Nebulisation of Paclitaxel, Sotatercept and Iloprost for pulmonary hypertension for lung cancer. From In vitro to In vivo.

Background: Pulmonary hypertension is common symptom among several diseases. The consequences are severe for several organs. Pulmonary hypertension is usually under-diagnosed and the main symptom observed is dyspnea with or without exercise. Currently we have several treatment modalities administered orally, via inhalation, intravenously and subcutaneously. In advanced disease then heart or lung transplantation is considered. The objective of the study was to investigate the optimum method of aerosol production for the drugs: iloprost, paclitaxel and the novel sotatercept. Materials and Methods: In our experiment we used the drugs iloprost, paclitaxel and the novel sotatercept, in an experimental concept of nebulization. We performed nebulization experiments with 3 jet nebulizers and 3 ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5µm in mass median aerodynamic diameter. Results: We concluded that paclitaxel cannot produce small droplets and is also still very greasy and possible dangerous for alveoli. However; iloprost vs sotatercept had smaller droplet size formation at both inhaled technologies (1.37<2.23 and 1.92<3.11, jet and ultrasound respectively). Moreover; residual cup designs C and G create the smallest droplet size in both iloprost and sotatercept. There was no difference for the droplet formation between the facemask and cone mouthpieces. Discussion: Iloprost and sotatercept can be administered as aerosol in any type of nebulisation system and they are both efficient with the residual cups loaded with small doses of the drug (2.08 and 2.12 accordingly).

Chronic Obstructive Pulmonary Disease and Non-Small Cell Lung Cancer an association.

Objectives: Lung cancer is known to be associated with chronic obstructive pulmonary disease. Moreover; nutritional status is associated with chronic obstructive disease treatment and lung cancer. Our aim was to evaluate the interaction of the COPD status and treatment of non-small cell lung cancer. Methods: Eighty-two patients were enrolled in our multicenter study. Chronic obstructive disease stage, spirometry and treatment was recorded along with the treatment and Body Mass Index (BMI), Mediterranian Diet Score, Pack Years, Basic Metabolsim (RMR) (kcal/day), VO2 (ml/min), Ve (lt/min) and Physical Activity. The statistical analysis was performed using the JMP 14.3 (SAS Inc 2018) software. Results: The drug pairs showed a steady and unchanged by time health condition for 48 patients. Overall, 31 patients were recorded with worse COPD health conditions. The one-way ANOVA clearly indicated that chemotherapy induced the best FEV1-difference conditions with a positive effect of 8.56 mean FEV volume, the combined treatment simply did not have an effect (-0.9), while immunotherapy and patients receiving radiation decreased their FEV1 volume down to -4.23 and -5.15 mean values. Conclusions: Patients receiving chemotherapy alone had their chronic obstructive disease improved with less drugs and exacerbations, while patients receiving immunotherapy had their chronic obstructive disease stable, while all other treatment combinations worsened the patients chronic obstructive disease. Nutritional status did not affect the chronic obstructive disease of these patients in any way.

Salicylate- and Noise-induced Tinnitus. Different Mechanisms Producing the same Result? An Experimental Model.

