Ketamine Promoted Breast Cancer Invasion and Metastasis Through Up-regulating Wnt, BMP, and EGFR Signaling.

BACKGROUND/AIM: In this study, we used an orthotropic breast cancer model combined with ketamine addiction and next-generation sequencing (NGS) to comprehensively investigate molecular alterations in ketamine-mediated metastasis. Ketamine is widely used in anesthesia and drug abuse. Our previous study revealed that ketamine promotes the growth of breast cancer cells; however, the detailed molecular mechanism remains unknown. MATERIALS AND METHODS: An orthotropic breast cancer model was established by injecting EO771 breast cancer cells into the mammary fat pad of mice intraperitoneally administered ketamine (30 mg/kg, daily) for 68 days. Tumors collected at day 38 were frozen for future analysis, and their metastasis state was checked at day 68. RESULTS: Tumors were grouped and subjected to NGS analysis, followed by differential gene expression analysis (DEseq) and pathway identification. DEseq analysis showed that ketamine up-regulated metastasis-related signaling, and the key genes were BMP5, FZD6, MMP1B, EGFR, WNT5A, BMP7, and DCN. CONCLUSION: Ketamine addiction up-regulates the expression of genes involved in the Wnt, EGFR, and BMP signaling cascades, which may be associated with breast cancer progression and metastasis.

Massive pulmonary embolism in Klippel-Trenaunay syndrome after leg raising: A case report.

BACKGROUND: Klippel-Trenaunay syndrome (KTS) is a rare congenital disorder characterized by a combination of capillary malformations, soft-tissue or bone hypertrophy, and varicose veins or venous malformations. The syndrome predisposes patients to hypercoagulable states, including venous thromboembolism and pulmonary embolism (PE). CASE SUMMARY: A 12-year-old girl with KTS was scheduled excision of verrucous hyperkeratosis in the left foot and posterior aspect of the left leg and left thigh and excision of a cutaneous hemangioma in the right buttock. After induction, the surgeon elevated the patient's leg for sterilization, whereupon she experienced a massive PE and refractory cardiac arrest. Extracorporeal membrane oxygenation (ECMO) was performed after prolonged resuscitation, and she had a return of spontaneous circulation. After this episode, the patient was discharged without any neurologic complications. CONCLUSION: The mechanism of PE, a lethal disease, involves a preexisting deep vein thrombosis that is mechanically dislodged by compression or changing positions and travels to the pulmonary artery. Therefore, patients predisposed to PE should be prescribed prophylactic anticoagulants. If the patient has unstable vital signs, resuscitation should be started immediately, and extracorporeal cardiopulmonary resuscitation should be considered in settings with existing ECMO protocols, expertise, and equipment. Awareness of PE in patients with KTS while leg raising for sterilization is critical.

Ketamine promotes breast tumor growth in a mouse breast tumor model involving with high expression of miR-27b-3p and EGFR.

Non-medical use of ketamine as an adulterant to ecstasy is more prevalent than amphetamine in Taiwan. Ketamine's effect on immunosuppression might play some functional role in tumor growth, while it is still controversial whether ketamine abuse could increase tumor growth or not. This study aimed to investigate the influence of ketamine addiction in breast tumors and related gene expressions. The effect of ketamine treatment on proliferation, colony formation, migration, and invasion of triple-negative breast cancer cell line EO771 was examined. In addition, a ketamine addiction mice model was established by intraperitoneal injection (IP) of ketamine in mice and used to investigate the effects of ketamine addiction on tumor growth and the possible mechanisms. In the in vitro studies, ketamine treatment at different concentrations did not affect EO771 cell proliferation and colony formation. But ketamine did enhance migration and invasion of EO771 cells. The in vivo experiments showed significantly increased breast tumor volume and weight in ketamine-addicted mice than in normal saline groups. miR-27b-3p level, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor (EGFR) significantly increased in tumors of ketamine addiction mice compared to control mice. In vivo evidence showed that Ketamine might increase tumor growth on the tumor microenvironment, and miR-27b-3p, HER2, and EGFR might play a role in the process.

