Observational Study for Adverse Effects and Discontinuation with Long-Term Post-Operative Hormonal Treatment for Endometriosis in Real-World Practice

Objectives: To evaluate the side effects and causes of discontinuation of either combined oral contraceptives or dienogest (DNG) used to prevent recurrence in patients with surgically confirmed endometriosis.Methods: We retrospectively analyzed the medical records of 213 women with endometriosis who had been treated with combined oral contraceptives (ethinyl estradiol 0.02 mg/drospirenone 3 mg [EE/DRSP]) or DNG 2 mg for 12 months or more. The side effects reported by the patients, laboratory parameters, causes of discontinuation of medication, and recurrence rates were evaluated one, two, three, four, and five years after starting medication (Y1, Y2, Y3, Y4, and Y5).Results: EE/DRSP were administered to 59 patients, while DNG was administered to 154 patients. The mean durations of postoperative use of EE/DRSP and DNG were 44.5 ± 22.6 months and 23.6 ± 13.5 months, respectively. The prevalence of side effects was 27.1%, 19.0%, 10.0%, 10.5%, and 7.4% in the EE/DRSP group and 29.2%, 15.7%, 14.0%, 23.1%, and 0.0% in the DNG group at Y1, Y2, Y3, Y4, and Y5, respectively. The discontinuation rates were 1.7%, 1.7%, 4.0%, 0.0%, and 7.4% at Y1, Y2, Y3, Y4, and Y5, respectively, in the EE/DRSP group and 10.4%, 3.3%, 4.0%, 3.8%, and 0.0% at the same times in the DNG group. The recurrence rates were less than 4% in both the groups.Conclusions: The side effects of commonly prescribed postoperative hormone treatments were relatively mild, and the occurrence of side effects decreased with continuous administration. Further, the long-term use of postoperative hormone treatments is likely to prevent recurrence of endometriosis after surgery.

Pre-treatment and continuous administration of simvastatin during sepsis improve metabolic parameters and prevent CNS injuries in survivor rats

Sepsis causes overproduction of inflammatory cytokines, organ dysfunction and cognitive impairment in survivors. In addition to inflammation, metabolic changes occur according to the stage and severity of the disease. Understanding the role and place of metabolic disturbances in the pathophysiology of sepsis is essential to evaluate the framework of septic patients, predict the syndrome progress and define treatment strategies. We investigated the effect of simvastatin on the disease time course and on metabolic alterations, especially with respect to their possible consequences in the CNS of surviving rats. The animals of this study were weighed daily and followed for 10 days to determine the survival rate. In the first experiment, control or CLP-animals were randomized in 24 h, 48 h and 10 days after septic induction, for bacterial load determination and, quantification of cytokines. In the second experiment, control or CLP-animals were treated or not with simvastatin and randomized in the same three time points for cytokines quantification and assessment of their body metabolism and locomotor activity (at 48 h and 10 days), as well as the evaluation of cytoarchitecture and astrogliosis (at 10 days). The CLP-rats treated with simvastatin showed a reduction in plasma cytokines and improvement in metabolic parameters and locomotor activity, followed by minor alterations compatible with apoptosis and astrogliosis in the hippocampus and prefrontal cortex. These results suggest that the anti-inflammatory effect of simvastatin plays a crucial role in restoring energy production, maintaining a hypermetabolic state necessary for the recovery and survival of these CLP-rats.

Bilateral Choroidal Metastases In Triple-Negative Breast Cancer: Radiotherapy And Eribulin For Vision Preservation And Prolong Survival

Introduction: Choroidal metastases are infrequent in breast cancer, but if they present, they usually signify the disseminated disease and poor prognosis. The challenges in treating choroidal metastases are not only to prolong survival but also to preserve vision, improving the quality of life. Case Presentation: Our patient was firstly diagnosed with stage-three triple-negative breast cancer at the age of 32 years. She had surgery, adjuvant chemotherapy with anthracycline regime, as well as adjuvant radiotherapy. Her disease firstly recurred two years later with pleural effusion, but it was controlled with six cycles of docetaxel. She was in remission until ten years later when she presented with a worsening dry cough and progressive blurring of vision in both eyes. CT restaging showed multiple sub-centimeter bilateral lung nodules, singular pleural metastases, and multiple bone metastases. Choroidal metastases were also confirmed with the ophthalmological assessment which includes CT of the orbit. She received short-course palliative radiotherapy followed immediately by eribulin. Then, she started monthly bisphosphonates. She was able to read again four months after radiotherapy, and her vision remains normal to date. The latest PET scans showed no FDG avid disease in the lungs with pleural metastases significantly reduced in size. Bone metastases remain stable and asymptomatic. It has been nearly four years since the diagnosis of choroidal metastases. She is still on eribulin at an adjusted dose and interval. She remains asymptomatic from her bone, lung, and choroidal metastases. Conclusions: Short-course radiotherapy to the orbit, followed by continuous administration of eribulin, can lead to prolonged survival with a good quality of life in triple-negative breast cancer with choroidal metastases