PURPOSE: Tinnitus, the generation of phantom sounds, can be the result of noise exposure, however, understanding of its underlying mechanisms is limited. Purpose of the study was is to determine whether different concentrations of salicylate can cause tinnitus of different intensity. METHODS: For the purposes of this study 50 male Wistar rats were used. The animals were divided into 5 groups (10 rats in each group). The animals that did not receive any substance were allocated to the control group (Group A). The second group (Group B) of rats received salicylate (Sigma Aldrich) intraperitoneally for 7 days (300 mg/Kg/day). The 3rd group (Group C) received salicylate intraperitoneally for 7 days, but at twice the concentration of the animals in the second group (600 mg/kg/d). The 4th group (Group D) simultaneously received salicylate (300 mg/Kg/day) and pure Memantine (Sigma Aldrich, 10 mg/kg/d) intraperitoneally for 7 days. The 5th group (Group E) did not receive any substance but was exposed for 168 consecutive hours (7 days) to sound to induce tinnitus. Cochlear activity was evaluated with the use of Distortion Product Otoacoustic Emissions (DPOAEs). At the end of the experimental period, the animals were sacrificed, and the right cochlea was removed and prepared for further histological and immunohistochemical studies. RESULTS: The DPOAEs of animals treated either with salicylate as monotherapy or salicylate combined with memantine were indistinguishable from the noise floor, did not differ significantly compared to the animals of the control group or those expose to constant noise. The cochlear structures of Group E remained anatomically and functionally unaffected from the exposure to constant noise. Memantine does not seem to offer substantial protection to the cochlear structures, according to histological examination and hearing tests, however, the rats receiving it exhibited better results in behavioral tests. CONCLUSIONS: The administration of memantine does not contribute significantly to the reduction of tinnitus.

Pharmacologic Stewardship in a Rural Community Pharmacy.

BACKGROUND: Pharmacotherapy is an essential part of patient care. In order to achieve optimal health outcomes, safe and effective prescribing and administering of medications is crucial, especially since the process of pharmacotherapy can cause serious problems, mainly adverse events and/or interactions, that often pass undetected. OBJECTIVE(S): To investigate the feasibility of using community pharmacies as checkpoints to detect errors and failures in prescribing, as well as patients' compliance with pharmacotherapy. To this end, analysis and recording of the prescribing process was carried out and error-prone points were identified. METHODS: Patients and caregivers filling prescriptions during the first 4 weeks of November 2017 and February 2018 answered questions in order to evaluate their attendance of regular checkups and their compliance with prescribing instructions. All prescriptions filled at the pharmacy were examined for detection of prescription errors and drug-drug interactions. Statistical analyses, including calculations of the correlation coefficient phi (φ), chi-square, and confidence intervals, were carried out. Detected errors and failures were evaluated by application of the Health Failure Mode Effect Analysis (HFMEA) quality tool. RESULTS: A significant number of patients (16.7%) failed to regularly attend checkups regarding known health problems (95% CI: 10.6-22.7%), a corresponding percentage (16%, 95% CI: 10.1-21.9%) did not comply with prescribed pharmacotherapy, and a significant proportion of patients self-medicated regularly (32%, 95% CI: 24.5-39.5%). A total of 8.6% of prescriptions included medication combinations with a potential for severe drug-drug interactions (95% CI: 7.1-10.2%) while 58.7% of the prescriptions included combinations that could lead to moderate ones (95% CI: 56.1-61.4). The HFMEA indicated that all problems recorded required immediate interventions, except for prescribing errors. CONCLUSIONS: Community pharmacies can be potential checkpoints for the detection and evaluation of prescribing errors and pharmacotherapy failures.

Immunotherapy for the elderly. Maybe the best option for lung cancer?

Lung cancer is usually diagnosed at advanced stage and systematic therapy is administered. New current diagnostic techniques such as the convex-endobronchial ultrasound, radial endobronchial ultrasound, cone beam ct, electromagnetic navigation and robotic bronchoscopy provide us with a high diagnostic yield. These techniques are minimal invasive and patients with comorbidities such as chronic obstructive pulmonary disease and heart failure can be diagnosed with minimal adverse effects. All these techniques provide sufficient sample for molecular investigation. Since immunotherapy was first administered, we have more and more information regarding the appropriate patient target group. Several published studies divided patients as elderly ≥75 and non-elderly ≤74 and investigated the adverse effects of different drugs and survival. In our current commentary we present information on patients receiving immunotherapy versus chemoimmunotherapy in two groups of elderly and non-elderly. Elderly patients can receive both combinations without differences between the two groups, however; more studies are needed to clarify certain aspects.

Sotorasib after immune checkpoint inhibitor administration induces hepatotoxicity. True, false or just another adverse effect of NSCLC treatment.

