How can we optimize the use of methotrexate to treat pediatric patients with inflammatory skin diseases?

INTRODUCTION: Methotrexate (MTX) is a folic acid antagonist used in clinical practice in oncology and rheumatology, as well as in the treatment of inflammatory skin conditions in children. The low-doses of MTX are commonly used in children for the treatment of many inflammatory and autoimmune conditions, including inflammatory skin diseases, due to its anti-inflammatory and immunomodulatory effects. AREAS COVERED: This review discusses the possibilities for optimizing the use of methotrexate in the treatment of pediatric patients with inflammatory skin diseases. A thorough search through PubMed and Embase databases was performed to identify relevant literature. EXPERT OPINION: Clinical observations confirm the high efficacy and safety of low-dose MTX in children with inflammatory skin diseases. Unfortunately, to date there are few studies providing guidelines on the optimal dosage of MTX in children with inflammatory skin diseases; routes of administration; principles of monitoring; and the safety of long-term use of this medication in children. There is still a need for specific recommendations on the safest and most effective dosing and monitoring regimen for children treated with methotrexate for inflammatory skin diseases.

The effect of plasma cytokines on the expression of adiponectin and its receptors in the synovial membrane of joints and the infrapatellar fat pad in patients with rheumatoid arthritis and osteoarthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to joint destruction. Numerous pro-inflammatory mediators, including adipokines, play an important role in the pathogenesis of RA. OBJECTIVE: The aim of the study was to investigate the relationships between selected plasma cytokines and expression of adiponectin and its receptors in the synovium and the infrapatellar fat pad in patients with RA and osteoarthritis (OA). METHODS: Blood, synovium and fat pad samples from 18 patients with RA and 18 with OA were collected during joint replacement surgery. Spearman rank correlations between plasma concentrations of selected cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 p40, IL-13, IL-17, G-CSF and GM-CSF) and the expression of adiponectin and its receptors were determined. Plasma levels of cytokines were determined using a magnetic bead-based multiplex assay, mRNA expression of adiponectin and its receptors were determined by real-time PCR. RESULTS: In OA patients, there were significant positive correlations between adiponectin expression in the synovial membrane and plasma levels of IL-1ß, IL-4, G-CSF and GM-CSF, as well as a significant positive correlation between adiponectin expression in the fat pad and plasma levels of GM-CSF. In addition, OA patients showed significant negative correlations between AdipoR1 and AdipoR2 expression in the synovial membrane and plasma IL-6 levels, as well as between AdipoR2 expression in the synovial membrane and plasma MCP-1 and TNF-α levels. In patients with RA, there were no significant correlations between adiponectin expression in the synovial membrane and infrapatellar fat pad and plasma levels of the cytokines studied. In addition, RA patients showed a statistically significant negative correlation between AdipoR1 expression in the synovial membrane and plasma levels of TNF-α, IL-7, IL-12 and IL-13, and a significant negative correlation between AdipoR1 expression in the infrapatellar fat pad and plasma levels of IL-1ß. CONCLUSIONS: Adiponectin and its receptors showed the correlations with several plasma cytokines, however, a thorough understanding of the role of adiponectin in RA and OA requires further investigation.

New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma-Today and Tomorrow.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.

The Role of Extracellular Vesicles in the Pathogenesis and Treatment of Rheumatoid Arthritis and Osteoarthritis.

Cells can communicate with each other through extracellular vesicles (EVs), which are membrane-bound structures that transport proteins, lipids and nucleic acids. These structures have been found to mediate cellular differentiation and proliferation apoptosis, as well as inflammatory responses and senescence, among others. The cargo of these vesicles may include immunomodulatory molecules, which can then contribute to the pathogenesis of various diseases. By contrast, EVs secreted by mesenchymal stem cells (MSCs) have shown important immunosuppressive and regenerative properties. Moreover, EVs can be modified and used as drug carriers to precisely deliver therapeutic agents. In this review, we aim to summarize the current evidence on the roles of EVs in the progression and treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), which are important and prevalent joint diseases with a significant global burden.

Anaplastic lymphoma kinase inhibitors-a review of anticancer properties, clinical efficacy, and resistance mechanisms.

