Lusutrombopag for the Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Invasive Procedures (L-PLUS 2).

Thrombocytopenia may be associated with increased bleeding risk impacting timing and outcome of invasive procedures in patients with chronic liver disease (CLD). Lusutrombopag, a small-molecule, thrombopoietin (TPO) receptor agonist, was evaluated as a treatment to raise platelet counts (PCs) in patients with thrombocytopenia and CLD undergoing invasive procedures. L-PLUS 2 was a global, phase 3, randomized, double-blind, placebo-controlled study. Adults with CLD and baseline PCs < 50 × 109 /L were randomized to receive once-daily lusutrombopag 3 mg or placebo ≤ 7 days before an invasive procedure scheduled 2-7 days after the last dose. The primary endpoint was avoidance of preprocedure platelet transfusion and avoidance of rescue therapy for bleeding. A key secondary endpoint was number of days PCs were ≥ 50 × 109 /L throughout the study. Safety analysis was performed on patients who received at least one dose of study drug. This study occurred between June 15, 2015, and April 19, 2017, with a total of 215 randomized patients (lusutrombopag, 108; placebo, 107); 64.8% (70/108) of patients in the lusutrombopag group versus 29.0% (31/107) in the placebo group met the primary endpoint (P < 0.0001; difference of proportion 95% confidence interval [CI], 36.7 [24.9, 48.5]). The median duration of PCs ≥ 50 × 109 /L was 19.2 days with lusutrombopag (without platelet transfusion) compared with 0.0 in the placebo group (with platelet transfusion) (P = 0.0001). Most adverse events were mild or moderate in severity, and rates were similar in the lusutrombopag and placebo groups (47.7% and 48.6%, respectively). Conclusion: Lusutrombopag was superior to placebo for reducing the need for platelet transfusions and achieved durable PC response in patients with thrombocytopenia and CLD undergoing invasive procedures, with a safety profile similar to placebo.

Avatrombopag Before Procedures Reduces Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia.

BACKGROUND & AIMS: Patients with thrombocytopenia and chronic liver disease (CLD) may require platelet transfusions before scheduled procedures to decrease risk of bleeding. We performed 2 randomized, placebo-controlled, phase 3 trials in patients with thrombocytopenia and CLD undergoing scheduled procedures to evaluate the safety and efficacy of avatrombopag in increasing platelet counts in this patient population. METHODS: In the ADAPT-1 and ADAPT-2 studies, adults with thrombocytopenia and CLD (n = 231 and n = 204, respectively) were in 1 of 2 cohorts according to their baseline platelet count (below 40 × 109/L or 40 to below 50 × 109/L) and within each cohort were randomized (2:1) to receive 5 daily doses of avatrombopag (60 mg if baseline platelet count below 40 × 109/L or 40 mg if 40 to below 50 × 109/L) or placebo. ADAPT-1 was conducted at 75 study sites in 20 countries, from February 2014 through January 2017, and ADAPT-2 was conducted at 74 sites in 16 countries, from December 2013 through January 2017. The primary endpoint was the proportion of patients not requiring platelet transfusions or rescue procedures for bleeding up to 7 days after a scheduled procedure. RESULTS: In the ADAPT-1 study, 65.6% of patients who received 60 mg avatrombopag and 88.1% of patients who received 40 mg avatrombopag met the primary endpoint compared with 22.9% and 38.2% of patients receiving placebo, respectively (P < .0001 for both). In the ADAPT-2 study, 68.6% of patients who received 60 mg avatrombopag and 87.9% of patients who received 40 mg avatrombopag met the primary endpoint compared with 34.9% and 33.3% of patients who received placebo, respectively (P < .001 for both). Avatrombopag led to a measured increase in platelet counts and increased the proportion of patients who achieved the target platelet count ≥ 50 × 109/L on procedure day vs placebo. The incidence and severity of adverse events were similar for the avatrombopag and placebo groups and were consistent with those expected in the CLD population. CONCLUSIONS: In 2 phase 3 randomized trials, avatrombopag was superior to placebo in reducing the need for platelet transfusions or rescue procedures for bleeding in patients with thrombocytopenia and CLD undergoing a scheduled procedure. ClinicalTrials.gov nos.: NCT01972529 and NCT01976104.