Non-small cell lung cancer is still diagnosed at a late disease stage and systematic therapy is necessary. Currently we have three main treatment modalities; chemotherapy, targeted with tyrosine kinase inhibitors and immune check point inhibitors. In the recent years and based on new studies we can administer combination of chemotherapy and immunotherapy, or radiotherapy and immunotherapy. Every treatment approach is based on the specific gene expression of the tumor. Tyrosine kinase inhibitors have been used for more than a decade for epidermal growth factor positive tumors, the same for anaplastic lymphoma kinase and proto-oncogene 1. Programmed death-ligand 1 expression has been found to be associated with the efficiency of immune checkpoint inhibitors. However; there are still several subpopulations in non-small cell lung cancer patients. We will comment on the group with KRAS G12C mutation and the targeted therapy with sotorasib for its efficiency and toxicity based on new studies.

Inhaled nintentanib, pirfenidone and macitentan for pulmonary fibrosis: a laboratory experiment.

Aim: Idiopathic pulmonary fibrosis is a rare disease with few efficient drugs in the market. The consequences of this disease are mainly respiratory failure and pulmonary hypertension. Materials & methods: In our experiment we used the drugs pirfenidone, nintetanib and macitentan. We performed nebulization experiments with three jet nebulizers and three ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5 µm in mass median aerodynamic diameter. Results: Pirfenidone versus nintetanib had smaller droplet size formation at both inhaled technologies (1.37 < 2.23 and 1.92 < 3.11, jet and ultrasound respectively). Discussion: Pirfenidone and nintetanib can be administered as aerosol in any type of nebulization system.

Epithelial Ovarian Cancer: A Five Year Review.

Ovarian cancer is a malignant disease that affects thousands of patients every year. Currently, we use surgical techniques for early-stage cancer and chemotherapy treatment combinations for advanced stage cancer. Several novel therapies are currently being investigated, with gene therapy and stem cell therapy being the corner stone of this investigation. We conducted a thorough search on PubMed and gathered up-to-date information regarding epithelial ovarian cancer therapies. We present, in the current review, all novel treatments that were investigated in this field over the past five years, with a particular focus on local treatment.

Endobronchial Radiofrequency Ablation for pulmonary nodules with Radial-Ebus and Navigation: Pros and Cons.

Introduction: Pulmonary nodules are common in the everyday clinical practice. There is always a diagnostic issue with this imaging finding. Based on the size we can use a variety of imaging and diagnostic techniques. Moreover; in the case of primary lung cancer or metastasis we can use radiofrequency ablation endobronchially. Patients and Methods: We used the radial-endobronchial ultrasound with C-arm and Archemedes, Bronchus electromagnetic navigation in order to acquire biopsy sample and we also used rapid on-site evaluation as a rapid diagnosis for pulmonary nodules. After rapid diagnosis we used the radiofrequency ablation catheter in order to ablate central pulmonary nodules. Results: Both techniques provide efficient navigation, however, with the Bronchus system less time is needed. The new radiofrequency ablation catheter provides efficient results in central lesions with low watts ≤40. Conclusion: We provided in our research a protocol to diagnose and treat such lesions. Future larger studies will provide more data on this subject.

Positron Emission-Computed Tomography, Cryobiopsy versus Bronchoalveolar Lavage and Computed Tomography Findings for Interstitial Lung Disease: A Long-Term Follow-Up.