Modified paramedian versus conventional paramedian technique in the residency training: an observational study.

BACKGROUND: Residency training includes positive and negative aspects. Well-trained doctors must be educated, but the process may bring additional risks to patients. Anesthesiologists' performance when conducting neuraxial anesthesia is related to their experience. We hypothesized that a modified neuraxial anesthesia method would improve both residency training and patient safety. METHODS: We recruited 518 patients who were scheduled for a cesarean section and used spinal anesthesia (n = 256), epidural anesthesia (n = 154), and combined spinal-epidural anesthesia (SEA; n = 108). We observed and evaluated the anesthesia performance of five second-year resident anesthesiologists in elective cesarean sections using the conventional and modified methods. The number of attempts, implant error rate, and the incidence of complications were recorded and analyzed. RESULTS: Better success puncture attempts occurred in all three groups when the modified method was applied. For the groups with an implant assessment, the complication rate and implant error rate were lower when using the modified method. We employed generalized estimating equation (GEE) analysis to correct for possible confounding factors. When using the conventional method, the resident anesthesiologists required more attempts, made more implant errors, and caused more complications in patients. CONCLUSIONS: We found that a modified method for neuraxial anesthesia could improve residency performance and patient safety. The modified method may be a suitable training process for resident anesthesiologists when practicing neuraxial anesthesia. TRIAL REGISTRATION: The study was approved by the Research Ethics Committee of National Taiwan University (IRB:200812040R) Clinicaltrials register: NCT03389672 .

Comparison of inhaled nitric oxide with aerosolized prostacyclin or analogues for the postoperative management of pulmonary hypertension: a systematic review and meta-analysis.

Background: This study aims to compare the effectiveness of inhaled prostacyclin or its analoguesversus nitric oxide (NO) in treating pulmonary hypertension (PH) after cardiac or pulmonary surgery remains unclear.Methods: PubMed, Cochrane, and Embase databases were searched for literature published prior to December 2019 using the following keywords: inhaled, nitric oxide, prostacyclin, iloprost, treprostinil, epoprostenol, Tyvaso, flolan, and pulmonary hypertension. Randomized controlled trials and multiple-armed prospective studies that evaluated inhaled NO versus prostacyclin (or analogues) in patients for perioperative and/or postoperative PH after either cardiac or pulmonary surgery were included. Retrospective studies, reviews, letters, comments, editorials, and case reports were excluded.Results: Seven studies with a total of 195 patients were included. No difference in the improvement of mean pulmonary arterial pressure (pooled difference in mean change= -0.10, 95% CI: -3.98 to 3.78, p = .959) or pulmonary vascular resistance (pooled standardized difference in mean change= -0.27, 95% CI: -0.60 to 0.05, p = .099) were found between the two treatments. Similarly, no difference was found in other outcomes between the two treatments or subgroup analysis.Conclusions: Inhaled prostacyclin (or analogues) was comparable to inhaled NO in treating PH after cardiac or pulmonary surgery.Key messagesThis study compared the efficacy of inhaled prostacyclin or its analogues versus inhaled NO to treat PH after surgery. The two types of agent exhibited similar efficacy in managing MPAP, PVR, heart rate, and cardiac output was observed.Inhaled prostacyclin may serve as an alternative treatment option for PH after cardiac or pulmonary surgery.

Evidence-based prophylaxis strategies for postoperative nausea and vomiting when considering ethnicity factor.

In most western countries, postoperative nausea and vomiting (PONV) is an important issue and prophylaxis guideline for PONV will be followed in clinical practice. We tried to conduct a review study and a local study to elucidate the incidence and severity of PONV to see if considering ethnicity factor, should we still need to follow those prophylaxis guidelines from western countries. The PubMed, and MEDLINE were consulted from January 2000 to 2018 and also Cochrane Central Register of Controlled Trials (CENTRAL 2010). The key word for searching is PONV (incidence, severity and prevention strategy), without language limitation and focus on Asian countries. The results showed that the overall incidence and severity of PONV in Asian countries was less significant than in western countries. PONV in western countries could be a serious issue and prophylaxis strategy adjusted by Apfel score could be adopted in routine practice. After this review consultation, the issue of PONV in different ethnic countries (including Taiwan) might be over emphasized and we may suggest not to follow west countries PONV prophylaxis guideline as our routine practice.

