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Background: Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with multiple independent risk factors contributing to its development. The objective of this study was represented by the impact of independent risk factors, such as smoking, anemia, cachexia or COPD (chronic obstructive pulmonary disease) for lung cancer development., Methods: We conducted a retrospective study, and we analyzed a database of 412 patients hospitalized between 1 February and 31 December 2023 in the Pulmonology Department of the Mureș County Clinical Hospital. Following the analysis of the inclusion and exclusion criteria, the final analyzed group included 115 patients., Results: From the study group, 88 patients were diagnosed with non-small cell lung cancer and 27 with small cell lung cancer. Of the non-small cell lung cancer patients, 50% had adenocarcinoma and 50% had squamous cell carcinoma. Chronic obstructive pulmonary disease and cardiovascular diseases predominate as concomitant pathologies, with 82 and 81 cases identified among the patients evaluated, respectively. The incidence of diabetes mellitus was n = 20 for the patients, followed by asthma and other neoplasms. The body mass index was also analyzed with an average of 24.6. Body mass index does not correlate with histological type. The mean hemoglobin value in the group of patients was 12.8, and this could not be correlated with the histopathological type., Conclusions: Chronic obstructive pulmonary disease and lung cancer may just be two different clinical presentations based on the same etiological factors, which also have a lot of overlapping pathophysiological mechanisms. Therefore, Chronic obstructive pulmonary disease represents an individual risk factor for developing lung cancer. Smoking, as well as anemia, cachexia or other comorbidities (COPD), are individual risk factors for lung cancer.

Background/Objectives : Melanoma is an aggressive skin malignancy, and the majority of deaths associated with melanoma result from malignant skin lesions. Our study aims to evaluate the expression of the markers CD133 and NANOG, associated with tumor stem cells, and to analyze their link with epidemiological and histological parameters, thus contributing to early diagnosis and the development of targeted therapies. Methods : We performed a retrospective study in the Mureș Clinical County Hospital, Romania, which included 66 cases of melanoma: 50 primary cutaneous melanomas, 10 metastases, and 6 local recurrences. CD133 and NANOG marker expression was assessed by immunohistochemistry and quantified using the H score. Statistical analyses were applied to determine the correlations between marker expression and clinicopathological parameters. Results : CD133 expression was identified in six cases (12%) of primary melanoma, with a mean H-Score of 29, and was associated with an increased Breslow index and a higher number of mitoses. NANOG expression was positive in 30 cases (60%) of primary melanoma, with a median H-Score of 15 and with increased expression observed in cases with pagetoid migration and lesions in situ. In metastases, eight cases (80%) were positive for NANOG and four (40%) for CD133. Local recurrences showed positive expression for NANOG in four cases (66%). Conclusions : The expression of CD133 and NANOG markers highlights the role of tumor stem cells in melanoma progression. Early identification of these markers could improve diagnosis and treatment, including the application of targeted therapies.

(1) Background: Melanoma represents the most aggressive form of skin cancer, with an increasing incidence and numerous risk factors. The COVID-19 pandemic has led to modifications in work protocols. This study aims to elucidate potential changes in the number and characteristics of primary melanomas diagnosed in the Pathology Department of the Târgu Mureș County Clinical Hospital before, during, and after the COVID-19 pandemic. (2) Methods: This study included 140 patients grouped into six periods: two pre-COVID-19 periods, the COVID-19 pandemic period, and three post-COVID-19 periods. Epidemiological data, diagnoses, and histopathological reports were analyzed. (3) Results: The number of cases diagnosed during the COVID-19 pandemic was significantly lower than in the other analyzed periods. Regarding the monitored parameters, a statistically significant increase was observed in the first two post-COVID-19 periods, with a return to values similar to those of the first period in the last analyzed period. Additionally, a statistically significant increase in the incidence of distant metastases was identified in the post-COVID-19 periods. (4) Conclusions: The COVID-19 pandemic had a negative impact on the diagnosis of new melanoma cases, leading to an increase in the number of cases and a worsening of prognostic parameters.

Background and aim Psychiatric pathology does not always start on its own but may be conditioned or triggered by a comorbidity with a high impact on the human psyche. When there are comorbidities, psychiatric pathology can occur due to the high diagnostic burden. Our study aims to find out if there is a correlation between the diagnosis of breast cancer and its severity, and psychiatric symptoms such as depressive mood, atypical anxiety, or even autolytic ideation that directly influence the quality of life of patients. Materials and methods The study is a prospective, cross-sectional, single-center study carried out between December 2023 and June 2024 at the Mureș County Clinical Hospital in Romania. The sample population had to be at least 18 years old and had to be diagnosed with breast cancer recently. We applied two tests, WHODAS 2 (World Health Organization's Disability Assessment Schedule 2.0) and level 1 (level 1 of cross-sectional measurements of symptoms), to be able to measure and aid assessment of mental health domains that are important across psychiatric diagnoses and also the degree of disability triggered by breast cancer. The statistical analysis included descriptive statistics and interferential statistics. Statistical tests, such as Shapiro-Wilk, Kruskal-Wallis, and Mann-Whitney U tests with Bonferroni correction tests, were used. The p-value was set to 0.05 with a confidence interval (CI) of 95%. Results The study included 120 women diagnosed with breast cancer, with a mean age of 56.64 ± 9.46 years. Regarding the severity of the diagnosis, 44 women (36.66%) had non-invasive cancer, 58 (48.33%) had invasive cancer, and 18 (15%) had metastases. There was a statistically significant difference between three of the five selected level 1 domains across cancer types. The WHODAS 2.0 disability scores showed a significant difference between groups (p < 0.001). Subjects with non-invasive cancer had the lowest WHODAS 2.0 score, followed by the invasive group, while metastases had the highest score. Conclusions Following the application of the two tests, level 1 and WHODAS 2.0, to our group of subjects, statistically significant differences were observed between the three categories of subjects. The degree of disability and the occurrence of psychological symptoms differed according to the severity of breast cancer. Adapting to the status of an oncological patient entails multiple changes from a psycho-emotional, social, occupational, and professional point of view. Although the most recent medications prolong survival, a holistic approach that considers psychological aspects can improve patients' long-term results., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Commission of the “George Emil Palade” University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș issued approval 1853/13.09.2022. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Andra et al.)

Psychiatric pathology stands out in contemporary society not only as independent but also through its association with other medical comorbidities such as neoplastic diseases. Specialized literature confirms over time the coexistence of these diseases. There is a tendency to develop various psychiatric manifestations such as mood disorders and somatoform disorders, as well as decompensation of underlying existing psychiatric pathologies (anxiety disorders and psychotic disorders) or personality disorders (a good example is the exacerbation of anxiety in obsessive-compulsive personality disorder). Breast cancer, like any disabling disease, affects the person's psyche and behaviors as a whole. It is scientifically proven that mental balance influences the quality of life of patients and also the evolution and prognosis of the disease, psychological processes being able to modulate the activity of the tumor process. It is necessary to expand clinical practice and research beyond the simple evaluation of symptoms, and the goal of treatment should not only be to reduce symptoms but also to improve in terms of both physically and mentally the quality of life of cancer patients., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Andra et al.)

The use of natural products as alternatives to traditional pharmacological treatments in orthodontics is gaining interest due to their anti-inflammatory, antibacterial, and antioxidant properties. This systematic review synthesizes evidence from clinical trials to evaluate the efficacy of natural products in reducing inflammation and bacterial presence in orthodontic and orthognathic treatment settings. The database search was conducted across PubMed, Scopus, and Embase up to January 2024. The review focused on randomized controlled trials only. The selected studies centered on the anti-inflammatory, antibacterial, and antioxidant effects of natural products, adhering to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for data extraction. Nine studies, totaling 358 participants, were included. Significant findings demonstrated a reduction in gingival inflammation by over 40% with the use of Aloe vera compared to chlorhexidine. Another study noted a decrease in bleeding on probing by 13.6 points in the treatment group over placebo. Additionally, honey showed a rapid modulation of plaque pH and significantly reduced bacterial counts of Streptococcus mutans . Furthermore, the use of resveratrol emulgel was linked to substantial improvements in gingival health, with a reduction in the gingival index and probing pocket depth. The results indicate that natural products can significantly enhance orthodontic treatment outcomes by reducing inflammation and bacterial levels. These products offer effective alternatives to traditional treatments and show potential for integration into routine orthodontic care protocols. Further research is encouraged to standardize application methods and dosages to maximize clinical benefits and patient satisfaction.

Introduction: Peripheral nerve injuries are a significant clinical challenge. The rat sciatic nerve serves as an ideal model for studying nerve regeneration. Extensive research has been conducted to unravel the intricate mechanisms involved in peripheral nerve regeneration, aiming to develop effective therapeutic strategies for nerve injury patients. Research including different types of materials that can be used as nerve guides like synthetic polymers have been investigated for their biocompatibility and molding properties. Among multiple stem cell types, adipose-derived stem cells (ASCs), bone marrow-derived mesenchymal stem cells (BM-MSCs), and induced pluripotent stem cells (iPSCs) have shown neuroprotective and regenerative important properties., Methods: The purposes of our study were to develop a protocol for rat sciatic nerve injury treated with 3D-printed guide and adipose stem cells to investigate nerve regeneration through histologic examination and biomechanical characteristics of muscular tissue. We use 20 (100%) male Wistar rats, measuring between 350 g ± 35 g, who underwent complete transection of the right sciatic nerve, resulting in a 1 cm defect. The group was separated into three subgroups: the first subgroup (n = 8) was treated with a 3D-printed guide with adipose stem cells, the second subgroup (n = 8) was treated with a 3D-printed guide without adipose stem cells, and the third subgroup (n = 4) was the control group. At four, eight, and 12 weeks, we measured with ultrasonography the grade of muscular atrophy. At 12 weeks, we harvested the sciatic nerve and performed a histological examination and mechanical investigation of the tibialis anterior muscle., Results: On the examined specimen of the first subgroup, cross-sectioned nerve structures were present, surrounded by a mature fibro-adipose connective tissue, with blood vessels. In the second subgroup, no nerve structure was observed on the examined sections, but in the polymorphic inflammatory infiltrate and control group, no signs of regeneration were found., Conclusions: The present study shows a promising potential when utilizing adipose stem cell-based therapies for promoting peripheral nerve regeneration following large (>1 cm) nerve defects knowing that at this size, regeneration is impossible with known treatments., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: The Committee of Ethics in Scientific Research of the George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, Romania Issued protocol number 1734/12.05.2022. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This research was funded by George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Romania (grant number: 510/18/17.01.2022). Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Trambitas et al.)