Multiscale modeling of tumor response to vascular endothelial growth factor (VEGF) inhibitor

Vascular endothelial growth factor (VEGF) has been known as a key mediator of angiogenesis in cancer. Bevacizumab is anti-VEGF monoclonal antibody that has been approved by the FDA as a first-line treatment in many types of cancer. In this paper, we extend a previously validated multiscale tumor model to comprehensively include the multiple roles of VEGF during the course of angiogenesis and its binding mechanism with bevacizumab. We use the model to simulate tumor system response under various bevacizumab concentrations, both in stand-alone treatment and in combination with chemotherapy. Our simulation indicates that periodic administration of bevacizumab with lower concentration can achieve greater efficacy than a single treatment with higher concentration. The simulation of the combined therapy also shows that the continuous administration of bevacizumab during the maintenance phase can lead to antitumor activity which further suppresses its growth. Agreement with experimental results indicates the potential of the model in predicting the efficacy of anti-VEGF therapies and could therefore contribute to developing prospective clinical trials.

Continuous administration of voriconazole enhances therapeutic effect for recalcitrant fungal keratitis

Purpose To evaluate the therapeutic effect of incorporating continuous administration of voriconazole in the treatment of recalcitrant fungal keratitis. Methods In this prospective case study, 5 consecutive patients (5 eyes) with fungal keratitis were treated with a standard protocol after the failing maximal conventional medical treatment. The protocol involved continuous lavage of the ulcer with 1% voriconazole through an irrigator for 2 h, twice a day, combined with local and systemic antifungals. Visual acuity, slit lamp findings of the ulcer, and fungal hyphae density by confocal microscope were documented, respectively. Results In 4 patients, the clinical symptoms and slit lamp examination were significantly improved after only 3 days of treatment. The hyphae were shown to decrease in number and morphologically fragmented in corneal stroma by confocal microscopy. After the infection was controlled, 2 cases required further keratoplasty. In one case, the treatment was deemed ineffective and a conjunctival flap had to be created to help control the infection. In all 5 patients, the best spectacle-corrected visual acuity had improved after treatment. With more than 3 months of follow-up, no recurrence of infection was seen in any cases. Conclusion Our treatment protocol demonstrated improvement in the treatment of clinically resistant fungal keratitis. Continuous lavage of voriconazole is easy to be implemented and well-tolerated by patients. Modification of the current protocol should be further explored to optimize the therapeutic effectiveness in future.

Embedded Upconversion Nanoparticles in Magnetic Molecularly Imprinted Polymers for Photodynamic Therapy of Hepatocellular Carcinoma

Programmed death-ligand 1 protein (PD-L1) is often expressed in various malignant tumors; thus, it is an appropriate marker for targeted cancer therapies. Photodynamic therapy (PDT) uses light and photosensitizers to create singlet oxygen to kill cells. An important approach to PDT is the use of upconversion nanoparticles (UCNPs) to convert near-infrared (NIR) light, which penetrates tissues well, into visible light, allowing PDT to be effective at greater tissue depths. In this work, high-temperature pyrolysis was used to prepare both the core and shell of lanthanide-doped UCNPs with lithium yttrium tetrafluoride (LiYF4) to enhance the green luminescence. The photosensitizer Merocyanine 540 (MC540) was grafted onto the magnetic nanoparticles, and then one peptide sequence from PD-L1 was used as the template and imprinted onto poly(ethylene-co-vinyl alcohol) particles formed by precipitation in a non-solvent. UCNPs in the non-solvent bath were thus entrapped in the imprinted particles to generate composite nanoparticles for the targeting and photodynamic therapy of PD-L1 in tumor cells. Finally, the in vitro cytotoxicity of the nanoparticles in HepG2 human liver cancer cells was evaluated with the continuous administration of MC540/MNPs@MIPs/UCNPs under irradiation by an NIR laser. To understand the delivery of the UCNP-embedded molecularly imprinted polymers, the intrinsic and extrinsic pathways were also investigated.