A case of congenital long QT syndrome, type 8, undergoing laparoscopic hysterectomy with general anesthesia.

OBJECTIVE: Patients with Long QT syndrome (LQTS) P may present with torsades de pointes, ventricular tachycardia (VT), or ventricular fibrillation (VF) and are at risk of sudden cardiac death. MATERIALS AND METHODS: A 38 y/o female patient with uterus myoma developed VF during laparoscopic assisted vaginal hysterectomy surgery. Defibrillation was delivered and the electrocardiogram (ECG) returned to sinus rhythm after CPR. RESULTS: Patient survived and implantable cardioverter-defibrillator was implanted and received beta-blocker therapy. ECG obtained in out-patient clinic still showed QT interval prolongation, but revealed no prolongation few months after persistent beta-blocker therapy. LQTS type 8 (CACNA1C E768del mutation) was identified by genetic DNA sequencing study. CONCLUSIONS: Patients with concealed LQTS may have normal QT interval unless exposing to stress or specific stimuli. Unexpected ventricular arrhythmia may happen during any medical management. We should avoid triggers of QT prolongation, and get familiar with management of the episode.

Effects of systemic and neuraxial morphine on the immune system.

In the study, we tried to evaluate the effects of morphine injected through the systemic or neuraxial route on immune cell function and cytokine production in healthy women.In total, 29 paired samples of fresh peripheral blood were collected from healthy women who had been administered morphine for anesthetic analgesia through intravenous (IV), epidural, or spinal route postpartum. Their isolated peripheral blood mononuclear cells were mitogen-activated and stained with fluorochrome-conjugated anti-CD4, anti-CD8, anti-interleukin (IL)-2, and anti-interferon (IFN)-γ antibodies for flow cytometry, and the plasma levels of cytokines, including IL-6, IFN-α2, IL-10, IL-8, GM-CSF, and monocyte chemoattractant protein (MCP)-1, were measured through enzyme-linked immunosorbent assay.The results demonstrated that regardless of the administration route, morphine delivery slightly reduced IL-2 expression in CD4 cells after activation, and the same effect was not noted for CD8 cells. Intravenous or epidural morphine tended to reduce IFN-γ expression in CD8 cells. Spinal and IV morphine substantially increased IL-6 production, whereas epidural morphine hindered IL-10 and GM-CSF production. IV morphine injection reduced MCP-1 production in plasma. Compared with spinal morphine, IV or epidural morphine may more effectively inhibit the expression of various cytokines and thus affect immune response.All 3 routes of morphine injection tended to decrease IL-2 production by CD4 cells, whereas IV or epidural morphine injection showed lower IFN-γ production by CD8 cells. However, additional large-scale studies with longer follow-up durations are warranted.

Next Chapter of the Taiwan Biobank: Sustainability and Perspectives.

The emergence of biobanks has expanded the scope of biomedical research, ushering in an era of "precision medicine" to improve the treatment of disease. However, biobanks also face sustainability challenges comprising three dimensions-"financial," "operational," and "social." The Taiwan Biobank (TWB), as a large-scale national biobank that supplies valuable phenotypic and genetic information to biomedical researchers on an application basis to investigate the relationship among personal health, genes, lifestyle, environment and diseases of the Taiwanese population, has not been sufficiently explored by researchers. Although the TWB has successfully reached a few milestones since its inception, it faces many sustainability challenges. For the next chapter of the TWB, we propose three strategies to improve sustainability. First, the Ministry of Health and Welfare launched the TWB as an infrastructure project under the leadership of Academia Sinica in 2012. We now believe that it is time that the TWB is transformed into a legal entity as a nondepartmental public body. This would not only ensure efficient, effective, and flexible operation, but would also facilitate cooperation with commercial entities. Second, we suggest that the TWB integrates with other Taiwanese biobanks to reduce cost, improve low utilization, and expand specimen collection. Third, self-financing is important if funding is ceased. Besides implementing a cost-recovery model, the commodities developed by the TWB (e.g., TWB 2.0 microarray) will help increase income. After each of these strategies has been discussed in detail, this article will conclude by highlighting how these practices can help improve biobank sustainability.