Individual personality refers to the Ego and the interpersonal sector. The Ego corresponds to consciousness and self-esteem, including the capacities for emotional self-regulation, self-control, self-evaluation, and self-direction in relation to personal goals. When neoplastic and psychiatric diseases coexist, a patient's quality of life is significantly impacted. While there are somatic differences in disease progression, how the illness is perceived and mainly experienced depends on personality traits. In this study, we administered the DECAS Personality Inventory (a Romanian-validated instrument based on the Five-Factor model of personality) to a group of 121 patients diagnosed with breast cancer to explore the relationships among their personality traits. Descriptive statistics revealed that the mean T scores for openness, extroversion, and emotional stability were low, while the scores for conscientiousness and agreeableness were at an average level. Our findings suggest that, in the studied group, low levels of emotional stability, extroversion, and openness were unfavorable personality dimensions that should be a primary focus of therapeutic strategies, as they significantly affect the quality of life in patients with breast cancer., Competing Interests: The authors declare no conflict of interest., (© 2024 by the authors.)

Melanoma represents a public health issue. One of the biggest goals of current research is to develop new therapeutic options for patients affected by this aggressive tumor. We conducted a retrospective study including 105 patients diagnosed with cutaneous and ocular melanoma, with stages varying from pT1a to pT4b and pT4e, respectively, and we performed immunohistochemistry reactions with the new potential prognostic marker, VISTA (V-domain Ig suppressor of T cell activation). We quantified the expression by applying the H-score adapted for VISTA and divided the patients, based on the median value, into groups that presented high, low, and negative expression. Therefore, we obtained 65 cases with positive expression for cutaneous melanoma and 8 cases with positive expression for ocular melanoma. Forty-one cases presented high expression in cutaneous melanoma and three cases presented high expression in ocular melanoma. In cutaneous melanoma, analytic statistics showed that VISTA expression was associated with a high Breslow index, high mitotic count, high Ki67 expression, and advanced clinicopathological stage. The majority of ocular melanoma cases demonstrating a positive reaction were classified as stage pT3, whereas earlier stages showed a negative reaction. Our findings underscore a significant correlation between VISTA expression and key prognostic factors in melanoma. Looking ahead, the prospect of future randomized studies holds promise in corroborating the clinical relevance of our findings. By further elucidating the intricate relationship between VISTA expression and melanoma progression, new treatment strategies could be found, improving patient outcomes in this challenging neoplasm.

(1) Background : Arteriovenous fistula (AVF) is the preferred type of vascular access for dialysis in patients with end-stage kidney disease (ESKD). However, the primary patency of AVF at one year is under 70% due to several risk factors and comorbidities. Leukocyte glucose index (LGI), a new biomarker based on blood leukocytes and glucose values, has been found to be associated with poor outcomes in cardiovascular disease. The aim of this study is to analyze the impact of LGI on the long-term primary patency of AVF following dialysis initiation. (2) Methods : We conducted a retrospective observational study in which we initially enrolled 158 patients with ESKD admitted to the Vascular Surgery Department of the Emergency County Hospital of Targu Mures, Romania, to surgically create an AVF for dialysis between January 2020 and July 2023. The primary endpoint was AVF failure, defined as the impossibility of performing a chronic dialysis session due to severe restenosis or AVF thrombosis. After follow-up, we categorized patients into two groups based on their AVF status: "functional AVF" for those with a permeable AVF and "AVF failure" for those with vascular access dysfunction. (3) Results : Patients with AVF failure had a higher prevalence of atrial fibrillation ( p = 0.013) and diabetes ( p = 0.028), as well as a higher LGI value (1.12 vs. 0.79, p < 0.001). At ROC analysis, LGI had the strongest association with the outcome, with an AUC of 0.729, and an optimal cut-off value of 0.95 (72.4% sensitivity and 68% specificity). In Kaplan-Meier survival analyses, patients in the highest tertile (T3) of LGI had a significantly higher incidence of AVF failure compared to those in tertile 1 ( p = 0.019). Moreover, we found that patients with higher baseline LGI values had a significantly higher risk of AVF failure during follow-up (HR: 1.48, p = 0.003). The association is independent of age and sex (HR: 1.65, p = 0.001), cardiovascular risk factors (HR: 1.63, p = 0.012), and pre-operative vascular mapping determinations (HR: 3.49, p = 0.037). (4) Conclusions : In conclusion, high preoperative values of LGI are positively associated with long-term AVF failure. The prognostic role of the biomarker was independent of age, sex, cardiovascular risk factors, and pre-operative vascular mapping determinations.

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are the most frequently occurring non-melanocytic skin cancers. The objective of our study is to present the pathophysiology of BCC and cSCC and its direct relationship with the histopathological diagnostics and the differential diagnostics of these types of cancer, based on the morphological characteristics, immunohistochemical profile, and genetic alterations. The qualitative study was based on emphasizing the morphological characteristics and immunohistochemistry profiles of BCC and cSCC and the differential diagnostics based on the tissue samples from the Clinical Pathology Department of Mures Clinical County Hospital between 2020 and 2022. We analyzed the histopathological appearances and immunohistochemical profiles of BCC and cSCC in comparison with those of Bowen disease, keratoacanthoma, hyperkeratotic squamous papilloma, metatypical carcinoma, pilomatricoma, trichoblastoma, Merkel cell carcinoma, pleomorphic dermal sarcoma (PDS), and melanoma. Our study showed the importance of the correct histopathological diagnosis, which has a direct impact on the appropriate treatment and outcome for each patient. The study highlighted the histopathological and morphological characteristics of NMSCs and the precursor lesions in HE and the immunohistochemical profile for lesions that may make the differential diagnosis difficult to establish.

From the first reports of SARS-CoV-2, at the end of 2019 to the present, the global mortality associated with COVID-19 has reached 6,952,522 deaths as reported by the World Health Organization (WHO). Early intubation and mechanical ventilation can increase the survival rate of critically ill patients. This prospective study was carried out on 885 patients in the ICU of Mureș County Clinical Hospital, Romania. After applying inclusion and exclusion criteria, a total of 54 patients were included. Patients were monitored during hospitalization and at 6-month follow-up. We analyzed the relationship between invasive mechanical ventilation (IMV) and non-invasive mechanical ventilation (NIMV) and radiological changes on thoracic CT scans performed at 6-month follow-up and found no significant association. Regarding paraclinical analysis, there was a statistically significant association between patients grouped by IMV and ferritin level on day 1 of admission ( p = 0.034), and between patients grouped by PaO 2 /FiO 2 ratio with metabolic syndrome ( p = 0.03) and the level of procalcitonin ( p = 0.01). A significant proportion of patients with COVID-19 admitted to the ICU developed pulmonary fibrosis as observed at a 6-month evaluation. Patients with oxygen supplementation or mechanical ventilation require dynamic monitoring and radiological investigations, as there is a possibility of long-term pulmonary fibrosis that requires pharmacological interventions and finding new therapeutic alternatives.

Background: The neurological complications of coronavirus disease 2019 (COVID-19) infection and the side effects of vaccination include immune-mediated diseases of the central nervous system (CNS) such as acute disseminated encephalomyelitis (ADEM). It is an acute-onset demyelinating disease that involves a rapid evolution and multifocal neurological deficits that develops following a viral or bacterial infection or, less frequently, following vaccination. Acute hemorrhagic leukoencephalitis (AHLE) is the hemorrhagic variant of ADEM that presents a more severe evolution which can be followed by coma and death. The objectives of this study consist in evaluating the diagnosis, clinical characteristics, imaging and laboratory features, evolution, and treatment of ADEM and AHLE following COVID-19 infection or vaccination., Methods: We performed a systematic review of the medical literature according to PRISMA guidelines that included ADEM cases published between 1 January 2020 and 30 November 2022 following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination and also included our own clinical experience regarding this pathology., Results: A total number of 74 patients were diagnosed with ADEM, 45 following COVID-19 infection and 29 after a SARS-CoV-2 vaccine. A total of 13 patients (17.33%) presented AHLE. The moderate form of COVID-19 presented a positive correlation with AHLE (r = 0.691, p < 0.001). The existence of coma and AHLE was correlated with poor outcomes. The following more aggressive immunomodulatory therapies applied in severe cases were correlated with poor outcomes (major sequelae and death): therapeutic plasma exchange (TPE) treatment (r = 382, p = 0.01) and combined therapy with corticosteroids and TPE (r = 0.337, p = 0.03)., Conclusions: Vaccinations are essential to reduce the spread of the COVID-19 pandemic, and the monitoring of adverse events is an important part of the strategic fight against SARS-CoV-2. The general benefits and the overall good evolution outweigh the risks, and prompt diagnosis is associated with a better prognosis in these patients.

