Therefore, aggressive multidisciplinary management is necessary. CASE PRESENTATION: A 29-year-old Asian man who had undergone surgical debridement at another hospital to treat a perianal abscess 5 days earlier was admitted to our hospital for severe scrotal and perianal pain, swelling, and high fever. A physical examination revealed a perianal abscess. Furthermore, the scrotum was gangrenous and exhibited extensive cellulitis in the perineum and bilateral inguinal area. Crepitations between the skin and fascia were palpable. A diagnosis of Fournier's gangrene was made. The patient was treated with immediate surgical debridement under general anesthesia. He received broad-spectrum antibiotics, and debridement was repeated until the wound exhibited healthy granulation. Because both testes were severely exposed, they were transpositioned back into the scrotum 1 week after surgery. The patient was discharged on the 11th postoperative day. CONCLUSIONS: The mainstay of treatment for Fournier's gangrene should include fluid resuscitation, broad-spectrum antibiotic therapy, intensive care, nutritional support, and early aggressive surgical debridement of all necrotic tissue.

A novel minimal invasive mouse model of extracorporeal circulation.

Extracorporeal circulation (ECC) is necessary for conventional cardiac surgery and life support, but it often triggers systemic inflammation that can significantly damage tissue. Studies of ECC have been limited to large animals because of the complexity of the surgical procedures involved, which has hampered detailed understanding of ECC-induced injury. Here we describe a minimally invasive mouse model of ECC that may allow more extensive mechanistic studies. The right carotid artery and external jugular vein of anesthetized adult male C57BL/6 mice were cannulated to allow blood flow through a 1/32-inch external tube. All animals (n = 20) survived 30 min ECC and subsequent 60 min observation. Blood analysis after ECC showed significant increases in levels of tumor necrosis factor α, interleukin-6, and neutrophil elastase in plasma, lung, and renal tissues, as well as increases in plasma creatinine and cystatin C and decreases in the oxygenation index. Histopathology showed that ECC induced the expected lung inflammation, which included alveolar congestion, hemorrhage, neutrophil infiltration, and alveolar wall thickening; in renal tissue, ECC induced intracytoplasmic vacuolization, acute tubular necrosis, and epithelial swelling. Our results suggest that this novel, minimally invasive mouse model can recapitulate many of the clinical features of ECC-induced systemic inflammatory response and organ injury.

Successful hybrid method to occlude a narrowed persistent left superior vena cava after cardiac surgery.

A 25-year old woman with complicated cyanotic heart disease and a large persistent left superior vena cava (PLSVC) with dysplasia of the innominate vein draining into the left atrium underwent cardiac surgery. Six months later, the narrowed PLSVC was successfully occluded using a muscular ventricular septal occluder (nitinol wire mesh). No complications occurred during or immediately following the catheterization. This case report is the first to describe the utilization of a hybrid method to occlude a narrowed PLSVC after cardiac surgery.

[Establishment and evaluation of extracorporeal circulation model in rats].

OBJECTIVE: To establish an extracorporeal circulation (ECC) rat model, and evaluate the inflammatory response and organ injury induced in the model. METHODS: SD rats were anesthetized and cannulated from right common carotid artery to left femoral vein to establish the bypass of extracorporeal circulation. Then the rats were randomly divided into ECC group and sham group. The rats in ECC group were subjected to extracorporeal circulation for 2 hours and then rest for 2 hours, while the rats in sham group were only observed for 4 hours without extracorporeal circulation. After that, blood routine examination, blood gas analysis, the measurement of pro-inflammatory factors in bronchoalveolar lavage fluid and lung tissue were performed to evaluate the lung injury induced by ECC. Circulating endothelial cells were also calculated by flow cytometry to assess the vascular endothelial injury. RESULTS: At 2 hours after ECC, red blood cell counts in both groups kept normal, while leukocyte and neutrophil counts, plasmatic tumor necrosis factor-a level and neutrophil elastase level, circulating endothelial cells in the rats of ECC group were significantly higher than those in sham group. Tumor necrosis factor-alpha in bronchoalveolar lavage fluid and water content in lung of the ECC rats were also significantly higher, while the oxygenation index was significantly lower. Neutrophil infiltration was also observed in lung tissues with increased thickness of alveolar membrane in ECC group. CONCLUSION: The ECC model established from right common carotid artery to left femoral vein in our study can successfully induce systemic inflammatory response, and acute lung injury associated with inflammation.