Pharmacogenetic study of pruritus induced by epidural morphine for post cesarean section analgesia.

OBJECTIVE: The mechanism through which neuroaxial morphine causes pruritus has not been elucidated clearly and thoroughly. MATERIALS AND METHODS: a study in 129 female parturients was conducted to investigate the effect of 14 single nucleotide polymorphisms (SNPs) on phenotype (pruritus) induced by neuroaxial (including intrathecal or epidural) morphine for cesarean section. Clinical phenotype, subjective complaints and objective observations were recorded. DNA from blood samples was used to record the SNPs. Eleven SNPs were then analyzed further. RESULTS: no significant association with the presence of phenotype (pruritus) versus genotype was observed (all p-values > 0.05). No significant association with severity of phenotype versus genotype of the 11 SNPs was observed except for unadjusted data for rs2737703. There was no significant difference between severity or incidence of IVPCA morphine-induced nausea and vomiting and genotype (11 SNPs). CONCLUSION: our results showed no association between SNPs of any of the genes studied with neuroaxial morphine inducing pruritus.

The use of tenoxicam to prevent symptoms of discomfort induced by vagotonia during uterus manipulation in cesarean sections.

PURPOSE: Symptoms such as nausea, vomiting, tightness of the chest, bradycardia, and shoulder or abdominal discomfort, caused by vagotonia occurring during uterus manipulation, have concerned healthcare professionals for some time. Patients sometimes report these symptoms when undergoing spinal anesthesia for cesarean sections (CSs). We designed a prospective, double-blind study to investigate the effectiveness of tenoxicam in preventing these symptoms of discomfort. METHODS: A total of 105 American Society of Anesthesiologists (ASA) class I-II nulliparous pregnant women, who were scheduled for a CS, were enrolled into this prospective, double-blind study. Spinal anesthesia was conducted to reach a peak dermatome level of no more than T3. The 100 patients were randomly divided into 2 groups having completed study course: Group T (N = 50) received a 20 mg dose of tenoxicam in 5 mL of normal saline (NS) immediately after skin incision and Group N (N = 50) only received 5 mL NS. The incidence and severity of the symptoms experienced by the patients were recorded by a nurse anesthetist who was blinded to the injection regimen the patients were receiving. A chi-square test was used for statistical analysis t test and P < .05 was defined as significant. RESULTS: The incidence and degree of severity of nausea and vomiting were same in both the groups. The incidence and degree of severity of bradycardia, nausea, vomiting, tightness of the chest, shoulder discomfort, and abdominal discomfort were lower in Group T than in Group N. CONCLUSION: Tenoxicam might theoretically block the parasympathetic vagus pathway and decrease the visceral pain or visceral-specific symptoms, alleviating the symptoms caused by vagotonia. However, the prophylactic effect of tenoxicam in reducing the incidence and severity of nausea and vomiting was not statistically significant. This could be because nausea and vomiting are not solely caused by vagotonia, but also by other mechanisms.

Prospective observational pharmacogenetic study of side effects induced by intravenous morphine for postoperative analgesia.