Background and objective Nonalcoholic fatty liver disease (NAFLD) is closely linked to metabolic syndrome, leading to consequences related to dyslipidemia, endothelial dysfunction, type 2 diabetes, and obesity. Due to a limited understanding of the factors contributing to the progression of NAFLD, predicting clinical outcomes in patients remains challenging. In light of this, this study aimed to evaluate the association between the occurrence of NAFLD and the neutrophil-percentage-to-albumin ratio (NPAR) as well as the neutrophil-to-lymphocyte ratio (NLR). Methods A total of 115 adult patients (mean age: 58 ± 12.5 years; 55.65% male) who underwent abdominal non-contrast-enhanced CT scans were included in the study. The analysis of CT scans was conducted to assess the attenuation values of liver parenchyma. Results  There was a statistically significant difference in terms of gamma-glutamyl transpeptidase (GGT), triglyceride (TG), albumin, and NPAR between individuals with and without hepatic steatosis (GGT p<0.0001, TG p=0.0006, albumin p<0.0001, NPAR p=0.001). However, NLR values between the two groups did not show any statistical differences. NPAR (r=-0.27, p=0.0029) had a weak inverse correlation with liver attenuation value, which is expressed in Hounsfield units (HU). Conclusions Significant differences were observed in GGT, TG, albumin, and NPAR levels between individuals with and without hepatic steatosis. An inverse correlation between NPAR and liver attenuation values was also observed., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Cucoranu et al.)

At present, obesity, as a part of metabolic syndrome, represents the leading factor for disability, and is correlated with higher inflammation status, morbidity, and mortality. The purpose of our study is to add new insights to the present body of knowledge regarding the correlations between chronic systemic inflammation and severe obesity, which cannot be treated without considering other metabolic syndrome conditions. Biomarkers of high-level chronic inflammation are recognized as important predictors of pro-inflammatory disease. Besides the well-known pro-inflammatory cytokines, such as WBCs (white blood cells), IL-1 (interleukin-1), IL-6 (interleukin-6), TNF-alpha (tumor necrosis factor-alpha), and hsCRP (high-sensitivity C-reactive protein), as well as anti-inflammatory markers, such as adiponectin and systemic inflammation, can be determined by a variety of blood tests as a largely available and inexpensive inflammatory biomarker tool. A few parameters, such as the neutrophil-to-lymphocyte ratio; the level of cholesterol 25-hydroxylase, which is part of the macrophage-enriched metabolic network in adipose tissue; or levels of glutamine, an immune-metabolic regulator in white adipose tissue, are markers that link obesity to inflammation. Through this narrative review, we try to emphasize the influence of the weight-loss process in reducing obesity-related pro-inflammatory status and associated comorbidities. All data from the presented studies report positive results following weight-loss procedures while improving overall health, an effect that lasts over time, as far as the existing research data show.

Introduction: Concerns about how non-alcoholic fatty liver disease (NAFLD) might contribute to the development of cardiovascular disease (CVD) have grown as the importance of NAFLD and its relationship to the metabolic syndrome has grown. The purpose of this cross-sectional retrospective is to investigate potential correlations between hepatic steatosis in liver segments seen when measuring calcium score and the presence of atherosclerotic CAD (coronary artery disease)., Methods: Two hundred patients (mean age, 57 years±10) who underwent coronary cardiac computed tomography (CT) scans were included. CT scans were analysed to assess the attenuation of liver parenchyma and the coronary artery calcification (CAC)., Results: Age, gender, body mass index (BMI) and CAC score were significantly associated with hepatic steatosis. Among all patients, CAC score (r=-0.31, p<0.0001), and BMI (r=-0.40, p<0.0001) had a moderate negative correlation with the values of liver attenuation. BMI (OR: 1.109, p=0.001), CAC score (OR: 1.629, p<0.001), and age (OR: 1.050, p<0.001) were found to be independent predictors of hepatic steatosis through logistic regression., Conclusions: A statistically significant correlation between CAC score and the presence of NAFLD as evaluated by non-contrast-enhanced CT was demonstrated. BMI, CAC score, and age were identified as independent predictors of hepatic steatosis., Competing Interests: None to declare., (Copyright © 2023, Medical University Publishing House Craiova.)

Melanoma is a malignant cancer of the skin, the incidence of which has been increasing year by year. This neoplasm has high aggressivity as well as the potential for invasion and metastases. Multiple factors related to the proliferation of this type of tumor have been identified, such as exposure to ultraviolet (UV) radiation and specific genetic backgrounds. From a histological and cytological point of view, the most common cells that are found in melanoma are epithelioid or spindle cells. To confirm the diagnosis and the melanocytic origin of the tumor, specific and sensitive markers are used. Also, observation of the behavior of this cancer, including its proliferative properties, has led to the development of multiple therapies, each of which is characteristic of the pathological stage at the time of diagnosis. While surgery is the most important therapeutic and curative option in cases of melanoma in situ, chemotherapy has been the main treatment for advanced stages of melanoma for many years. However, recently, targeted therapy and immunotherapy have changed the approach to treatment. At present, multiple studies are attempting to obtain further data about the tumor microenvironment and investigating how targeting particular molecules can change the prognosis of patients.

Background : With a growing frequency, nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. NAFLD has a strong correlation with other metabolic disorders, such as obesity, particularly abdominal obesity, even though the underlying causes or risk factors are not entirely understood. This study aims to investigate correlations between abdominal anthropometric measurements and the presence and intensity of liver steatosis as assessed by unenhanced computed tomography (CT). Methods : One hundred and nineteen patients (male/female, 66/53; mean age 54.54 +/- 12.90 years) underwent abdominal non-contrast-enhanced CT. CT images were examined to determine the attenuation of liver parenchyma, subcutaneous fat depth, and waist circumference (WC). Results : Among all patients, WC (r = -0.78, p < 0.0001), infraumbilical subcutaneous fat thicknesses (r = -0.51, p < 0.0001), right paraumbilical subcutaneous fat thicknesses (r = -0.62, p < 0.0001), and left paraumbilical subcutaneous fat thicknesses (r = -0.53, p < 0.0001) had a high inverse correlation with the liver attenuation values. The presence of T2D (OR: 2.40, p = 0.04), WC (OR: 11.45, p < 0.001), right paraumbilical (OR: 10.09, p < 0.001), left paraumbilical (OR: 2.81, p = 0.01), and infraumbilical (OR: 3.06, p = 0.007) were strongly independent predictors of NAFLD risk. Moreover, regarding the laboratory parameters, only the higher value of GGT (OR: 2.84, p = 0.009) is a predictor of NAFLD risk. Conclusions : Our data show that higher baseline values of all abdominal anthropometric measurements are correlated with liver attenuation and act as predictors of NAFLD risk.

Background: Critical ischemia of the lower limbs refers to the last stages of peripheral arterial disease. It is characterized by resting discomfort or trophic disorders such as ulceration, skin necrosis, or gangrene in the lower limbs. Critical ischemia corresponds to Leriche-Fontaine (LF) stages III-IV and Rutherford stages 4-6. The purpose of this study was to observe the patency and postoperative complications of patients who have had infra-inguinal surgical revascularization and compare the results based on the kind of graft utilized., Methods: The present study was designed as an observational retrospective cohort study, including all patients from 2018 to 2019 diagnosed with severe ischemia of the lower limbs who were hospitalized at the Vascular Surgery Clinic of the County Emergency Clinical Hospital of Targu Mures., Results: Patients with a polytetrafluoroethylene (PTFE) graft had a higher incidence of chronic obstructive pulmonary disease ( p = 0.01), stage III LF (70.41% vs. 55.29%), p = 0.03), and a lower incidence of stage IV LF (29.95% vs. 44.71%, p = 0.03). As for complications, the PTFE group showed a lower incidence of bypass thrombosis (29.59% vs. 44.71%; p = 0.03) and graft infection (9.18% vs. 21.18%; p = 0.02), but no statistical significance in the event of bleeding ( p = 0.40). Regarding the outcomes, no statistical significance was seen for below-the-knee amputations or death. However, the PTFE group had a lower incidence of above-the-knee amputations (11.22% vs. 24.71%; p = 0.01). At multivariate analysis, the PTFE graft is an independent predictor of primary patency at 6, 12, and 24 months (OR: 2.15, p = 0.02; OR: 1.84, p = 0.04; and OR: 1.89, p = 0.03), as well as a protective factor against bypass thrombosis (OR: 0.52; p = 0.03), graft infection (OR: 0.37; p = 0.02), and above-the-knee amputation (OR: 0.38; p = 0.01).; Conclusions: According to this study's findings, there were minor differences regarding the long-term patency, bypass thrombosis, graft infections, and above-the-knee amputations. In addition, the PTFE graft group had a higher incidence of primary patency at 6, 12, and 24 months, as well as a lower incidence of bypass thrombosis, graft infection, and above-the-knee amputations.