Fusions and mutations of anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, have been identified in several neoplastic diseases. Rearranged ALK is a driver of tumorigenesis, which activates various signaling pathway associated with proliferation and survival. To date, several agents that target and inhibit ALK have been developed. The most studied ALK-positive disease is non-small cell lung cancer, and three generations of ALK tyrosine kinase inhibitors (TKIs) have been approved for the treatment of metastatic disease. Nevertheless, the use of ALK-TKIs is associated with acquired resistance (resistance mutations, bypass signaling), which leads to disease progression and may require a substitution or introduction of other treatment agents. Understanding of the complex nature and network of resistance mutations may allow to introduce sequential and targeted therapies. In this review, we aim to summarize the efficacy and safety profile of ALK inhibitors, describe off-target anticancer effects, and discuss resistance mechanisms in the context of personalized oncology.

The use of glucarpidase as a rescue therapy for high dose methotrexate toxicity - a review of pharmacological and clinical data.

INTRODUCTION: This review aims to summarize recent data on the pharmacodynamic, pharmacokinetic, and safety of glucarpidase. This is an enzymatic agent that catalyzes the conversion of methotrexate (MTX) into inactive metabolites. Glucarpidase is used to manage high-dose MTX (HDMTX) toxic plasma concentration, especially in patients with impaired renal function. AREAS COVERED: In this review, studies on glucarpidase clinical efficacy as a therapeutic option for patients suffering from MTX kidney toxicity were presented. Pharmacodynamic and pharmacokinetic properties of glucarpidase were included. Moreover, potential interactions and safety issues were discussed. EXPERT OPINION: The use of glucarpidase is an effective therapeutic strategy in both adults and children treated with high doses of MTX for various types of cancer who have developed acute renal failure. Glucarpidase causes MTX to be converted to nontoxic metabolites and accelerates the time for its complete elimination. After administration of glucarpidase, it is possible to resume HDMTX.

Small cell carcinoma with neuroendocrine differentiation of subglottic larynx- a case report.

Small cell cancer (SCC) is a neuroendocrine neoplasm, which is most frequently found in the lungs. Extrapulmonary location of SCC is rare and may involve 2.5-5% of SCCs. We present a case of a 31-year-old male patient with an extremely uncommon subglottic SCC. The patient was qualified for a radical sequential chemoradiotherapy. After treatment, patient's condition suggested complete remission. Recurrence was detected one year later, and the disease rapidly progressed, despite a second line chemotherapy. The patient died 29 months after initial diagnosis. This case aims to raise awareness on the aggressive laryngeal SCC and its good response to first line chemotherapy composed of cisplatin and etoposide, followed by radiotherapy.

Comparison of peripheral blood saturation with brain oxygenation in patients undergoing thoracic surgery.

Introduction: Near-infrared spectroscopy (NIRS) is a non-invasive method of regional tissue oxygenation measurement. Intraoperative use of NIRS to monitor brain oxygenation (BO) during surgery might be beneficial to identify cerebral desaturations. Aim: To compare peripheral blood saturation (SpO2) with BO measurements and evaluate the utility of BO in thoracic surgery. Material and methods: We took BO and SpO2 measurements in a group of 100 patients undergoing standard thoracic surgery. Measurements were made every 15 minutes. The Mann-Whitney U test was used to compare study groups. Spearman's rank correlation coefficient was used to determine correlation between studied parameters. Results: We found a negative correlation between patients' age and BO at the beginning of surgery. Operations lasted between 30 and 200 minutes. We found a positive correlation between BO and SpO2 between 15 and 90 minutes of surgery. Subsequently, BO remained at a low level while SpO2 returned to baseline values. Higher minimum SpO2 values were noted in patients undergoing left-sided procedures. Conclusions: Cerebral oxygenation does not return to baseline values until the end of the surgery as opposed to the SpO2. Furthermore, both SpO2 and BO correlate negatively with the overall duration of thoracic surgery. In addition, after 90 minutes of surgery, SpO2 stopped reflecting brain oxygenation.

Examination of resistance of various methods of pulmonary vessel occlusion to hydrostatic pressure.