Predicting anesthetic infusion events using machine learning

Recently, research has been conducted to automatically control anesthesia using machine learning, with the aim of alleviating the shortage of anesthesiologists. In this study, we address the problem of predicting decisions made by anesthesiologists during surgery using machine learning; specifically, we formulate a decision making problem by increasing the flow rate at each time point in the continuous administration of analgesic remifentanil as a supervised binary classification problem. The experiments were conducted to evaluate the prediction performance using six machine learning models: logistic regression, support vector machine, random forest, LightGBM, artificial neural network, and long short-term memory (LSTM), using 210 case data collected during actual surgeries. The results demonstrated that when predicting the future increase in flow rate of remifentanil after 1 min, the model using LSTM was able to predict with scores of 0.659 for sensitivity, 0.732 for specificity, and 0.753 for ROC-AUC; this demonstrates the potential to predict the decisions made by anesthesiologists using machine learning. Furthermore, we examined the importance and contribution of the features of each model using Shapley additive explanations—a method for interpreting predictions made by machine learning models. The trends indicated by the results were partially consistent with known clinical findings.

Infectious complications related to radiofrequency ablation of liver tumors: The role of antibiotics

Background and aim Prophylactic administration of antibiotics within 24 hours of surgery is recommended to reduce the risk of infection. We conducted a prospective study to compare the efficacy of single administration of antibiotics with a historical control of continuous administration of antibiotics for radiofrequency ablation (RFA) of malignant liver tumors. Methods Between February 1, 1999 and November 30, 2010, a total of 6,763 RFA treatments were performed in 2,355 patients, using a protocol with continuous administration of prophylactic antibiotics. On December 1, 2010, we began using a revised protocol with a single administration of prophylactic antibiotics, while continuing to use the old continuous administration protocol for patients who declined the new protocol. Interim analysis was performed to assess the safety of the single administration protocol. Thereafter, from April 1, 2012, all patients were treated using the new protocol. Risk factors for infectious complications of RFA were assessed using logistic regression. Results From December 2010 to March 2012, 766 RFA treatments were performed in 663 patients using the new antibiotic protocol. Infectious complications were observed following 4 of these treatments (0.52%). As the upper limit of the confidence interval (CI) resulting from a one-sided binomial test was exactly the prespecified limit of 1.0%, from April 2012 onwards, we treated all patients using the new protocol with single administration of prophylactic antibiotics. A total of 3,547 RFA treatments were performed using the single administration protocol. Univariable logistic regression indicated that prior transcatheter arterial chemoembolization (TACE) and maximal tumor diameter were significant risk factors for infectious complications (P = 0.04 and P < 0.001, respectively). Multivariable analysis indicated that the adjusted hazard ratio of single vs. continuous administration of antibiotics was 1.20 (95% CI: 0.53–2.75; P = 0.66). Conclusions The rate of infectious complications related to RFA was acceptably low. Single administration of prophylactic antibiotics did not significantly increase the rate of infectious complications related to RFA, compared with a more intensive antibiotic protocol.

Metronomic Chemotherapy for Metastatic Breast Cancer

Background: As disease control and quality of life play a leading role in metastatic breast cancer (MBC), metronomic chemotherapy (MCT) is gaining popularity alongside conventional chemotherapy (CCT) and targeted therapies. Summary: MCT, defined as continuous administration of low-dose chemotherapeutic agents, is accepted as a therapy that exerts its effects via immunomodulation, anti-angiogenesis and direct cytotoxic effects. Oral administration of MCT is safe, easy to handle, and allows for flexible drug dosing. Dose accumulations associated with non-tolerable side effects are rare, so the medication can be administered for longer periods of time. Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic disease resistant to endocrine-based therapy and not requiring rapid tumor response are generally suitable for MCT. However, MCT may also be promising in patients with triple-negative and HER2-positive tumors without aggressive disease who prefer a lower toxicity profile compared to CCT. The most commonly used agents are cyclophosphamide (CTX), methotrexate (MTX), capecitabine (CAPE), and vinorelbine (VRL), whereby a combination of agents is frequently applied. Key Messages: Based on the growing body of evidence, MCT can be considered as a suitable treatment option in selected MBC patients. Nevertheless, there is an urgent need for randomized controlled trials comparing MCT with CCT, but also with best supportive care. Due to the multimodal mechanisms of action, the combination with targeted and immunological therapies may represent a new promising approach for the treatment of MBC.