Amiodarone hydrochloride is an antiarrhythmic drug, with proven efficacy in prevention and treatment of numerous arrhythmias, atrial fibrillation especially, or ventricular arrhythmias, with a long half-life (55-60 days). The increased risk of developing amiodarone-induced pulmonary fibrosis is directly related to the dose and the duration of the intake. Amiodarone-induced pulmonary toxicity is conditioned by dose, patient's age, and pre-existent pulmonary pathologies. The pattern for drug-induced lung injury may vary in many forms, but the amiodarone can cause polymorphous injuries such as diffuse alveolar damage, chronical interstitial pneumonia, organizing pneumonia, pulmonary hemorrhage, lung nodules or pleural disease. The pathological mechanism of pulmonary injury induced by amiodarone consists of the accumulation of phospholipid complexes in histocytes and type II pneumocytes. Differential diagnosis of pulmonary fibrosis induced by amiodarone is made mainly with idiopathic pulmonary fibrosis, left ventricular failure or infectious disease. Before starting treatment with amiodarone, patients should be informed of potential adverse effects and any new respiratory symptoms should promptly be reported to their family physician or attending physician. The assessment carried out at the initiation of amiodarone treatment should include at least chest X-ray and respiratory function tests and extrapulmonary evaluation.

Background: Abdominal trauma is defined as a variety of injuries to the abdominal wall, solid or hollow intra-abdominal organs, and various intra-abdominal vessels. Recently, there has been a significant amount of interest in the establishment of a reliable biomarker that can predict the outcome in patients with an abdominal injury. The purpose of this study is to confirm the predictive role of inflammatory biomarkers and underlying risk factors and the risk of acute kidney insufficiency (AKI) developing and mortality in abdominal trauma patients; Materials and methods: The current study was intended as an observational, analytical, retrospective cohort study and included all patients over 18 years of age with a diagnosis of abdominal trauma confirmed through a CT scan admitted to the County Emergency Clinical Hospital of Targu-Mureș, Romania between January 2017, and December 2021; Results: Non-survivor patients had a greater age (p = 0.02), as well as a higher prevalence of ischemic heart disease (IHD) (p = 0.007), history of myocardial infarction (MI) (p = 0.002), peripheral arterial disease (PAD) (p = 0.01), chronic kidney disease (CKD) (p = 0.01), and all risk factors (p = 0.0004 and p < 0.0001). In terms of injured organs, we have in the second group a higher incidence of kidney injury (p = 0.003) and hemoperitoneum (p = 0.008). Multivariate analysis showed a high baseline value for all inflammatory biomarkers that are independent predictors of adverse outcomes for all recruited patients. Furthermore, for all hospitalized patients, the history of MI (p = 0.03; p = 0.001; and p = 0.003), PAD (p = 0.01; p = 0.01; and p = 0.002), obesity (for all p < 0.0001), CKD (p < 0.001; p = 0.01; and p = 0.001), and kidney injury (p = 0.02; p = 0.004; and p = 0.01) were independent predictors of all outcomes. Moreover, IHD (p = 0.008 and p = 0.02), tobacco (p < 0.0001 and p = 0.02), and hemoperitoneum (p = 0.009 and p = 0.01) were predictors of mortality and composite endpoint, but not for AKI risk, as well as atrial fibrillation [AF] (p = 0.04) as predictors of the composite endpoint Conclusions: Higher monocyte to lymphocyte ratio (MLR), platelets to lymphocyte ratio (PLR), systemic inflammatory index (SII), neutrophil to lymphocyte ratios (NLR), aggregate inflammatory systemic index (AISI), and systemic inflammatory response index (SIRI) levels at admission, according to our data, highly predict AKI risk and death.

Background: Abdominal aortic aneurysm (AAA) is a complex vascular disease characterized by progressive and irreversible local dilatation of the aortic wall. Currently, the indication for repair is linked to the transverse diameter of the abdominal aorta, using computed tomography angiography imagery, which is one of the most used markers for aneurysmal growth. This study aims to verify the predictive role of imaging markers and underlying risk factors in AAA rupture. Methods: The present study was designed as an observational, analytical, retrospective cohort study and included 220 patients over 18 years of age with a diagnosis of AAA, confirmed by computed tomography angiography (CTA), admitted to Vascular Surgery Clinic of Mures County Emergency Hospital in Targu Mures, Romania, between January 2018 and September 2022. Results: Patients with a ruptured AAA had higher incidences of AH (p = 0.006), IHD (p = 0.001), AF (p < 0.0001), and MI (p < 0.0001), and higher incidences of all risk factors (tobacco (p = 0.001), obesity (p = 0.02), and dyslipidemia (p < 0.0001)). Multivariate analysis showed that a high baseline value of all imaging ratios markers was a strong independent predictor of AAA rupture (for all p < 0.0001). Moreover, a higher baseline value of DAmax (OR:3.91; p = 0.001), SAmax (OR:7.21; p < 0.001), and SLumenmax (OR:34.61; p < 0.001), as well as lower baseline values of DArenal (OR:7.09; p < 0.001), DACT (OR:12.71; p < 0.001), DAfemoral (OR:2.56; p = 0.005), SArenal (OR:4.56; p < 0.001), SACT (OR:3.81; p < 0.001), and SThrombusmax (OR:5.27; p < 0.001) were independent predictors of AAA rupture. In addition, AH (OR:3.33; p = 0.02), MI (OR:3.06; p = 0.002), and PAD (OR:2.71; p = 0.004) were all independent predictors of AAA rupture. In contrast, higher baseline values of SAmax/Lumenmax (OR:0.13; p < 0.001) and ezetimibe (OR:0.45; p = 0.03) were protective factors against AAA rupture. Conclusions: According to our findings, a higher baseline value of all imaging markers ratios at CTA strongly predicts AAA rupture and AH, MI, and PAD highly predicted the risk of rupture in AAA patients. Furthermore, the diameter of the abdominal aorta at different levels has better accuracy and a higher predictive role of rupture than the maximal diameter of AAA.

Background: Numerous tools, including nutritional and inflammatory markers, have been evaluated as the predictors of poor outcomes in COVID-19 patients. This study aims to verify the predictive role of the prognostic nutritional index (PNI), CONUT Score, and inflammatory markers (monocyte to lymphocyte ratio (MLR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic inflammatory index (SII), Systemic Inflammation Response Index (SIRI), and Aggregate Index of Systemic Inflammation (AISI)) in cases of deep vein thrombosis (DVT) and acute pulmonary embolism (APE) risk, as well as mortality, in COVID-19 patients. Methods: The present study was designed as an observational, analytical, retrospective cohort study, and included 899 patients over the age of 18 who had a COVID-19 infection, confirmed through real time-polymerase chain reaction (RT-PCR), and were admitted to the County Emergency Clinical Hospital and Modular Intensive Care Unit of UMFST “George Emil Palade” of Targu Mures, Romania between January 2020 and March 20212. Results: Non-Surviving patients were associated with a higher incidence of chronic kidney disease (p = 0.01), cardiovascular disease (atrial fibrillation (AF) p = 0.01; myocardial infarction (MI) p = 0.02; peripheral arterial disease (PAD) p = 0.0003), malignancy (p = 0.0001), tobacco (p = 0.0001), obesity (p = 0.01), dyslipidemia (p = 0.004), and malnutrition (p < 0.0001). Multivariate analysis showed that both nutritional and inflammatory markers had a high baseline value and were all independent predictors of adverse outcomes for all enrolled patients (for all p < 0.0001). The presence of PAD, malignancy, and tobacco, were also independent predictors of all outcomes. Conclusions: According to our findings, higher MLR, NLR, PLR, SII, SIRI, AISI, CONUT Score, and lower PNI values at admission strongly predict DVT risk, APE risk, and mortality in COVID-19 patients. Moreover, PAD, malignancy, and tobacco, all predicted all outcomes, while CKD predicts APE risk and mortality, but not the DVT risk.

Background: Carotid endarterectomy (CEA) is the first-line surgical intervention for cases of severe carotid stenoses. Unfortunately, the restenosis rate is high after CEA. This study aims to demonstrate the predictive role of carotid plaque features and inflammatory biomarkers (monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic inflammatory index (SII), Systemic Inflammation Response Index (SIRI), and Aggregate Index of Systemic Inflammation (AISI)) in carotid restenosis and mortality at 12 months following CEA., Methods: The present study was designed as an observational, analytical, retrospective cohort study and included all patients over 18 years of age with a minimum of 70% carotid stenosis and surgical indications for CEA admitted to the Vascular Surgery Clinic, Emergency County Hospital of Targu Mures, Romania between 2018 and 2021., Results: According to our results, the high pre-operative values of inflammatory biomarkers-MLR (OR: 10.37 and OR: 6.11; p < 0.001), NLR (OR: 34.22 and OR: 37.62; p < 0.001), PLR (OR: 12.02 and OR: 16.06; p < 0.001), SII (OR: 18.11 and OR: 31.70; p < 0.001), SIRI (OR: 16.64 and OR: 9.89; p < 0.001), and AISI (OR: 16.80 and OR: 8.24; p < 0.001)-are strong independent factors predicting the risk of 12-month restenosis and mortality following CEA. Moreover, unstable plaque (OR: 2.83, p < 0.001 and OR: 2.40, p = 0.04) and MI (OR: 3.16, p < 0.001 and OR: 2.83, p = 0.005) were independent predictors of all outcomes. Furthermore, AH (OR: 2.30; p = 0.006), AF (OR: 1.74; p = 0.02), tobacco (OR: 2.25; p < 0.001), obesity (OR: 1.90; p = 0.02), and thrombotic plaques (OR: 2.77; p < 0.001) were all independent predictors of restenosis, but not for mortality in all patients. In contrast, antiplatelet (OR: 0.46; p = 0.004), statin (OR: 0.59; p = 0.04), and ezetimibe (OR:0.45; p = 0.03) therapy were protective factors against restenosis, but not for mortality., Conclusions: Our data revealed that higher preoperative inflammatory biomarker values highly predict 12-month restenosis and mortality following CEA. Furthermore, age above 70, unstable plaque, cardiovascular disease, and dyslipidemia were risk factors for all outcomes. Additionally, AH, AF, smoking, and obesity were all independent predictors of restenosis but not of mortality in all patients. Antiplatelet and statin medication, on the other hand, were protective against restenosis but not against mortality.

