Tom 56 (2018): Zeszyt 3 (September 2018)

Introduction. LIM Homeobox 6 (LHX6) encodes a LIM homeodomain transcription factor, contributes to tissue development and morphogenesis, and is mostly expressed in medial ganglionic eminence and odontogenic mesenchyme. However, it has been reported to play a role in cancer progression. This narrative review summarizes literatures that emphasize the molecular regulation of LHX6 in tumorigenesis.

Methods. In our systematic review, the PubMed database was used for the literature search using the combination of words that included “LHX6” and “cancer”. Relevant studies, including in vitro, in vivo experiments, and clinical studies, were analyzed in this review.

Results. We found evidences that LHX6 might be important in the inhibition of tumor cell proliferation, growth, invasion, and metastasis through the suppression of Wnt/β-catenin signaling pathway. Moreover, LHX6 is observed to be downregulated in certain types of cancer due to hypermethylation, thus hindering its tumor suppressing ability. In addition, hypermethylation can also be used to determine the stage of cancer development.

Conclusion. The downregulation of LHX6 expression might be responsible in promoting cancer progression. Future studies are necessary to investigate the potential of LHX6 as a novel cancer biomarker as well as its therapeutic implications towards certain types of cancer.

Introduction. Our research strategy was aimed at evaluating the possible implication of the type of factor VIII product administered as substitution treatment to haemophilia A patients in the occurrence of inhibitors and their consequences on the management.

Methods. Scientific articles from July 2015 to July 2017 were searched using the PubMed and PubMed Central databases. The used search terms included “haemophilia A”, “inhibitors”, “plasma-derived factor VIII” and “recombinant factor VIII”.

Results. The risk factors for inhibitors occurrence may be patients-related (genetic and nongenetic) and treatment-related. The possibility of a correlation between the increased purity of factor VIII given as substitution treatment and the occurrence of inhibitors is discussed in the light of literature data. Plasma-derived factor VIII is less immunogenic, but not entirely safe from the point of view of the possibility of transmitting biological agents. It is obvious that there is not enough plasma-derived factor VIII for the planet’s needs. Recombinant factor VIII products have revolutionized the treatment of patients with haemophilia A over the past 3 decades by the disappearance of transfusion-related infections and their complications. They are safer in terms of pathogens and the new long-acting factor VIII products are based on recombinant DNA technology.

Conclusion. Plasma-derived or recombinant factor VIII products must co-exist on the market for the benefit of haemophilic patients. Future solutions could be: less immunogenic factor VIII products, nonfactor replacement strategies, or bispecific antibody that mimics the function of coagulation factor VIII.

Introduction. The neutrophil-to-lymphocyte ratio (NLR) as calculated from the white cell differential blood count is a marker that has been used as a prognostic index when assessing patients suffering from several clinical syndromes, including sepsis. The aim of this study was to evaluate the relationship between NLR and the commonly used severity scores of sepsis SOFA, APACHE II and SAPS II in a population of emergency admitted adult patients with sepsis in a tertiary center.

Methods. A prospective observational study was conducted in the Emergency Department of the University Hospital of Patras, Greece, based on data extracted from 50 patients consecutively enrolled, suffering from sepsis of multiple origin. The study period was from May 01, 2017 until June 30, 2017. The NLR was calculated from the total white blood cell (WBC) count values measured from a peripheral venous blood specimen drawn on admission. C-reactive protein (CRP) was also measured. The sepsis severity prognostic scores APACHE II, SAPS II and SOFA were calculated for each patient.

Results. NLR was positively correlated with the sepsis severity prognostic scores on admission (SOFA, r_s = 0.497, p < 0.001; APACHE II, r_s = 0.411, p = 0.003; SAPS II, r_s = 0.445, p = 0.001). Total WBC was also significantly correlated with the scores (SOFA, r_s = 0.342, p = 0.015; APACHE II, r_s = 0.384, p = 0.006; SAPS II, r_s = 0.287, p = 0.043). Serum CRP did not show any significant correlation either to NLR or to the sepsis severity scores on admission.

Conclusions. NLR is an easily calculated, cost-efficient index that could be used as a tool for clinicians when assessing sepsis patients in the Emergency Department. Although NLR measurement is simple, and rapidly available, future and larger prospective studies are warranted to confirm its definite value as a prognostic index in sepsis patients.

Background. Regulatory T (Treg) cell plays a key role in autoimmune diseases. We evaluated the regulatory function and frequency of Treg cells and secreted IL-10, IL-35 concentration in Crohn’s disease (CD).