FibroScan® versus Biochemical Scores: A Study of Liver Fibrosis in HIV with HBV Co-Infection.

The study aimed to determine liver fibrosis in human immunodeficiency virus (HIV) positive individuals using transient elastography (FibroScan®), Fibrosis-4 (FIB-4) score, and aspartate aminotransferase (AST) to Platelet Ratio Index (APRI) in the HIV Department from Infectious Diseases Hospital "Victor Babeș" Craiova, Romania. Of the analyzed HIV-positive subjects (n = 161), 93 (57.76%) had HIV mono-infection, and 68 (42.24%) had Hepatitis B Virus (HBV) co-infection. The prevalence of advanced liver fibrosis was higher (F2: 11.76% and F3: 13.24%, F4: 4.41%) in the HIV-HBV co-infected group compared to the HIV mono-infected group. The univariate and multivariate analysis identified HBV co-infection (OR = 5.73) male sex (OR = 5.34), serum aspartate amino-transferase levels (Pearson's rho = 0.273), low platelet count (Pearson's rho = -0.149) and erythrocyte sedimentation rate (OR = 1.030) as risk factors for the presence of liver fibrosis. Body mass index (OR = 1.08), serum lipid levels (OR = 0.96), viral load at diagnosis (OR = 1.00005), and low CD4+ cell count (OR = 0.977) were also correlated with liver fibrosis. The FIB-4 and APRI scores were strongly correlated with each other. In conclusion, HBV co-infection seems to be a determinant factor for liver fibrosis development in people living with HIV, together with other risk factors.

Interleukin-4 receptor -3223T→C polymorphism is associated with increased gastric adenocarcinoma risk.

BACKGROUND: Gastric cancer remains one of the most common types of cancer worldwide, with a large geographical variation in incidence and mortality rates. Cytokine polymorphisms are the most studied host polymorphisms and are associated with an increased risk of stomach cancer in many regions, but have not been studied extensively in Eastern European populations. OBJECTIVE: To investigate the potential association between five cytokine promoter polymorphisms (interleukin [IL] 1b -511C→T [rs16944], IL-4 receptor [IL-4R] -3223C→T [rs2057768], IL-8 -251T→A [rs4073], IL-10 -1082A→G [rs1800896] and tumour necrosis factor-alpha -308G→A [rs1800629]) and susceptibility to gastric adenocarcinoma in a Romanian population. METHODS: A total of 347 subjects, consisting of 105 patients with gastric adenocarcinoma and 242 controls, were included. All cytokine polymorphisms were genotyped using allele-specific, commercially available probes. Hardy-Weinberg equilibrium in both groups was analyzed using the chi squared test, and the relationship between targeted polymorphisms and the risk of gastric cancer was estimated using OR and 95% CI. RESULTS: A significant association between the IL-4R -3223C→T polymorphism and risk of gastric cancer was found. Carriers of the IL-4R -3223TT genotype were at a 2.5-fold increased risk for gastric cancer (OR 2.51 [95% CI 1.08 to 5.84]; P=0.041). Moreover, the presence of the IL-4R -3223TT genotype was associated with an increased risk of noncardia gastric adenocarcinoma (OR 3.08 [95% CI 1.25 to 7.58]; P=0.023). No associations were found among the other polymorphisms. CONCLUSION: The results suggest that the IL-4R -3223C→T polymorphism may increase the risk of gastric adenocarcinoma, mainly for the noncardia type, in the Romanian population.

The Importance of Accurate Early Diagnosis and Eradication in Helicobacter pylori Infection: Pictorial Summary Review in Children and Adults.