Objective: The aim of this study was to compare pressure resistance of the most common methods of vessel occlusion during thoracic surgical procedures: ligations, clips, and vascular endostaplers. Methods: Pulmonary vessels were obtained during routine thoracic surgeries. A ball-tipped cannula was inserted through an opening in the side wall and secured with a linen ligature from slipping out. Subsequently, saline was infused into the vessel. We recorded the pressure on which a leakage occurred. Results: A total of 65 vessels, divided between 3 groups, were enrolled in the study. In the endostaplers group, median bursting pressures were 262.5 mmHg and 300 mmHg for arteries and veins, respectively. In the case of clips, it was over 750 mmHg in both types of the vessels. The same results were observed in the ligation group. Minimal bursting pressures in endostapler occlusion were 187.5 mmHg and 225 mmHg in arteries and veins, respectively. In the case of clips, it was 600 mmHg for arteries and 675 mmHg for veins. A total of 525 mmHg (arteries) and 750 mmHg (veins) were the minimal leaking values observed in vessels occluded with ligations. Comparative analysis showed statistically significant differences in endostapler-clips and endostapler-ligations pairs (p < 0.001). There were no differences between clips and ligations. Conclusions: The examined methods are capable of occluding pulmonary vessels under physiological conditions. Furthermore, ligations and clips are resistant to pressures highly exceeding physiological values.

Post-thoracotomy intercostal artery pseudoaneurysm manifesting as a chest wall metastasis.

Intercostal artery pseudoaneurysm (IAP) represents an extremely rare vascular abnormality developing after an insult to the vascular wall with blood collection within the vascular wall layers and subsequent dilatation. Treatment options, apart from observation, include embolization, endovascular stenting, and surgical correction. We describe the case of a 73-year-old male patient with colonic adenocarcinoma pulmonary metastasis. Repetitive wedge resections and a right lower lobectomy were performed to remove multiple metastatic lesions. At follow-up assessment, the patient reported localized thoracotomy site pain progressing with time and unresponsive to oral analgesics. Chest computed tomography (CT) revealed a pseudoaneurysm of 4-cm diameter of the right 5th intercostal artery. The patient underwent embolization of the lumen and was discharged from the hospital after 24 h. Successive CT re-assessment checks were unremarkable.

Arterial sleeve lobectomy for lung cancer invading chest wall.

Lung cancer is a leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is a predominant subtype and treatment may include immunotherapy, radiotherapy, chemotherapy, and surgery. Tumors of bigger size infiltrating large bronchi and vessels require more invasive resection such as pneumonectomy. To save lung parenchyma, sleeve lobectomy can be performed in certain patients.We report the case of a patient with NSCLC infiltrating the chest wall who underwent arterial sleeve lobectomy with rib resection. Furthermore, we discuss other surgical treatment strategies.A 58-year-old female patient was admitted to the hospital in 2020 with pain in her left posterolateral chest. Radiological imaging revealed a tumor (5.0×3.5×4.8 cm) in the top of the left lung, infiltrating pulmonary artery and ribs. Therefore, left upper sleeve lobectomy together with resection of rib blocks II to V was performed. The surgery was uncomplicated, but a few weeks postoperatively, the patient experienced repeated episodes of consciousness disturbances. Contrast CT revealed a cerebral malformation in the patient who died 3.5 months after surgery.Sleeve lobectomy can be safely performed in patients with lung tumors infiltrating larger bronchi and vessels who would not tolerate pneumonectomy.

The Role of Adipokines in the Pathogenesis of Psoriasis.

Psoriasis is a chronic and immune-mediated skin condition characterized by pro-inflammatory cytokines and keratinocyte hyperproliferation. Dendritic cells, T lymphocytes, and keratinocytes represent the main cell subtypes involved in the pathogenesis of psoriasis, while the interleukin-23 (IL-23)/IL-17 pathway enhances the disease progression. Human adipose tissue is an endocrine organ, which secretes multiple proteins, known as adipokines, such as adiponectin, leptin, visfatin, or resistin. Current evidence highlights the immunomodulatory roles of adipokines, which may contribute to the progression or suppression of psoriasis. A better understanding of the complexity of psoriasis pathophysiology linked with adipokines could result in developing novel diagnostic or therapeutic strategies. This review aims to present the pathogenesis of psoriasis and the roles of adipokines in this process.

Basic Operative Tactics for Pulmonary Echinococcosis in the Era of Endostaplers and Energy Devices.