Methods. Twenty-three patients with CD and 25 healthy controls (HC) were included in this study. We analysed the alteration of Tregs frequency using flow cytometry for CD4, CD25, CD127 and FoxP3 markers. Surface expression of CD4, CD25 and CD127 markers were used for isolation of relatively pure Treg cells. Suppressive activity of Tregs was determined by measuring their ability to inhibit the proliferation of T responder (Tres) cells. In addition, the amounts of IL-10 and IL-35 cytokines in co-culture supernatants were measured by ELISA assay after stimulation with anti-CD2/CD3/CD28.

Results. CD patients had significantly lower frequency of CD4⁺ CD25⁺ CD127^low FoxP3⁺ Treg cells in comparison with controls (2.17 ± 1.04 vs. 2.83 ± 1.07, p = 0.0352). Additionally, Treg cells mediated suppression was not significantly different in CD patients compared to controls. There was a significant difference in IL-10 secretion in response to anti-CD2/CD3/CD28 stimulation compared with HC (p = 0.0074).

Conclusion. The frequency of CD4⁺ CD25⁺ CD127^low FoxP3⁺ Tregs decreased in active stage of CD but there was no impaired suppressive function of CD4⁺ CD25⁺ CD127^low FoxP3⁺ Treg cells. We suggest that an alteration in the balance of Tregs and T effectors may contribute to pathogenesis of CD.

Background. It is now suggested an association between non-alcoholic fatty liver disease (NAFLD) and the occurrence of coronary artery disease even in non-diabetic patients. We will determine the rate of NAFLD and its main determinants in non-diabetic patients undergoing coronary angiography.

Methods. This cross-sectional study was accomplished on 264 patients who were candidates for coronary angiography during the year 2016. Coronary angiography has been done to depict the presence or absence of coronary involvement, and the severity of coronary artery disease by determining the number of vessels involved and also the SYNTAX score. During 48 hours after coronary angiography, the patients underwent abdominal ultrasonography for detection of NAFLD.

Results. The overall prevalence of NAFLD in the patients was 72.3%. The prevalence of NAFLD in those with and without coronary involvement was 71.9% and 73.1% respectively, with no notable difference (p = 0.837). The mean SYNTAX score in the patients with and without NAFLD was 22.32 ± 11.10 and 21.75 ± 10.71 respectively with no difference (p = 0.702). According to the multivariable regression models, the presence of NAFLD could not predict the likelihood of coronary artery disease (OR = 0.879, p = 0.669) or its severity assessed by the SYNTAX score (beta = 0.046, p = 0.456). NAFLD grade was also not a determinant for coronary artery disease (OR = 1.139, p = 0.178) or its severity (beta = 0.058, p = 0.165).

Conclusion. It seems that the presence and grade of NAFLD may not be correlated with atherosclerotic involvement of coronary arteries and its severity in non-diabetic patients. Future large studies and trials could elucidate the independent role of fatty liver in nondiabetic non-alcoholic patients.

Introduction. Combinations of gefitinib and radiotherapy have been observed to have synergistic and anti-proliferative effects on lung cancer in vitro. In the clinical setting, patients who presented with respiratory difficulties such as superior vena cava syndrome (SVCS), radiotherapy should be given immediately to address the emergency while waiting for the results of epidermal growth factor receptor (EGFR) mutation test. However, there has been no study that described the role of radio-therapy in Indonesian patients with EGFR-mutant lung adenocarcinoma.

Methods. This preliminary study aimed to evaluate the efficacy and toxicities of gefitinib and radiotherapy combination in lung adenocarcinoma patients in Persahabatan National Respiratory Referral Hospital, Jakarta, Indonesia. Subjects were consecutively recruited between January 2013 and December 2016.

Results. Thirty-one lung adenocarcinoma with EGFR mutations were enrolled. Most of them were male (51.61%) with a median age of 54.5 years old (range 38-70 years old). EGFR mutation characteristics were on exon 21 L858R point mutation (61.30%), exon 21 L861Q point mutation (16.12%) and exon 19 deletion (22.58%). Radiotherapy was given at doses between 30-60 Gy. Among these subjects, median progression-free survival (PFS) was 185 days (95%CI; 123.69 – 246.30), 1-year survival rate (1-yr) was 45.2%, and median overall survival (OS) was 300 days (95%CI; 130.94 – 469.06). There were no grade 3/4 hematological and nonhematological toxicities recorded. The most frequent grade 1 and 2 non-hematological toxicities were skin rash, diarrhea, and paronychia that might be related to tyrosine kinase inhibitor (TKI).

Conclusion. The combination of TKI with radiation may be considered in EGFR-mutant lung adenocarcinoma subjects.

Background. We aimed to determine the relationship between endocan and cirrhotic cardiomyopathy.

Materials and methods. Patients with liver cirrhosis and no heart disease were included in a prospective observational study with liver disease decompensation and death as primary outcomes.