Among the most widespread childhood infections, Helicobacter pylori (H. pylori) develops potentially life-threatening conditions in adults if not appropriately treated. Helicobacter pylori is a common human pathogen that was first described in the stomach many years ago. The discovery of H. pylori was crucial in gastroenterology; this bacterium is associated with chronic gastritis, peptic ulcers, gastric cancer, and lymphoid tissue lymphoma related to the gastric mucosa. Studies published so far estimate that approximately 10% of subjects infected with H. pylori develop a peptic ulcer, and 1-3% of subjects develop gastric cancer. The clinical manifestations are variable and characteristically depend on the individual factors of the host. Various methods of detection and diagnosis of H. pylori infection have been developed, each with advantages, disadvantages, and/or limitations. Available diagnostic tests are usually performed using invasive (endoscopy, biopsy, rapid urease test, cultures, and molecular tests) and noninvasive methods (urea breath test, stool antigen examination, and serological and molecular tests). Although there is extensive accessibility for diagnosing and treating H. pylori infection, the prevalence of antibiotic resistance is not negligible. Thus, numerous studies and meta-analyses are focused on a new orientation of gastroenterologists in diagnosing and treating H. pylori infections. A fascinating perspective hypothesis is the administration of probiotics to reduce H. pylori adhesion to gastric epithelial cells, preventing H. pylori colonization, especially in children, or reinfection with H. pylori in high-risk adult patients.

Challenges in the Differential Diagnosis of COVID-19 Pneumonia: A Pictorial Review.

COVID-19 pneumonia represents a maximum medical challenge due to the virus's high contagiousness, morbidity, and mortality and the still limited possibilities of the health systems. The literature has primarily focused on the diagnosis, clinical-radiological aspects of COVID-19 pneumonia, and the most common possible differential diagnoses. Still, few studies have investigated the rare differential diagnoses of COVID-19 pneumonia or its overlap with other pre-existing lung pathologies. This article presents the main radiological features of COVID-19 pneumonia and the most common alternative diagnoses to establish the vital radiological criteria for a differential diagnosis between COVID-19 pneumonia and other lung pathologies with similar imaging appearance. The differential diagnosis of COVID-19 pneumonia is challenging because there may be standard radiologic features such as ground-glass opacities, crazy paving patterns, and consolidations. A multidisciplinary approach is crucial to define a correct final diagnosis, as an overlap of COVID-19 pneumonia with pre-existing lung diseases is often possible and suggests possible differential diagnoses. An optimal evaluation of HRTC can help limit the clinical evolution of the disease, promote therapy for patients and ensure an efficient allocation of human and economic resources.

Risk Factors and Genetic Predisposition in Colorectal Cancer: A Study on Young and Old Adults.

According to GLOBOCAN 2018 data Colorectal cancer (CRC) represents the third most commonly diagnosed cancer in the world and has the second-highest mortality rate. The incidence of CRC has been rising worldwide, the majority of cases being in developing countries mostly due to the adoption of an unhealthy lifestyle. The main driving factors behind CRC are a sedentary lifestyle, obesity, red meat consumption, alcohol, and tobacco; however, early detection screenings and standardized treatment options have reduced CRC mortality. Better family history and genetic testing can help those with a hereditary predisposition in taking preventative measures.

Metabolic Impact of Diabetes Mellitus Type 2 in Hepatitis C Virus Infected Patients.

OBJECTIVE: Patients with chronic hepatitis C are subjected to a greater risk of cardiovascular disease and difficult to control diabetes mellitus type 2 (T2DM) comparatively to people that have never contracted Hepatitis C Virus (HCV). We aimed to investigate the impact of T2DM on HCV patients with the help of Fibromax test results compared to nonT2DM patients, and the metabolic differences between the 2 study groups. Our long term goals are to observe the long term impact of achieving systemic virusologic response (SVR) by means of Direct-Acting antivirals (DAA) between the 2 cohorts. RESEARCH DESIGN AND METHODS: We selected a lot of 200 patients with HCV that will undergo interferon-free DAA-based antiviral treatment for HCV and we used the results of the Fibromax Test to compare the biological parameters of T2DM and nonT2DM patients. RESULTS Among patients with T2DM compared to NonT2DM there is a significant correlation on Steatotest, NashTest, GGT, Glycemia, body weight, height and BMI. Test also showed that 15,5% of the test group had elevated glycemia, indicating the probability of developing diabetes in the future. CONCLUSIONS: Our results suggest that HCV patients that also have T2DM are subjected to a combined higher risk of accelerated steatosis development, steatohepatitis, added difficulty in controlling glycemic levels. All these previous elements combined with a prevalence for patients to be overweight have a negative metabolic impact. Eradication of HCV with the help of DAA is important in order to help improving the metabolic impact of diabetes on steatosis, steatohepatitis. An added benefit is better management of glycemic control by decreasing insulin use and eliminating one risk factor of T2DM.