Background and Objectives: Interstitial lung diseases have always been an issue for pulmonary and rheumatology physicians. Computed tomography scans with a high-resolution protocol and bronchoalveolar lavage have been used along with biochemical blood tests to reach a diagnosis. Materials and Methods: We included 80 patients in total. First, all patients had their diagnosis with computed tomography of the thorax, serological/ immunological blood tests and bronchoalveolar lavage. However; after 3 months, all were divided into 2 groups: those who had bronchoalveolar lavage again and those who had cryobiopsy instead of bronchoalveolar lavage (40/40). Positron emission-computed tomography was also performed upon the first and second diagnosis. The patients' follow-up was 4 years from diagnosis. Results: Patients suffered most from chronic obstructive pulmonary disease (56, 70%), while lung cancer was rarely encountered in the sample (7, 9.75%). Age distribution ranged between 53 and 68 years with a mean value of 60 years. The computed tomography findings revealed 25 patients with typical diagnosis (35.2%), 17 with interstitial pulmonary fibrosis (23.9%) and 11 with probable diagnosis (11%). The cryobiopsy technique led to a new diagnosis in 28 patients (35% of the total sample). Patients who had a new diagnosis with cryobiopsy had a mean survival time of 710 days (<1460). Positron emission-computed tomography SUV uptake was positively associated with the cryobiopsy technique/new disease diagnosis and improved all respiratory functions. Discussion: Positron emission-computed tomography is a tool that can be used along with respiratory functions for disease evaluation. Conclusions: Cryobiopsy is a safe tool for patients with interstitial lung disease and can assist in the diagnosis of interstitial lung diseases. The survival of patients was increased in the cryobiopsy group versus only bronchoalveolar lavage for disease diagnosis.

Sentinel Lymph Node Staging in Early-Stage Cervical Cancer: A Comprehensive Review.

Cervical cancer (CC) continues to be a significant global public health concern, even with preventive measures in place. In women with early-stage CC, the status of lymph nodes is of paramount importance, not only for the final prognosis but also for determining the best therapeutic strategy. According to main international guidelines, pelvic full lymphadenectomy (PLND) is recommended for lymph node staging. However, in these early stages of CC, sentinel lymph node biopsy (SLNB) has emerged as a precise technique for evaluating lymph node involvement, improving its morbidity profile. We performed a literature review through PubMed articles about progress on the application of SLNB in women with early-stage CC focusing on the comparison with PET/CT and PLND in terms of oncological outcomes and diagnostic accuracy. While the superiority of SLNB is clear compared to radiologic modalities, it demonstrates no clear oncologic inferiority over PLND, given the higher detection rate of positive lymph nodes and predominance of no lymph node recurrences. However, due to a lack of prospective evidence, particularly concerning long-term oncological safety, SLNB is not the current gold standard. With careful patient selection and adherence to straightforward protocols, a low false-negative rate can be ensured. The aim of the ongoing prospective trials is to address these issues.

A health condition index for assessing disease progression.

INTRODUCTION: Currently immunotherapy is considered a cutting edge pharmaceutical treatment for non-small cell lung cancer. Tumor profile plays a crucial role in identifying the correct patient group. METHODS: Therefore, initial biopsies and re-biopsies are necessary in order to identify the expression of programmed death-ligand-1. RESULTS: This information is crucial and therefore all future immunotherapy studies have to be built upon a specific statistical model which associates the tumor profile and tumor profile expression along with treatment efficiency. DISCUSSION: We present a novel statistical methodology for future immunotherapy studies of non-small cell lung cancer.

Factors Affecting the Nuclei in Newborn and Children.

It is known that children are more sensitive to the effects of medical treatments and environment than adults. Today there is limited information regarding the differences in genotoxic effects in children. The micronucleus assay is a method that is used to monitor genotoxicity, and it was validated several years before. Today there is international interest for exfoliated buccal cells. Most of the micronuclei studies in children have been performed with the analyses of lymphocytes. However, there is vast interest in using exfoliated cells from the oral cavity. The reason is that other type of cells are acquired non-invasively, this is an important issue in paediatric cohorts. Unfortunately a limitation of measuring micronuclei frequency is that it has been observed to be low in newborns and on the other hand there are a large number of patients and cell sample counts. It has been observed that radiation exposure and environmental pollutants increase the micronuclei frequency in newborn and children. Regarding the medical treatments, there is little data and several studies are needed to optimise the doses. There is the need to observe if there is a relationship between micronuclei in lymphocytes and exfoliated cells and to identify the baseline of the micronuclei levels. Moreover, we evaluate the changes in response to the toxic agents. Prospective cohorts studies will clarify the predictive value of micronuclei for cancer and chronic diseases for both children and adults. Novel molecular technologies will assist in the elucidation of different biological pathways and molecular mechanisms connected with the micronulcei levels in newborn and children.