Human echinococcosis is a zoonotic infection caused by the larvae of the tapeworm species Echinococcus. The liver is the most common location for a primary echinococcosis. However, the parasite may bypass or spread from the liver to the lungs, causing primary or secondary pulmonary echinococcosis, respectively. Pulmonary echinococcosis is a clinically challenging condition in which anthelminthic regiments are important, but surgery has the central role in removing the cysts and preventing recurrences. Surgical treatment may involve cystotomy, enucleation, capitonnage, or atypical resections, which occasionally are in combination with hepatic procedures. The utilization of modern devices is greatly underdescribed in surgery for thoracic infections, even though these facilitate much of the work. Therefore, this article aims to describe pulmonary echinococcosis and the role of modern surgical devices in the treatment process. Furthermore, we report surgical treatment of three different cases of pulmonary echinococcosis. Surgeries of uncomplicated and ruptured hepatic or pulmonary cysts are described. Simple small pulmonary echinococcal lesions can be excised by endostaplers both for diagnostic and curative reasons. Larger cysts can be removed by energy devices unless large bronchial air leaks occur. Complicated cysts require treatment by more extensive techniques. Inexperienced surgeons should not abstain but should carefully decide preoperatively how to proceed.

The role of selected non-coding RNAs in the biology of non-small cell lung cancer.

Lung cancer is the second most frequently diagnosed cancer worldwide and a leading cause of cancer-related deaths. Non-small cell lung carcinoma (NSCLC) represents 85% of all cases. Accumulating evidence highlights the outstanding role of non-coding RNA (ncRNA) in regulating the tumorigenesis process by modulating crucial signaling pathways. Micro RNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA) are either up- or downregulated in lung cancer patients and can promote or suppress the progression of the disease. These molecules interact with messenger RNA (mRNA) and with each other to regulate gene expression and stimulate proto-oncogenes or silence tumor suppressors. NcRNAs provide a new strategy to diagnose or treat lung cancer patients and multiple molecules have already been identified as potential biomarkers or therapeutic targets. The aim of this review is to summarize the current evidence on the roles of miRNA, lncRNA and circRNA in NSCLC biology and present their clinical potential.

Extremely Rare Pulmonary Metastases of Skin Basal Cell Carcinoma: Report of Two Cases with Clinicopathological Features.

Basal cell carcinoma (BCC) is the most frequent human skin cancer, but metastasizing BCC (MBCC) is extremely rare, developing in approximately 0.0028% to 0.55% of BCC patients. Herein, we report two cases of pulmonary MBCC. The first one developed in a 72-year-old male who underwent surgical resection due to multiple recurrences and adjuvant radiotherapy. Immunohistochemistry showed that neoplastic cells expressed Ber-EP4, CK5/6, p63, EMA (focally), BCL-2, and CD10, but were negative for CK7, CK20, S100, estrogen and progesterone receptors, and TTF-1. The second case is a 64-year-old female treated with vismodegib. Clinicopathological features and differential diagnoses are described.

The Potential Role of Connexins in the Pathogenesis of Atherosclerosis.

Connexins (Cx) are members of a protein family which enable extracellular and intercellular communication through hemichannels and gap junctions (GJ), respectively. Cx take part in transporting important cell-cell messengers such as 3',5'-cyclic adenosine monophosphate (cAMP), adenosine triphosphate (ATP), and inositol 1,4,5-trisphosphate (IP3), among others. Therefore, they play a significant role in regulating cell homeostasis, proliferation, and differentiation. Alterations in Cx distribution, degradation, and post-translational modifications have been correlated with cancers, as well as cardiovascular and neurological diseases. Depending on the isoform, Cx have been shown either to promote or suppress the development of atherosclerosis, a progressive inflammatory disease affecting large and medium-sized arteries. Cx might contribute to the progression of the disease by enhancing endothelial dysfunction, monocyte recruitment, vascular smooth muscle cell (VSMC) activation, or by inhibiting VSMC autophagy. Inhibition or modulation of the expression of specific isoforms could suppress atherosclerotic plaque formation and diminish pro-inflammatory conditions. A better understanding of the complexity of atherosclerosis pathophysiology linked with Cx could result in developing novel therapeutic strategies. This review aims to present the role of Cx in the pathogenesis of atherosclerosis and discusses whether they can become novel therapeutic targets.

Clinicopathological Features of Intrathoracic Liposarcoma-A Systematic Review with an Illustrative Case.