Background and objectives: Deep vein thrombosis (DVT) is one of the most serious post-operative complications in the case of total knee arthroplasty (TKA). This study aims to verify the predictive role of inflammatory biomarkers [monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelets-to-lymphocyte ratio (PLR), systemic inflammatory index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI)] in acute DVT following TKA. Materials and methods: The present study was designed as an observational, analytical, retrospective cohort study and included all patients over 18 years of age with surgical indications for TKA, admitted to the Department of Orthopedics, Regina Maria Health Network, Targu Mures, Romania, and the Department of Orthopedics, Humanitas MedLife Hospital, Cluj-Napoca, Romania between January 2017 and July 2022. The primary endpoint was the risk of acute DVT following the TKA, and the secondary endpoint was the length of hospital stay, and the outcomes were stratified for the baseline’s optimal MLR, NLR, PLR, SII, SIRI, and AISI cut-off value. Results: DVT patients were associated with higher age (p = 0.01), higher incidence of cardiac disease [arterial hypertension (p = 0.02), atrial fibrillation (p = 0.01)], malignancy (p = 0.005), as well as risk factors [smoking (p = 0.03) and obesity (p = 0.02)]. Multivariate analysis showed a high baseline value for all hematological ratios: MLR (OR: 11.06; p < 0.001), NLR (OR: 10.15; p < 0.001), PLR (OR: 12.31; p < 0.001), SII (OR: 18.87; p < 0.001), SIRI (OR: 10.86; p < 0.001), and AISI (OR: 14.05; p < 0.001) was an independent predictor of DVT after TKA for all recruited patients. Moreover, age above 70 (OR: 2.96; p = 0.007), AH (OR: 2.93; p = 0.02), AF (OR: 2.71; p = 0.01), malignancy (OR: 3.98; p = 0.002), obesity (OR: 2.34; p = 0.04), and tobacco (OR: 2.30; p = 0.04) were all independent predictors of DVT risk. Conclusions: Higher pre-operative hematological ratios MLR, NLR, PLR, SII, SIRI, and AISI values determined before operations strongly predict acute DVT following TKA. Moreover, age over 70, malignancy, cardiovascular disease, and risk factors such as obesity and tobacco were predictive risk factors for acute DVT.

Introduction: Cutaneous squamous cell carcinoma (cSCC) is one of the most frequently occurring types of cancer in humans. Scientometric research is an innovative method for analyzing the research trends in various domains, with great implications in the field of medicine. Materials and Methods: We searched the Web of Science database with the following established query terms: "Squamous cell carcinoma", "skin", and "immunohistochemistry". After applying the inclusion and exclusion criteria, a total of 76 articles were selected. The present study aims to analyze, based on the frequency of use of keywords with scientometric algorithms and map-based distributions, the trends of the research concerning cSCCs in 2017-2022. Results: A graphical representation based on 11 scientometric maps presented the division of the keywords into seven clusters, from which seven categories of research interest were defined. The clusters represent a multidisciplinary approach to the diagnosis and treatment of cSCCs, cancer diagnostics, patient outcomes, histopathological importance, management of cSCCs, role of progression, and adequate treatment of and importance of immunohistochemistry for cSCCs. The distribution of the citations shows the importance of the available research on cSCCs by analyzing the first five most-cited articles included in our study in direct concordance with the seven defined clusters. Conclusion: The scientometric research method reveals the interest of research in the multidisciplinary approach used to obtain the best outcomes for the patient, including a targeted investigation, as well as diagnostic and treatment options. The trends in the research reveal that histopathological diagnostics and immunohistochemistry, combined with molecular techniques, are the most important tools used to establish a personalized diagnosis, thus increasing the quality of life and life expectancy for patients with cSCCs.

Melanoma is the most aggressive melanocytic tumor whose incidence is continuously increasing worldwide., Methods: We highlight the morphological, immunohistochemistry, and particularities of various melanoma types based on the cases diagnosed in our department from 2017 to 2021., Results: We present 100 melanoma cases and one capsular nevus case. The most common type was nodular melanoma. The immunohistochemistry markers used were SRY-box transcription factor 10 (SOX10), S100 protein, human melanoma black 45 (HMB45), and melanoma antigen recognized by T cells 1 (Melan-A). Uveal melanoma and conjunctival melanoma represent particular tumors with independent prognostic factors. Uveal melanoma requires assessment of macrophages, microvascularisation, and mitoses. Sentinel lymph node metastases are essential targets that provide staging tools. Conjunctival melanoma and capsular nevi are diagnostic pitfalls., Conclusion: Melanoma can appear in various forms, and sometimes the diagnosis might be unclear. Today, immunohistochemistry remains the most important tool in confirming the diagnosis and prognosis for this type of neoplasia.

Inflammation plays an important role in peripheral artery disease (PAD), contributing to the onset and progression of atherosclerosis, as well as to the rupture of atherosclerotic plaques. Studies have revealed that due to their inflammatory nature, leucocytes play an important role in the development of atherosclerosis. A retrospective study was conducted involving 203 patients with PAD admitted to Targu Mures Emergency County Hospital for revascularization surgery between January 2017 and June 2019 (of which 47 were treated by endovascular intervention, and 156 underwent classical surgical intervention). Among all patients included in the study, 47 patients required amputation following the revascularization intervention. The results indicated that though the mean patient age in the non-amputation group was higher than that in the amputation group, that the difference was not significant. With regard to sex distribution, 72% of the patients from the amputation group were male, while from the non-amputation group, 74% were male. The neutrophil-to-lymphocyte ratio (NLR) cut-off value for the prediction of amputation in PAD was 3.485 (sensitivity, 60.42%; specificity 72.44%), whereas the platelet-to-lymphocyte ratio (PLR) value was 152, (sensitivity, 54.17%; specificity, 71.79%), and was 2.55 for the lymphocyte-to-monocyte ration (LMR; sensitivity, 56.25%; specificity, 66.88%). The study concluded that in patients with PAD, the NLR and PLR were increased, while the LMR was decreased, which was also associated with a higher rate of amputation after revascularization, despite the lack of correlation between these factors, Fontaine classification and the number of damaged vessels. Therefore, pre-operative alterations in NLR, PLR and LMR may predict the need for amputation in patients with PAD, or those who underwent a revascularization intervention., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Cosarca et al.)

Background and Objectives: Endometriosis is a benign inflammatory disease associated with infertility and chronic pelvic pain, estimated to affect 7−10% of reproductive-age women, with the possibility of malignant transformation. Recent studies focus on oxidative stress and genetic mutations as risk factors in the pathophysiology of endometriosis-associated infertility. Materials and Methods: This case-control study is the first in Eastern European women that aimed to investigate four genes’ genetic polymorphisms that encode antioxidant enzymes involved in oxidative stress (glutathione peroxidase 1, GPX1 198Pro > Leu, catalase CAT-262C > T, glutathione S-transferase M1, and T1 null genotype) and their association with endometriosis-related infertility. We compared 103 patients with endometriosis-associated infertility with 102 post-partum women as the control group. Results: The endometriosis group had a mean age of 34.5 +/− 6.12 years, while the control group’s mean age was 35.03 +/− 5.95 years. For CAT-262C > T polymorphism, the variant genotypes were significantly more frequent in the endometriosis group. Moreover, for the GPX1 198Pro > Leu, the endometriosis group had significantly more frequent CT and TT genotypes. The null genotype of GSTM1 was detected significantly higher in the endometriosis group. No significant differences were found in the frequency of GSTT1 between the two groups. This study suggests that GPX1 198Pro > Leu, CAT-262C > T, and GSTM1 polymorphisms may be risk factors and that the association between the GSTM1-GSTT1 null genotype may play a significant role in endometriosis-associated infertility. Moreover, this study suggests that the GSTT1 null genotype does not influence the disease. Visual identification of endometriotic lesions with microscopic confirmation is the accepted gold standard for diagnosing endometriosis, but general anesthesia and laparoscopy are required. Conclusions: In this regard, a panel of genetic or laboratory markers is needed for the early diagnostics of this prevalent disease, especially in the case of young patients with future pregnancy intention., Competing Interests: The authors declare no conflict of interest.

Background and Objectives : Basal carcinoma of the skin (BCC) is part of the nonmelanoma skin cancer (NMSC) family and is the most frequently occurring type of skin cancer in humans. A combination of clinical and histopathological approaches is necessary in order to establish the best treatment regime for patients who have been diagnosed with this type of cancer. The objective of the present study was to establish the statistical value of prediction for certain sociodemographic characteristics (age category and environment of origin) and histopathological parameters of the subjects that could be related to the incidence of diagnosis with certain histopathological subtypes of BCC. Materials and Methods : In order to verify the veracity of the established research hypotheses, we conducted a retrospective study based on the histopathological reports of 216 patients who were treated at the Pathology Department of Mureș Clinical County Hospital. Results : Cystic BCC is higher in patients who are older than 71 years of age, and the superficial multicentric and keratotic subtypes are more frequently diagnosed in urban areas. Patients who have been diagnosed with the superficial multicentric BCC subtype are not usually very old in contrast to the patients who tend to be diagnosed with the cystic BCC subtype. The nodular BCC subtype is positively associated with ulceration ( p = 0.004); the superficial multicentric BCC subtype is positively associated with intra- and peritumoral inflammatory infiltrate ( p = 0.022, p = 0.034) and negatively associated with ulceration (r = -0.218, p = 0.001). The infiltrative BCC subtype is positively associated with ulceration ( p = 0.021), and the keratotic BCC subtype is positively associated with peritumoral inflammatory infiltrate ( p = 0.02). Conclusions : Depending on each patient's epidemiological and sociodemographic data, a pattern can be established regarding the appropriate clinical and treatment approaches for that patient, which can be supported based on the implications of the histopathological diagnostic. This can lead to an improvement in the patient's quality of life and increased satisfaction with the provided medical services.