Results. 83 cirrhotic patients were included and 32 had cirrhotic cardiomyopathy. Endocan levels were significantly lower in patients with cirrhotic cardiomyopathy (5.6 vs. 7 ng/mL, p = 0.034). Endocan correlated with severity of cirrhosis, time to decompensation or death from liver disease (OR 4.5 95% CI 1.06-31.1).

Conclusion. Endocan is a promising biomarker of severity of cirrhosis and may help in the diagnosis of cardiac dysfunction in this population.

Background. The Roma population has a high prevalence of cardiovascular risk factors, higher mortality, and shorter life expectancy. It is found in the largest number in Romania, but published data are still scarce here. We studied cardiovascular risk factors and disease along with target organ damage on a population of Roma inhabitants from Bucharest, Romania.

Methods. This cross-sectional study enrolled 806 Roma subjects (18-83 years), in a community-based participatory research manner. Demographics included anthropometric data, a questionnaire on social status, education, medical history, and health deleterious behaviors. Medical evaluation included clinical examination, blood pressure, ankle-brachial index, pulse wave velocity measurements, blood tests (complete blood count, lipid profile, glucose, creatinine, uric acid), dip-stick microalbuminuria, dilated fundoscopy, ECG, and echocardiography.

Results. Prevalence of all cardiovascular risk factors was high, peaking in abnormal lipid metabolism (82.13%), heavy smoking (63.02% including ex-smokers) and obesity (50.99%). The first and the latter were actually similar to the general population in Romania. Almost half of subjects were at high or very high risk for fatal cardiovascular disease.

Conclusions. The study shows that the Roma population in a more affluent region in Romania shares a similarly high cardiovascular burden to their surrounding community.

Introduction. Hypertrophic cardiomyopathy (HCM) is a disease with increased left ventricular (LV) wall thickness not solely explained by abnormal loading conditions, with great heterogeneity regarding clinical expression and prognosis. The aim of the present study was to collect data on HCM patients from different centres across the country, in order to assess the general characteristics and therapeutic choices in this population.

Methods. Between December 2014 and April 2017, 210 patients from 11 Romanian Cardiology centres were enrolled in the National Registry of HCM. All patients had to fulfil the diagnosis criteria for HCM according to the European Society of Cardiology guidelines. Clinical, electrocardiographic, imaging and therapeutic characteristics were included in a predesigned online file.

Results. Median age at enrolment was 55 ± 15 years with male predominance (60%). 43.6% of the patients had obstructive HCM, 50% non-obstructive HCM, while 6.4% had an apical pattern. Maximal wall thickness was 20.3 ± 4.8 mm (limits 15-37 mm) while LV ejection fraction was 60 ± 8%. Heart failure symptoms dominated the clinical picture, mainly NYHA functional class II (51.4%). Most frequent arrhythmias were atrial fibrillation (28.1%) and non-sustained ventricular tachycardia (19.9%). Mean sudden cardiac death risk score (SCD-RS) was 3.0 ± 2.3%, with 10.4% of the patients with high risk of SCD. However, only 5.7% received an ICD. Patients were mainly treated with beta-blockers (72.9%), diuretics (28.1%) and oral anticoagulants (28.6%). Invasive treatment of LVOT obstruction was performed in a small number of patients: 22 received myomectomy and 13 septal ablation. Cardiac magnetic resonance was reported in only 14 patients (6.6%).

Conclusions. The Romanian registry of HCM illustrates patient characteristics at a national level as well as the gaps in management which need improvement – accessibility to high-end diagnostic tests and invasive methods of treatment.

Tracheoesophageal fistula (TEF) is frequently congenital and requires surgical correction. TEF can also occur secondary to malignant esophageal tumors or benign diseases and these cases are managed by endoscopic means, such as closing the defect with metallic stents. Although esophageal injury can occur secondary to nonsteroidal anti-inflammatory drugs (NSAIDs), TEF secondary to chronic NSAIDs use has not been described in the literature.

We report the case of a male patient with refractory migraine and chronic use of NSAIDs, with a history of esophageal stenosis presenting with acute-onset total dysphagia. Upper gastrointestinal endoscopy and CT-scan revealed TEF located at 25 cm from the incisors. An esophageal stent was placed endoscopically, and 6 weeks a second stent was placed in a stent-in-stent manner to allow removal of both stents. Endoscopic control after the removal of the stents showed the persistence of the fistula, so a third stent was placed as a rescue therapy.

Against medical advice, the patient continued to use OTC painkillers and NSAIDs in large doses. Three months later, he was readmitted with total dysphagia and recent-onset dysphonia. CT scan revealed a new fistula above the already placed stent. A second metallic stent was endoscopically placed through the old stent to close the newly developed fistula. The patient was discharged on the third day with no complications and he remains well at 6 months follow-up.

Due to small cases studies, recurrent TEF remains a therapeutic challenge. Endoscopic therapy is usually an effective solution, but complex cases might require multiple treatment sessions.