Nausea and vomiting are probably the most unpleasant side effects that occur when morphine used. A number of studies have investigated the effect on pain relief of single nucleotide polymorphisms (SNPs) in genes involved in morphine's metabolism, distribution, binding, and cellular action. The mechanism through which morphine causes nausea and vomiting has not been elucidated clearly. We examined all the reported SNPs which are associated with the complications of morphine, including SNPs in genes for phase I and phase II metabolic enzymes, ABC binding cassette drug transporters, κ and δ opioid receptors, and ion channels implicated in the postreceptor action of morphine.A prospective, observational study in 129 female patients was conducted to investigate the effect of 14 SNPs on nausea or vomiting induced by intravenous patient-controlled analgesia (IVPCA) with morphine after gynecology surgery. Clinical phenotype, subjective complaints, and objective observations were recorded. DNA from blood samples was used to record the SNPs. Eleven SNPs were then analyzed further.No significant association with the presence of phenotype (nausea or vomiting) versus genotype was observed (all P > .05). No significant association with severity of phenotype versus genotype of the 11 SNPs was observed except for unadjusted data for rs2737703.There was no significant difference between severity or incidence of IVPCA morphine-induced nausea and vomiting and genotype (11 SNPs). Further study should perhaps be focused on mRNA and proteinomics rather than SNPs.

Patient-controlled epidural levobupivacaine with or without fentanyl for post-cesarean section pain relief.

PURPOSE: The purpose of this study was to compare the analgesic properties of levobupivacaine with or without fentanyl for patient-controlled epidural analgesia after Cesarean section in a randomized, double-blinded study. METHODS: We enrolled American Society of Anesthesiologists class I/II, full-term pregnant women at National Taiwan University Hospital who received patient-controlled epidural analgesia after Cesarean section between 2009 and 2010. Eighty women were randomly assigned into two groups. In group A, the 40 subjects received drug solutions made of 0.6 mg/ml levobupivacaine plus 2 mcg/ml fentanyl, and in group B the 40 subjects received 1 mg/ml levobupivacaine. Maintenance was self-administered boluses and a continuous background infusion. RESULTS: There were no significant differences in the resting and dynamic pain scales and total volume of drug used between the two groups. Patient satisfaction was good in both groups. CONCLUSION: Our study showed that pure epidural levobupivacaine can provide comparative analgesic properties to the levobupivacaine-fentanyl combination after Cesarean section. Pure levobupivacaine may serve as an alternative pain control regimen to avoid opioid-related adverse events in parturients.

The effects of different epidural analgesia formulas on labor and mode of delivery in nulliparous women.

OBJECTIVES: Patient-controlled epidural analgesia (PCEA) and continuous epidural infusion (CEI) are popular and effective methods for pain relief during labor; however, there are concerns about increasing rates of cesarean section (C/S) and instrumental delivery. This prospective study investigated the effect of PCEA and CEI with different formulas on labor and the mode of delivery in nulliparous women. MATERIALS AND METHODS: A total of 480 nulliparous women were randomized into four groups, with 120 in each. Group A received a loading dose of 10 mL of 1 mg/mL ropivacaine with 2 µg/mL fentanyl, then an intermittent bolus of 5 mL with a background infusion of 5 mL/hour by PCEA. Group B received the same PCEA formula as Group A with 0.8 mg/mL bupivacaine. Group C received the same formula as Group A by CEI with 1 mg/mL ropivacaine at a rate of 10 mL/hour. Group D received the same formula as Group C with 0.8 mg/mL bupivacaine. The rates of C/S and instrumental delivery and the incidence of side effects were recorded. RESULTS: The rates of C/S were significantly different between Groups A and C, Groups A and D, and Groups B and D. The rates of instrumental delivery for normal spontaneous delivery were significantly different between Groups A and B, A and D, B and C, and C and D. CONCLUSION: The C/S rate was higher in Groups C and D; however, the instrumental delivery rate was lower in Groups A and C. We conclude that PCEA with 1 mg/mL ropivacaine might provide the greatest benefit for labor analgesia.

Polymorphism of µ-Opioid Receptor Gene (OPRM1:c.118A>G) Might Not Protect against or Enhance Morphine-Induced Nausea or Vomiting.