Airway local endoscopic pharmacological treatment; current applications and future concepts.

INTRODUCTION: Local treatment of the airways and lung parenchyma has been used in clinical practice for several years for a variety of diseases. METHODS: A variety of endoscopic tools for local treatment exist, especially for treating malignancies. Using these endoscopic tools, one can administer drugs specifically designed for the airways. DISCUSSION: This article presents all locally administered treatment options and provides useful insights for future local endoscopically applied treatments.

Priority of PET-CT vs CT Thorax for EBUS-TBNA 22G vs 19G: Mesothorax Lymphadenopathy.

Introduction: Lung lesions and undiagnosed mesothorax lymphadenopathy is an issue that several doctors face in the everyday clinical practice. PET-CT and CT of the thorax are usually the first examinations to identify characteristics of the lesions before biopsy. Patients and Methods: We performed a retrospective study with 450 patients that had EBUS-TBNA with 22G, Upgraded 22G and 19G needles with and without PET-CT in order to identify the cost effeteness of performing EBUS-TBNA before or after PET-CT. All centers used the same PET-CT equipment and EBUS-TBNA system. Three types of needle were used for the endoscopy in order to identify similarities and differences for the cost-effectiveness. The costs in every center for every examination and materials were the same. Results: There were more block slices for 19G>22Gupgraded>21G>22G and there was cost-effectiveness when in general PET-CT was performed prior to biopsy of any lesion. 19G needle was more effective for lymphomas, while 22Gupgraded and 21G needles were more cost-effective when used for smaller lesions for primary lung cancer of metastatic disease. Conclusions: We have been using PET-CT and EBUS-TBNA in the everyday clinical practice according to the current guidelines for initial disease staging and re-staging. However; we can also use both in a cost effective method based on the initial radiologic findings.

Antidepressants on Multiple Sclerosis: A Review of In Vitro and In Vivo Models.

Background: Increased prevalence of depression has been observed among patients with multiple sclerosis (MS) and correlated with the elevated levels of proinflammatory cytokines and the overall deregulation of monoaminergic neurotransmitters that these patients exhibit. Antidepressants have proved effective not only in treating depression comorbid to MS, but also in alleviating numerous MS symptoms and even minimizing stress-related relapses. Therefore, these agents could prospectively prove beneficial as a complementary MS therapy. Objective: This review aims at illustrating the underlying mechanisms involved in the beneficial clinical effects of antidepressants observed in MS patients. Methods: Through a literature search we screened and comparatively assessed papers on the effects of antidepressant use both in vitro and in vivo MS models, taking into account a number of inclusion and exclusion criteria. Results: In vitro studies indicated that antidepressants promote neural and glial cell viability and differentiation, reduce proinflammatory cytokines and exert neuroprotective activity by eliminating axonal loss. In vivo studies confirmed that antidepressants delayed disease onset and alleviated symptoms in Experimental Autoimmune Encephalomyelitis (EAE), the most prevalent animal model of MS. Further, antidepressant agents suppressed inflammation and restrained demyelination by decreasing immune cell infiltration of the CNS. Conclusion: Antidepressants were efficient in tackling numerous aspects of disease pathophysiology both in vitro and in vivo models. Given that several antidepressants have already proved effective in clinical trials on MS patients, the inclusion of such agents in the therapeutic arsenal of MS should be seriously considered, following an individualized approach to minimize the adverse events of antidepressants in MS patients.

Personalized Approach to Tissue and Liquid Biopsy after Failure of First-Line EGFR-TKIs: Is There an Issue When Tissue Is Not the Issue? A Case Series.