Melanoma is currently known as one of the most aggressive malignant tumors. The prognostic factors and particularities of this neoplasm are a persistent hot topic in the medical field. This review has multiple purposes. First, we aim to summarize the known data regarding the histological and immunohistochemical appearance of this versatile tumor and to look further into the analysis of several widely used prognostic markers, such as B-Raf proto-oncogene, serine/threonine kinase BRAF . The second purpose is to analyze the data on the new prognostic markers, V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) and Programmed death-ligand 1 (PD-L1). VISTA is a novel target that is considered to be highly important in determining the invasive potential and treatment response of a melanoma, and there are currently only a limited number of studies describing its role. PD-L1 is a marker with whose importance has been revealed in multiple types of malignancies, but its exact role regarding melanoma remains under investigation. In conclusion, the gathered data highlights the importance of correlations between these markers toward providing patients with a better outcome.

Introduction: Neoplasms with pagetoid features are a category of rare lesions defined by the presence of atypical cells at different levels of the epidermis. The most important diseases within this category are mammary Paget disease (MPD), extramammary Paget disease (EMPD), Bowen's disease, in situ melanoma, and pagetoid reticulosis., Aim: The aim of this analysis was to describe the importance of the cytokeratin 8∕18 (CK 8∕18) immunostaining in diagnosing MPD and EMPD and differentiating them from other lesions., Materials and Methods: A retrospective study was employed, based on the histopathological and immunohistochemical (IHC) characteristics of 30 cases that presented pagetoid features. The cases were processed and analyzed at the Department of Pathology, Mureş Clinical County Hospital, Târgu Mureş, Romania, from 2017 to 2020., Results: Five MPD cases, one EMPD case, one pagetoid reticulosis case, 10 Bowen's disease cases, and 13 in situ melanoma cases were collected. Under Hematoxylin-Eosin staining, cells presented pale cytoplasm in MPD, EMPD, and in 25% of the melanoma cases. Hyperchromasia with nuclear enlargement was seen in all cases. Immunostaining with CK 8∕18 was positive in all MPD and EMPD cases. Tests for CK7, p63, and CK AE1∕AE3 were positive in MPD, EMPD, and Bowen's cases. Tests for S100, SRY-box transcription factor 10 (SOX10), human melanoma black 45 (HMB45), and Melan A were positive in melanoma cases, while cluster of differentiation (CD)3, CD4, and CD8 tests were positive in the pagetoid reticulosis case., Conclusions: CK 8∕18 is an IHC marker that can help establish the diagnosis of MPD and EMPD and differentiate them from other pagetoid neoplasms, ensuring the proper diagnosis and prognosis are provided.

Hemophilia A (HA) and hemophilia B (HB) are rare disorders, being caused by the total lack or under-expression of two factors from the coagulation cascade coded by genes of the X chromosome. Thus, in hemophilic patients, the blood does not clot properly. This results in spontaneous bleeding episodes after an injury or surgical intervention. A patient-centered regimen is considered optimal. Age, pharmacokinetics, bleeding phenotype, joint status, adherence, physical activity, personal goals are all factors that should be considered when individualizing therapy. In the past 10 years, many innovations in the diagnostic and treatment options were presented as being either approved or in development, thus helping clinicians to improve the standard-of-care for patients with hemophilia. Recombinant factors still remain the standard of care in hemophilia, however they pose a challenge to treatment adherence because they have short half-life, which where the extended half-life (EHL) factors come with the solution, increasing the half-life to 96 hours. Gene therapies have a promising future with proven beneficial effects in clinical trials. We present and critically analyze in the current manuscript the pros and cons of all the major discoveries in the diagnosis and treatment of HA and HB, as well as identify key areas of hemophilia research where improvements are needed., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-747). CT serves as an unpaid editorial board member of Annals of Translational Medicine from Nov 2019 to Oct 2021. The other authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background and Objectives : The COVID-19 pandemic has globally affected health systems and services. Non-melanoma skin cancers (NMSCs) are the most common malignancies around the world. This study aimed to analyze the differences in the benign and malignant histopathological diagnoses performed on radical excision skin tumors and skin biopsies in the dermatopathology ward in Mures Clinical County Hospital, Targu Mures, Romania, 1 year prior to and during the COVID-19 pandemic, to emphasize the changes in the diagnostic process as per the new regulations. Materials and Methods: A total of 1168 histopathological diagnoses were included in the study-302 from the COVID-19 period and 866 from the non-COVID-19 period-considering the number, type, and frequency of the histopathological diagnoses as variables to be analyzed. Results : In the COVID-19 period, out of the 55 NMSC and melanoma histopathological diagnoses, 50.9% ( n = 28) were BCCs, 20% ( n = 11) were SCCs, 10.9% ( n = 6) were basosquamous cell carcinomas, and 18.18% ( n = 10) were melanoma cases. Regarding the non-COVID-19 period, out of the 173 NMSC and melanoma histopathological diagnoses, 46.82% ( n = 81) were BCCs, 22.54% ( n = 39) were SCCs, 7.51% ( n = 13) were basosquamous cell carcinomas, and 23.12% ( n = 40) were melanoma cases. Conclusions: During the COVID-19 pandemic, a decrease in histopathological diagnoses at the dermatopathology ward in our hospital was observed, for both benign and malignant pathologies, especially for NMSCs and melanomas, compared to the same period 1 year prior to the pandemic.

Introduction: Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from cells that are part of the diffuse neuroendocrine system., Patients, Materials and Methods: We conducted a retrospective study in which we included a number of 91 cases diagnosed with neuroendocrine tumors (NETs). Descriptive statistics was performed: number of cases based on location, distribution by gender (male∕female), distribution by age, and we also performed a morphological and immunohistochemical (IHC) study., Results: The highest number of cases was found in lungs (60 cases). Tumors located on the skin, breast or bladder have been discovered, locations considered rare for this type of tumor. Of all cases diagnosed in the lungs, 59 were diagnosed as small cell carcinomas (SCCs) and only one case as NET. All surgical specimens were positive for chromogranin A (CgA), with a different expression for the other immunomarkers. For the lung biopsies, the most frequently IHC staining was CgA and cluster of differentiation 56 (CD56), with an increased positivity for the latter., Conclusions: CgA remains the most sensitive immunomarker in the diagnosis of NETs. CD56 is the most widely used immunomarker for diagnosing small cell lung tumors. Positive expression of thyroid transcription factor 1 (TTF1) immunomarker does not confirm pulmonary origin of SCCs.

Objective: To summarize an innovative initiative in oncology nurse workforce development that addresses critical current and future gaps and encompasses use of dedicated education units for student nurse rotation and a transition-to-practice residency program., Data Sources: Review of institutional data including original pilot analysis and ongoing programmatic metrics (N=8 years), consensus, professional guidelines, and published literature., Conclusion: The dedicated education unit serves as a conduit for recruitment into institutional oncology nurse residency positions, and retention rates in the residency program continue to exceed national averages. Subsequent mentoring of these nurses in transition to practice has manifested high rates of promotion into nurse leadership roles year over year., Implications for Nursing Practice: Oncology nurse practice incorporates state-of-the-science approved therapies, early phase clinical trial implementation, and evidence-based complex oncology patient care management. A new model of student clinical nurse rotations in ambulatory settings, nurse resident transition to practice, and ongoing leadership mentoring is essential in creating a sustainable, highly skilled, and robust oncology nurse work force., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) represents an emerging pathology in modern medicine. Transthoracic echocardiography is an inexpensive and reproducible method and it is the most commonly used non-invasive diagnostic tool to asses pulmonary artery pressure (PAP) and the function of the right ventricle. Although, the right heart catheterization is still considered as the standard for the diagnosis, according to the last guidelines, the new echocardiographic methods may offer an improved value in the PAH evaluation., Aim: To evaluate if cardiac ultrasonography data correlate with catheterization results in patients with PAH (Group I Dana Point 2008), and to compare the ultrasonography evaluation of PAH patients with that of normal., Methods: 15 consecutive patients (pts) (52±15 yrs, 5 men, time from onset of symptoms 1.6±1.7 years) with PAH of different aetiologies (12 pts with idiopathic PAH, 2 pts with PAH associated with scleroderma and one with persistent PAH after atrial septal defect (ASD) closure) were evaluated through: 1. clinical examination (NYHA class); 2. exercise capacity (6 minute walking test - 6MWT); 3. conventional echocardiography (diameter of right ventricle - RVD and right atrium, fractional area shortening - FAS, TAPSE, pulmonary ascension time - PA, systolic and mean PAP -sPAP, mPAP, tricuspid E/A ratio, cardiac index-CI) and 4. Tissue Doppler Imaging - TDI (systolic and diastolic myocardial velocities at the tricuspid annulus - S, D, A); 5. right heart catheterization (sPAP, mPAP, CI, pulmonary vascular resistance - PVR)We compared classical and TDI echo parameters with those obtained from 15 normal subjects, matched in age and sex., Results: PAH patients had high sPAP and mPAP with right heart dilation (RV - 44.8±7.3 mm), depressed TAPSE (16.2±5.9 mm) and cardiac index and low TDI systolic velocities at tricuspid level (7.3±2.9 cm/s). All parameters differed statistically significant from normal. There were no significant correlations between ultrasonography and catheterization (cath) parameters (sPAP 92±28.2 echo vs. 106.4±25.8 mmHg cath; mPAP 47.9±8.4 echo vs. 65.8±17.3 mmHg cath), excepting for CI 2.3±1.2 l/min/m(2) vs. 2.08±0.3 ml/min/m(2)) and PVR (16.5 ± 15.3 Wood U echo, vs. 19.6 ± 7.9 cath)., Conclusion: Classic and TDI cardiac ultrasonography represents a good screening and monitoring tool for PAH patients, but tends to underestimate the severity of the disease, leaving right heart catheterization as the essential diagnostic method for this rare disease.