BACKGROUND: Liposarcoma (LPS) is one of the most common soft-tissue sarcomas. However, intrathoracic LPS is rare, as only 1% of all LPS cases are found in the thorax. METHODS: A systematic literature review through PubMed and Embase databases was performed. Only eligible case reports and case series reporting intrathoracic LPS in adult patients were included. Kaplan-Meier curves were calculated to evaluate the survival rate of included patients based on the histological subtype of LPS. RESULTS: 123 studies reporting 197 patients were included. We added a case of a 69-year-old female patient with recurrent giant intrathoracic LPS. The primary tumor measured 15.1cm × 22.9 cm × 21.9 cm and weighed 3100 g. Six months later, the patient was admitted to the hospital with another intrathoracic tumor measuring 9.5 cm × 9 cm× 1.4 cm. The immunohistochemical studies showed expression of murine double minute 2 (MDM2) antigen in both primary and recurrent tumor cells. CONCLUSIONS: Dyspnea, chest pain, and cough were the most common symptoms reported in included studies. Overall, the 5-year survival rate was 62%. The highest survival was observed in well-differentiated LPS patients (80%) and the lowest in myxoid LPS (31%).

Association of major postoperative wound and anastomotic complications in thoracic surgery with COVID-19 infection.

Background: One of the most uncommon manifestations of perioperative Covid-19 infection is impaired wound healing. The aim of this study is to present previously unreported observation of thoracotomy and esophageal anastomosis dehiscence in the course of Covid-19 infection after uncomplicated thoracic surgeries. Methods: This is a single-center study describing unusual wound and anastomosis complications in COVID-19 patients after uncomplicated thoracic surgeries. Medical data was prospectively collected and retrospectively reviewed. All patients admitted to the hospital were symptom free and tested negative for COVID-19 infection preoperatively. Clinical courses were compared to a non-infected control group from historical data. Results: The total of 14 patients were included. Study group involved 7 patients with major wound and anastomosis complications concurrent with COVID-19 infection. Control group was composed of 7 patients matched with the type of surgeries and treated before Coronavirus pandemic. Surgeries included lung transplantations, lung cancer surgeries and esophagectomies. The mean age of the study group was 65.7 years. Major wound and anastomosis complications occurred 13.6 days postoperatively while the mean time of Covid-19 detection was 21 days. The course of infection varied from mild to very severe which resulted in 3 deaths due to COVID-19 induced ARDS. The mean time of hospital stay was 40,9 days. There were no differences between both groups in baseline characteristics while hospitalization time was significantly longer in the study group. Conclusions: COVID-19 infection should be included in differential diagnosis in postoperative patients with major wound or anastomosis complications.

Central, peripheral ECMO or CPB? Comparsion between circulatory support methods used during lung transplantation.

BACKGROUND: Chronic obstructive pulmonary disease, cystic fibrosis and usual interstitial pneumonia are three most common indications for lung transplantation (LuTx) in Poland. As a result of irreversible destruction of pulmonary parenchyma and extended respiratory insufficiency that appear afterwards, it is crucial to estimate the reserve of gas exchange in each lung before and during surgery. Altering conditions of gas exchange require adaptation in circulatory system as well. In some of the cases the use of extracorporeal life support appears to be necessary to undergo the transplantation successfully. Cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) used during operation allow to replace the function of heart and lung, but they are also related to complications in the form of acute kidney failure, bleeding, heart arrhythmias or thromboembolic complications. METHODS: We reviewed 77 LuTx from 2009 to 2020 performed at the Department of Thoracic Surgery and Transplantation. 40/77 (51%) patients required intraoperative extracorporeal assistance: 8 required CBP and 32 required ECMO. In the ECMO group 14/32 (44%) patients had peripheral cannulation and 18/32 (56%) had central one. We have calculated the survival rates and reviewed postoperative complications after lung transplantations. Cumulative Kaplan-Meier survival curves were calculated. Differences between the groups were evaluated by the Chi- square analysis for discontinuous variables and t-test for continuous variables. RESULTS: The use of intraoperative central extracorporeal membrane oxygenator was associated with increased survival rates comparing to patients without external support (30-days, 1-year, 3-years, 5-years rates: 78%, 66%, 66%, 66% vs 83%, 65%, 59%, 44% respectively). Furthermore, survival was enhanced comparing to peripheral ECMO or cardiopulmonary bypass as well (50%, 41%, 41%, 33%; 75%, 50%, 50%, 38% respectively). Acute kidney injury and thromboembolic complications occurred statistically more often in case of patients that underwent lung transplantation with support devices (p = 0.005, p = 0.02 respectively). Frequency of other complications was comparable among groups. CONCLUSIONS: The use of central extracorporeal membrane oxygenation should be favorized over peripheral cannulation or cardiopulmonary bypass. CPB should be no longer used during LuTx. Trial registration Not applicable.

Leiomyosarcoma in adrenal gland.

Not required for Clinical Vignette.