A cohort, double blind, and randomized study was conducted to investigate the effect of a single nucleotide polymorphism of the µ-opioid receptor at nucleotide position 118 (OPRM1:c.118A>G) on the association with the most common side effects (nausea or vomiting) induced by intravenous patient control analgesia (IVPCA) with morphine, including incidence and severity analysis. A total of 129 Taiwanese women undergoing gynecology surgery received IVPCA with pure morphine for postoperative pain relief. Blood samples were collected and sequenced with high resolution melting analysis to detect three different genotypes of OPRM1 (AA, AG, and GG). All candidates 24 h postoperatively will be interviewed to record the clinical phenotype with subjective complaints and objective observations. The genotyping after laboratory analysis showed that 56 women (43.4%) were AA, 57 (44.2%) were AG, and 16 (12.4%) were GG. The distribution of genotype did not violate Hardy-Weinberg equilibrium test. There was no significant difference neither between the severity and incidence of IVPCA morphine-induced side effects and genotype nor between the association between morphine consumption versus genotype. However, there was significant difference of the relation between morphine consumption and the severity and incidence of IVPCA morphine-induced nausea and vomiting. The genetic analysis for the severity and incidence of IVPCA morphine-induced nausea or vomiting showed no association between phenotype and genotype. It might imply that OPRM1:c.118A>G does not protect against IVPCA morphine-induced nausea or vomiting.

Health care utilization and health outcomes: a population study of Taiwan.

Facing escalating health care expenditures, the governments of countries with national health insurance programs are trying to control or even to reduce health care utilization. Little research has examined the effects of decreased health care utilization on health outcomes. Applying a natural experiment design to the Taiwan population between 2000 and 2004, which includes the 2003 SARS epidemic when an average 20% decline in health care utilization occurred, this study examines the association between a decline in health care utilization and health outcomes measured by cause-specific mortality rates. We analyse the monthly mortality rates caused by infectious diseases, cancer, diabetes mellitus, nervous system diseases, cerebrovascular diseases, heart and other vascular diseases, respiratory system diseases, digestive system diseases, genitourinary system diseases and accidents. Models control for age, sex, month and year effects. Results show the heterogeneous effect of reduced health care utilization on health outcomes. Patients with diabetes mellitus or cerebrovascular diseases are vulnerable to short-term reductions in health care; compared with the non-SARS period, mortality caused by diabetes mellitus and cerebrovascular diseases significantly increased during the SARS epidemic by 8.4% and 6.2%, respectively. No significant change in mortality rates caused by the other diseases or accidents is found. This study suggests that governments of countries where health care utilization and spending are similar to or inferior to those in Taiwan should carefully evaluate the impact of policies that attempt to reduce health care utilization. Furthermore, when an area encounters an epidemic, governments should be aware of the negative consequences of voluntary restraints on access to health care that accompany decreases in utilization.

Risk factors for progressive deterioration of semen quality in patients with varicocele.

OBJECTIVE: To assess the risk factors for progressive deterioration of semen quality (PDSQ) in adult patients with varicocele. METHODS: A total of 32 men with left varicocele and impaired semen quality (group 1) and 30 age-matched patients with left varicocele and normal semen quality (group 2) were recruited for the present study. All the subjects received conservative treatment, and the parameters for evaluation every 12 months included semen quality, peak retrograde flow (PRF) and spontaneous venous reflux by color Doppler ultrasonography, body mass index, serum concentration of follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, testicular volume and discrepancy, grade of varicocele, and scrotal temperature. RESULTS: The mean follow-up time was 63.2 months (range 60-66). The patients in group 1 had a significantly greater PRF, lower testicular volume, greater testicular volume discrepancy, lower testosterone level, higher scrotal temperature, and greater follicle-stimulating hormone level than those in group 2 at first. The semen quality deteriorated in 28 subjects (87.5%) in group 1, but in only 6 patients (20%) in group 2 during follow-up. Furthermore, the 6 subjects with PDSQ in group 2 had greater PRF and scrotal temperature than those without. CONCLUSION: The rate of PDSQ was significantly greater in the varicocele patients with an initially abnormal semen quality than in those with initially normal semen quality (87.5% vs 20%). Furthermore, the varicocele patients with initially normal semen quality who had greater PRF and scrotal temperature might have a greater risk of PDSQ.