Colon cancer: clinical, macroscopic and microscopic aspects.

Although in developed countries the incidence of colorectal cancer is decreasing through the introduction of well-designed screening systems, the worrying worldwide increase of the mortality rate by colorectal neoplasm indicates the need for a thorough characterization of this pathology. Clinical, endoscopic, histopathological and immunohistochemical data provide important information for creating categories of patients that can benefit from intensive screening methods and for establishing the prognosis based on these data. Approximately 80% of the colorectal cancer develops from adenomas, which shows that early detection of premalignant lesions is an important step in reducing global incidence and mortality. Our study aims at providing information about the clinical, imaging and histopathological characterization of colorectal neoplasm and premalignant lesions. A total of 98 patients were evaluated, including 72 patients diagnosed with colorectal cancer and 26 with premalignant lesions. Patients underwent colonoscopy with biopsy specimens that were examined histopathologically. From the epidemiological data, we observe a higher incidence in men with a men/women ratio of 2/1, with a median age in colorectal cancer patients of 63.93 years. Different data on signs and symptoms were observed according to the colonoscopy location, with a slight difference between symptoms of patients with premalignant lesions compared to those diagnosed with colorectal neoplasm. Endoscopy showed that the rectum was the most frequent location, followed by the left colon, the tumor having a vegetative aspect in most cases. Histopathology confirms that the most common subtype is adenocarcinoma, described in 67 of the studied cases. The moderate differentiation degree is present in more than half of the cases.

Evaluation of Helicobacter pylori infection in patients with eso-gastro-duodenal pathology.

Helicobacter pylori (HP) infection is one of the most frequent bacterial infections in humans. The studies performed in the last 30 years showed that this bacterium is the main cause of chronic gastritis and the main etiological agent of peptic ulcer and gastric cancer. We investigated the prevalence of HP infection in a group of 1525 patients who addressed a gastroenterology medical center between 2010-2014, in Craiova, Romania, for dyspeptic symptoms. The patients underwent a clinical, endoscopic and serologic investigation for highlighting a possible HP infection. The age of the patients with gastric duodenal pathology varied between 16 and 87 years old. Of the 1525 patients, a number of 971 (63.67%) were diagnosed with HP infection, while the rest of 554 (36.33%) were not infected. The study on the distribution of gastric duodenal pathology and HP infection showed that the lesions of the upper digestive tract and HP infection emerged quite early, a number of 29 patients being aged less than 20 years old; among these, 21 (72.41%) patients were HP positive and only eight (27.59%) were HP negative. In the age group of 20-29 years old there were recorded 184 patients, of which 120 (65.22%) were HP positive and only 64 (34.78%) were HP negative. There may be observed that in the age group of 20-29 years old, both the patients with gastric duodenal pathology and the ones with HP infection increased six times in comparison to the first decade. Most cases were recorded in the patients aged between 50 and 69 years old. The two decades comprised a total number of 607 (39.8%) patients, of which 375 (61.78%) were HP positive and 232 (38.22%) were HP negative. By evaluating the distribution of HP infection according to the social environment, there was observed that there were no significant differences between the patients coming from the urban area and the ones from the rural area, as far as the HP infection was concerned.

Clinical importance of pharmacogenetics in the treatment of hepatitis C virus infection.