Aims: To report the four-month and nine-month angiographic results as well as one-year clinical follow-up from the first-in-man study with the silicon carbide and sirolimus-eluting bioabsorbable polymer (poly-L-lactic acid (PLLA) polymer) -coated cobalt-chromium Orsiro stent., Methods and Results: A group of 30 patients with documented myocardial ischaemia related to a single de novo coronary stenosis up to 22 mm in length, in vessels with a 2.5 to 3.5 mm reference diameter, and between >50% and <90% diameter stenosis were enrolled at two sites. The primary endpoint of the study was in-stent late lumen loss at nine months. The secondary endpoints included major adverse cardiac events (MACE) at one year defined as the composite of cardiac death, ischaemia-driven target lesion revascularisation (TLR) and target vessel myocardial infarction (MI). Procedural success was 100%. Angiographic late lumen loss was 0.12±0.19 mm and 0.05±0.22 mm at four and nine months respectively. At one-year clinical follow-up, the composite MACE was 10% with one patient who died from cardiac death and two patients who had ischaemia-driven target lesion revascularisation. There was no report of MI or stent thrombosis., Conclusions: The Orsiro drug-eluting stent demonstrated potency with low rates of in-stent neointimal hyperplasia and cardiovascular events but warrants further evaluation in a larger population cohort with longer follow-up time points.

The purpose of this study was to assess the feasibility and safety of direct coronary stenting in acute coronary syndromes using 5 Fr guiding catheters by transradial approach. A series of 119 patients with an acute coronary syndrome (unstable angina, n = 55; acute myocardial infarction, n = 45; recent acute myocardial infarction, n = 19) explored by transradial approach and eligible for direct stenting were included. A large proportion of patients (52%) was treated during the procedure by platelet IIb/IIIa receptor blockade. Only Medtronic 5 Fr guiding catheters were used in this study. Direct coronary stenting was attempted in all 119 highly selected patients. Failure of direct stenting was observed in only five cases (3.9%) and the stent successfully retrieved in each case in the 5 Fr guiding catheter. In these five cases, balloon predilation was performed and then the stent implanted successfully. Different stents were used: ACS stent (54%), AVE stent (33%), Velocity stent (10%), Nir stent (3%), with diameter ranging from 2.5 to 4 mm. In four cases, the dilation was finally performed using 6 Fr guiding catheters because the backup of the 5 Fr catheter was considered to be too low (3%). No vascular access site complications occurred in this series of patients. We conclude that direct coronary stenting using transradial approach and 5 Fr guiding catheters yields excellent procedural success rate. In the setting of acute coronary syndromes requiring platelet IIb/IIIa receptor blockade or after failure of thrombolysis, this mini-invasive strategy is very attractive because of the low risk of access site complications., (Copyright 2002 Wiley-Liss, Inc.)

We describe REMIND, a data mining framework that accurately infers missing clinical information by reasoning over the entire patient record. Hospitals collect computerized patient records (CPR's) in structured (database tables) and unstructured (free text) formats. Structured clinical data in the CPR's is often poorly recorded, and information may be missing about key outcomes and processes. For instance, for a population of 344 colon cancer patients, important clinical outcomes, such as disease state and its evolution, are stored only as unstructured data (doctors' dictations) in the CPR. Raw evidence (extracted directly from the CPR) is not a good predictor of disease state. Yet by combining this evidence in a principled fashion (using methods from uncertain and temporal reasoning), REMIND accurately infers disease state sequences for recurrence, a complex time-varying outcome, for these patients. These outcomes can now be added back into the CPR in structured form.

Background: Because saphenous vein grafts (SVGs) exhibit greater cellular heterogeneity and worse clinical outcomes than arterial grafts (AGs), we examined oxidative stress and lipid retention in different vascular conduits., Methods and Results: In a porcine model of graft interposition into carotid artery, superoxide anion (.O(2)(-)) was measured at 2 weeks after surgery. SVGs demonstrated increased.O(2)(-) production compared with AGs (SOD-inhibitable nitro blue tetrazolium reduction, P<0.01). The NAD(P)H oxidase inhibitor diphenyleneiodonium (P<0.01) abolished SVG-derived.O(2)(-), whereas the inhibitors of other pro-oxidant enzymes were ineffective. The change in oxidative stress was also reflected by lower activity of the endogenous antioxidant superoxide dismutase in SVGs than in AGs (P<0.001). SVG remodeling was associated with increased synthesis of sulfated glycosaminoglycans and augmented expression of a core protein, versican. These changes were accompanied by SVGs retaining significantly more (125)I-labeled LDL than AGs ex vivo (P<0.001). In hyperlipemic animals, lipid accumulation and oxidized epitopes were preferentially noted in the intima of SVGs at 1 month after surgery., Conclusions: This study demonstrated significant differences in the biology of SVGs and AGS: SVGs exhibited higher oxidative stress, LDL accumulation, and the presence of oxidized epitopes. These findings suggest that proatherogenic changes in SVGs may commence early after surgical revascularization.

Reactive oxygen species (ROS), produced by cellular constituents of the arterial wall, provide a signaling mechanism involved in vascular remodeling. Because adventitial fibroblasts are actively involved in coronary remodeling, we examined whether the changes in the redox state affect their phenotypic characteristics. To this end, superoxide anion production and NAD(P)H oxidase activity were measured in porcine coronary arteries in vivo, and the effect of ROS generation on adventitial fibroblast proliferation was examined in vitro. Superoxide production (SOD- and Tiron-inhibitable nitro blue tetrazolium [NBT] reduction) increased significantly within 24 hours after balloon-induced injury, with the product of NBT reduction present predominantly in adventitial fibroblasts. These changes were NAD(P)H oxidase-dependent, because diphenyleneiodonium (DPI) abolished superoxide generation (P<0.001). Furthermore, the injury-induced superoxide production was associated with augmented NAD(P)H oxidase activity and upregulation of p47(phox) and p67(phox) in adventitial fibroblasts (immunohistochemistry). Serum stimulation of isolated adventitial fibroblasts produced time-dependent increases in ROS production (peak 3 to 6 hours). The inhibition of ROS generation with NAD(P)H oxidase inhibitor (DPI) or the removal of ROS with antioxidants (Tiron, catalase) abrogated proliferation of adventitial fibroblasts. These results indicate that vascular NAD(P)H oxidase plays a central role in the upregulation of oxidative stress after coronary injury, providing pivotal growth signals for coronary fibroblasts.

There is increasing evidence to suggest that coronary smooth muscle cells (SMCs) differ from noncoronary SMCs. As integrin adhesion molecules regulate many SMC functions, we hypothesized that differences in integrin expression on coronary and noncoronary SMCs may account for cellular differences. Analysis of integrin expression on freshly isolated porcine coronary and noncoronary SMCs revealed that coronary SMCs express significantly less alpha(5)beta(1) than noncoronary SMCs, whereas the expression of total beta(1) and that of alpha(v)beta(3) are similar. Consistent with these findings, coronary SMCs demonstrated significantly less adhesion to fibronectin, compared with carotid artery SMCs. As alpha(5)beta(1)-mediated signaling has been associated with cellular proliferation, the effects of differential alpha(5)beta(1) expression on cell proliferation were examined by comparing primary coronary and carotid artery SMC proliferation. Coronary SMC growth was significantly lower than that of carotid artery SMCs when plated on fibronectin or type I collagen. Blocking alpha(5)beta(1) function on carotid artery SMCs produced a significant decrease in cellular proliferation, resulting in growth similar to that of coronary SMCs. Furthermore, blocking alpha(5)beta(1), but not alpha(v)beta(3), inhibited loss of alpha-smooth muscle actin in proliferating SMCs. Proliferating coronary SMCs were found to upregulate alpha(5)beta(1) expression, further indicating a role for alpha(5)beta(1) in SMC growth. These results suggest that dissimilar alpha(5)beta(1) integrin expression may mediate regional differences in phenotype of vascular SMCs.