Traditionally, tissue availability from rebiopsy is a prerequisite for adequate sequencing of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in therapy for advanced-stage lung cancer. Tissue biopsy truly is the gold standard for genetic analyses, but in some cases, such as with inadequate localization of the lesion or a patient's inadequate performance status, comorbidities, or unwillingness to undergo an invasive procedure, liquid biopsy-based ctDNA analysis can be a noninvasive alternative approach. However, in some cases the gold standard might not shine that much. It is known that tumor heterogeneity or an inadequate amount of tissue might significantly interfere with the results of testing. In this paper, we present cases of patients with a negative tissue biopsy but a positive liquid biopsy which identified coexisting T790M mutation. These results enabled adequate sequencing and treatment with third-line EGFR-TKIs. Such possibilities stress the need to individualize testing for driver mutations in cases where it is clinically highly indicated.

Intratumoral Treatment with Chemotherapy and Immunotherapy for NSCLC with EBUS-TBNA 19G.

Introduction: Immunotherapy is being used for the past five years either as first line or second line treatment with great results. Chemotherapy and radiotherapy have been also used as combination to immunotherapy to further enhance this type of treatment. Intratumoral treatment has been previously proposed as a treatment option for certain non-small cell lung cancer patients. Patients and Methods: We recruited in total seventy four patients with non-small cell lung cancer in their second line treatment who received only chemotherapy in their first line treatment with programmed death-ligand-1 ≤ 50. Only adenocarcinoma or squamous cell carcinoma, and all negative for epidermal growth factor receptor, anaplastic lymphoma kinase, proto-oncogene tyrosine-protein kinase-1 and proto-oncogene B-Raf. Data were first examined with descriptive statistics choosing frequencies for categorical variables and histograms for the continuous ones. Twenty five received only intravenous immunotherapy and forty-nine intravenous cisplatin with immunotherapy. Data were first examined with descriptive statistics choosing frequencies for categorical variables and histograms for the continuous ones. Results: The relationships between changes of performance status and disease progression were examined via a single correspondence analysis. The two-dimensional scores (coordinates) derived from the correspondence analysis were then regressed against the predictors to form distinct splits and nodes obtaining quantitative results. The best fit is usually achieved by lowering exhaustively the AICc criterion and looking in parallel the change of R2 expecting improvements more than 5%. both types of therapy are capable of producing best ameliorative effects, when either the programmed death-ligand-1 expression or parenchymal site in joint with low pack years are present in the sampling data. Conclusions: Intratumoral treatment combination with cisplatin plus immunotherapy indifferent of nivolumab or pembrolizumab combination is an effective choice. In specific for those with endobronchial lesions. Moreover; patients with programmed death-ligand-1 ≥ 50 had their performance status and disease progression improved over the eight month observation.

Long Term Respiratory Follow-Up for COVID-19 Patients a Multicenter Study.

BACKGROUND: The first wave of the COVID-19 pandemic initiated officially in October 2020. Since then several observations have been made regarding the disease and its symptoms. PATIENTS AND METHODS: We included eighty seven in our observational study. Our main aim was to investigate their long term respiratory follow-up in correlation with their initial radiological and laboratory findings and values. The nose swab PCR test for COVID-19 was used for diagnosis. Patients were monitored at 3 and 6 months after their hospital reception whereas basic parameters of health condition (smoking, PO2, SPO2, WBC, CXR, CRP, intercurrent findings, days of nursing, colchicine administration) in joint with gender and age were recorded. RESULTS: Males seem more susceptible to the viral disease than females in a ratio 1,8:1. The parameters FEV1 and FVC (as % relative changes) were not affected, apart from the DLCO to which CRP (in loge+1 transformation) and SPO2 showed a statistically significant effect. CONCLUSION: None of these patients were intubated, or admitted to the intensive care unit. The respiratory function is affected by the virus and the effect is reversed within the first three months. Males are more affected and the radiological and laboratory findings are associated with the respiratory functions.