Globally, over 4% of the world population is affected by hepatitis C virus (HCV) infection. The current standard of care for hepatitis C infection is combination therapy with pegylated interferon and ribavirin for 48 weeks, which yield a sustained virological response in only a little over half of the patients with genotype 1 HCV. We investigated the clinical importance of pharmacogenetics in treatment efficacy and prediction of hematotoxicity. A total of 148 patients infected with HCV were enrolled. All patients were treated for a period of 48 weeks or less with pegylated interferon and ribavirin. Four genotypes were investigated: inosine triphosphatase (ITPA) rs1127354, C20orf194 rs6051702, interferon lambda (IFNL)3 rs8099917, IFNL3÷4 rs12979860 in the population from southwestern Romania. Genetic variants for rs129798660 and rs6051702 proved once more to represent an indisputable clinical tool for predicting sustained virological response (SVR) (69.23%, chi-square p=0.007846, p<0.05 and 63.29%, chi-square p=0.007846, p<0.05, respectively). ITPA genetic variants protect against ribavirin-induced hemolytic anemia and C20orf194 also proved to be protective against thrombocytopenia. These clinical findings strengthen the belief that pharmacogenetics should play a constant role in treatment decisions for patients infected with hepatitis C virus.

Dendritic cells and hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents a major health burden in the modern world. Because current treatment options for HCC are capable of providing good survival rates to only a limited number of patients, new therapeutic opportunities should be looked upon. The particularities of dendritic cells (DC) populations existing in the liver, and their consecutive selective activation of certain immunotolerant T-cell subgroups, account for the high success rate of allogeneic hepatic transplantation, currently the most efficient treatment for HCC. The particularities of dendritic cells (DCs) populations existing in the liver, and their consecutive selective activation of certain immunotolerant T-cell subgroups, account for the high success rate of allogeneic hepatic transplantation for HCC. These molecular mechanisms also open new paths towards cancer preventing and cancer curative vaccines, as well as successful immunotherapy. Our aim was to summarize the main aspects of the biology of DCs populations, especially those present in the liver, and to draw attention to their current and future roles in the curative treatment of hepatocarcinoma.

Peritumoral inflammatory reaction in colon cancer. Histological and immunohistochemical study.

Colorectal cancer is one of the most frequent malignancies with an increasing incidence and prevalence. As in other malignancies, nor etiology, neither pathogenesis of colorectal cancer are well known. The link between inflammation and colorectal cancer has become a major concern in the past 20 years, since several clinical trials have shown that patients with chronic inflammatory intestinal diseases have a much higher risk of colorectal neoplasm development. In our study, we analyzed peritumoral inflammatory reaction from histological and immunohistochemical point of view, in 23 cases of stage III colon adenocarcinoma, operated during 2014. The immunohistochemical techniques were used in order to emphasize B-lymphocytes, T-lymphocytes, macrophages, mast cells and blood vessels. In all cases, we have noted the involvement of inflammatory cells present in peritumoral and tumoral stroma, in variable degrees, regardless the differentiation of the neoplasm or other known histological feature. In particular, the macrophages were the most numerous, especially in areas of tumoral necrosis, but also present in the lumen of tumoral glands, or even within tumoral cell islands. Mast cells appeared more abundant in the tumor stroma around blood vessels and were absent in the areas of tumor necrosis, while B-cells were almost absent. Tumor stroma showed a well-developed vascular network, consisting mainly of small vessels that do not seem to correlate with the intensity of the inflammatory reaction.

A double-blind, placebo-controlled pilot study to evaluate the effect of calcium fructoborate on systemic inflammation and dyslipidemia markers for middle-aged people with primary osteoarthritis.

The objective of this pilot study was to determine whether 15 days of dietary supplementation with calcium fructoborate could acutely modulate inflammatory and lipid blood markers in individuals diagnosed with primary osteoarthritis. During 2 weeks, a placebo-controlled, randomized, double-blind study was conducted on 116 subjects that were initially recruited. Seventy-two subjects started the study, being divided into four groups, and only 60 completed the study as designed. The aim was to compare the effects of calcium fructoborate to placebo on subjects diagnosed with knee primary osteoarthritis. The obtained outcomes were inflammation biomarkers (C-reactive protein, fibrinogen, and erythrocyte sedimentation rate) and lipid markers (triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol). No serious adverse events were reported. The calcium fructoborate showed beneficial effect on the inflammatory markers for all groups subjected to the treatment when compared with the placebo group and slight changes in the lipid metabolism. This study suggests that short-term (2 weeks) calcium fructoborate supplementation in patients with osteoarthritis symptoms has a favorable prognosis on inflammation diseases.