Myofibroblasts of adventitial origin have been linked to neointimal formation and remodeling after coronary injury. Accordingly, the goal of this study was to examine whether myofibroblasts contribute to focal accumulation of glycosaminoglycans (GAGs) and lipids during coronary repair. GAG synthesis was assessed by ex vivo labeling of balloon-injured porcine coronary arteries with (14)C-glucosamine. The synthesis of total GAGs transiently increased at 8 days in the normolipemic model (a 2.2-fold increase over baseline, p < 0.05). The majority of newly synthesized GAGs were sensitive to chondroitin ABC lyase (chondroitin/dermatan sulfate GAGs). Versican was localized to myofibroblast-rich regions in the adventitia and neointima [positive for alpha-smooth muscle (SM) actin, negative for h-caldesmon and SM myosin heavy chain]. In contrast, the adjacent SM-rich media showed no increase in versican expression. The association between injury-induced GAG accumulation and lipid retention was examined at 2 weeks after coronary injury in the hyperlipemic model. Lipid (Oil Red O) accumulated in the neointima and adventitia, but not in the adjacent media. Coronary repair under hyperlipemic conditions was associated with macrophage infiltration (19 +/- 5 vs. 3 +/- 2% of neointimal cells in normolipemic animals, p < 0.001) and increased neointimal formation (1.8 +/- 0.5 vs. 1.0 +/- 0.3 mm(2) in normolipemic animals, p < 0.01). In conclusion, this study demonstrated a transient increase in GAG synthesis following coronary injury. Chondroitin sulfate proteoglycans (e.g., versican) were rapidly synthesized by activated adventitial and neointimal cells which could contribute to early lipid retention in injured vessels., (Copyright 2000 S. Karger AG, Basel)

Background: Recent findings suggesting the involvement of adventitial cells in coronary repair have raised questions regarding the phenotypic "plasticity" of medial smooth muscle cells (SMCs). Accordingly, the aims of the present study were to examine the characteristics of coronary medial and adventitial cells and to compare the responses of coronary and noncoronary SMCs to stimulation., Methods and Results: Enzymatically isolated coronary SMCs (human and porcine) were distinct from noncoronary SMCs, showing poor adhesion and spreading, as well as lower proliferation, collagen synthesis, and LDL degradation. Several extracellular matrix components (Matrigel, collagen I and IV, laminin, vitronectin, fibronectin) or growth factors (epidermal growth factor, platelet-derived growth factor-BB, insulin growth factor-1, interleukin-1alpha) failed to augment the adhesion or proliferation of coronary SMCs to the levels observed in noncoronary SMCs. Unlike coronary SMCs, coronary fibroblasts demonstrated high adhesion, proliferation, collagen synthesis, and avid LDL metabolism. Limited responses of coronary SMCs were associated with sustained expression of differentiation markers (alpha-smooth muscle actin, h-caldesmon, and smooth muscle myosin heavy chain), whereas noncoronary SMCs showed marked phenotypic heterogeneity., Conclusions: Coronary SMCs appeared to maintain highly differentiated phenotype in response to stimulation, whereas coronary adventitial fibroblasts demonstrated several characteristics that are essential during vascular repair. Coronary SMCs, however, were distinct from noncoronary medial cells, which displayed greater phenotypic heterogeneity and versatility in culture. We postulate that the mechanism of vascular repair may differ among vascular beds, pointing to the importance of coronary artery-specific investigations in vascular biology.

The migration of vascular cells is regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Because the activation of adventitial fibroblasts has been implicated in coronary repair, we have examined regional differences in cell outgrowth and the synthesis of MMPs/TIMPs in different layers of porcine coronary arteries. Coronary medial explants demonstrated significantly slower cell outgrowth than coronary adventitia in culture (P<0.001). These observations were paralleled by the predominant expression of TIMP-1 and -2 in the media (14-fold and 37-fold higher than in adventitia, respectively, P<0.001), whereas higher gelatinolytic activities (MMP-2 and -9) were released from adventitial explants. Smooth muscle cell outgrowth from the media was regulated by endogenous TIMPs, since TIMP inhibition (recombinant MMP-2 or neutralizing anti-TIMP antibodies) facilitated cell outgrowth (P<0.001). In contrast, the addition of recombinant TIMP-1 or -2 decreased adventitial cell outgrowth. In the coculture experiments, the presence of coronary media retarded adventitial cell outgrowth, whereas medial damage abrogated these effects, allowing for fibroblast migration (P<0.001). In conclusion, this study demonstrated differential migratory properties and distinct MMP/TIMP synthesis by coronary fibroblasts and smooth muscle cells. Endogenous TIMPs in the media may play an important role in maintaining coronary arterial wall homeostasis, whereas high levels of matrix-degrading activities confer the "invasive" characteristics of adventitial fibroblasts.

Background: PTCA of an infarct-related lesion is associated with a high rate of restenosis and/or vessel occlusion. Recent studies have shown that coronary stenting in patients with stable or unstable angina is associated with a significant reduction in the restenosis rate compared with conventional balloon angioplasty. However, no information is available concerning the long-term effect of coronary stenting at infarct-related lesions compared with balloon angioplasty alone., Methods and Results: One hundred consecutive patients undergoing stent implantation at an infarct-related lesion and systematic 6-month angiographic follow-up were matched for major pre-PTCA clinical and angiographic variables with a group of patients undergoing conventional angioplasty. Preprocedural, postprocedural, and 6-month follow-up angiograms were analyzed with quantitative angiography. Coronary stenting was performed as a bailout procedure after failed balloon angioplasty in 20%, for a suboptimal result after balloon angioplasty in 71%, and electively in 9%. Stent implantation was associated with a higher acute gain than balloon angioplasty. At follow-up, the minimal lumen diameter was significantly (P<.0001) larger in the stent group (1.72+/-0.69 versus 1.23+/-0.72 mm). Restenosis (>50% DS at follow-up) occurred in 27% of the stent group versus 52% of the balloon group (P<.005). At follow-up, total occlusion at the dilated site occurred in 1% of the stent group versus 14% of the balloon group (P<.005)., Conclusions: Coronary stenting of infarct-related lesions is associated with a highly beneficial effect on 6-month angiographic outcome compared with balloon angioplasty alone. Further studies are needed to establish whether the beneficial effect of coronary stenting on long-term vessel patency is associated with an improvement in left ventricular function or in clinical outcome.

Chronic exposure of humans to benzene causes acute myelogenous leukemia (AML). The studies presented here were undertaken to determine whether benzene, or its reactive metabolite, hydroquinone (HQ), affects differentiation of myeloblasts. Benzene or HQ administered to C57BL/6J mice specifically induced granulocytic differentiation of myeloblasts. The ability of these compounds to induce differentiation of the myeloblasts was tested directly using the murine interleukin 3 (IL-3)-dependent 32D.3 (G) myeloblastic cell line, and the human HL-60 promyelocytic leukemia cell line. We have previously shown that benzene treatment of HL-60 myeloblasts activates protein kinase C (PKC) and upregulates the 5-lipoxygenase (LPO) pathway for the production of leukotriene D4 (LTD4), an essential effector or granulocytic differentiation. Differentiation was prevented by sphinganine, a PKC inhibitor, and, as shown here, by LPO inhibitors and LTD4 receptor antagonists. Benzene or HQ also induces differentiation in 32D.3 (G) myeloblasts. Both compounds interact with cellular signaling pathways normally activated by granulocyte colony stimulating factor (G-CSF) and can replace the requirement for G-CSF. While IL-3 induces a growth response in 32D.3 (G) cells, G-CSF has been shown to provide both growth and differentiated signals. Both HQ and LTD4 induce differentiation and synergize with IL-3 for growth; however, neither supports growth in the absence of IL-3. Benzene, like HQ, also provides a differentiation signal for 32D cells; however, it has no effect on their growth. Unlike G-CSF, benzene, or LTD4, each of which stimulates terminal differentiation; HQ blocks differentiation at the myelocyte stage, allowing only a small percentage of progenitors to proceed to mature segmented granulocytes. Benzene- and G-CSF-induced differentiation were prevented by the additional of either LPO inhibitors or LTD4 receptor antagonists, indicating that benzene, like G-CSF, upregulates LTD4 production. Hydroquinone-induced differentiation was not affected by the LPO inhibitors, but only by the specific receptor antagonists. Thus HQ appears to obviate the requirement for LTD4 by activating the LTD4 receptor directly.

Chronic exposure of humans of benzene affects hematopoietic stem and progenitor cells and leads to aplastic anemia. The stromal macrophage, a target of benzene toxicity, secretes interleukin-1 (IL-1), which induces the stromal fibroblast to synthesize hematopoietic colony-stimulating factors. In a mouse model, benzene causes an acute marrow hypocellularity that can be prevented by the concomitant administration of IL-1 alpha. The ability of benzene to interfere with the production and secretion of IL-1 alpha was tested. Stromal macrophages from benzene-treated mice were capable of the transcription to the IL-1 alpha gene and the translation of the message but showed an inability to process the 34-kDa pre-IL-1 alpha precursor to the 17-kDa biologically active cytokine. Treatment of normal murine stromal macrophages in culture with hydroquinone (HQ) also showed an inhibition in processing of pre-IL-1 alpha. Hydroquinone is oxidized by a peroxidase-mediated reaction in the stromal macrophage to p-benzoquinone, which interacts with the sulfhydryl (SH) groups of proteins and was shown to completely inhibit the activity of calpain, the SH-dependent protease that cleaves pre-IL-1 alpha. In a similar manner, HQ, via peroxidase oxidation to p-benzoquinone, was capable of preventing the IL-1 beta autocrine stimulation of growth of human B1 myeloid tumor cells by preventing the processing of pre-IL-1 beta to mature cytokine. Benzoquinone was also shown to completely inhibit the ability of the SH-dependent IL-1 beta converting enzyme. Thus benzene-induced bone marrow hypocellularity may result from apoptosis of hematopoietic progenitor cells brought about by lack of essential cytokines and deficient IL-1 alpha production subsequent to the inhibition of calpain by p-benzoquinone and the prevention of pre-IL-1 processing.