Reviews on Recent Clinical Trials - Volume 16, Issue 2, 2021

Background: In the current coronavirus disease 2019 (COVID-19) pandemic, health systems are struggling to prioritize care for affected patients; however, physicians globally are also attempting to maintain care for other less-threatening medical conditions that may lead to permanent disabilities if untreated. Idiopathic intracranial hypertension (IIH) is a relatively common condition affecting young females that could lead to permanent blindness if not properly treated. In this article, we provide some insight and recommendations regarding the management of IIH during the pandemic. Methods: The diagnosis, follow-up, and treatment methods of IIH during the COVID-19 pandemic period are reviewed. COVID-19, as a mimic of IIH, is also discussed. Results: Diagnosis and follow-up of papilledema due to IIH during the COVID-19 pandemic can be facilitated by nonmydriatic fundus photography and optical coherence tomography. COVID-19 may mimic IIH by presenting as cerebral venous sinus thrombosis, papillophlebitis, or meningoencephalitis, so a high index of suspicion is required in these cases. When surgical treatment is indicated, optic nerve sheath fenestration may be the primary procedure of choice during the pandemic period. Conclusion: IIH is a serious vision-threatening condition that could lead to permanent blindness and disability at a relatively young age if left untreated. It could be the first presentation of a COVID-19 infection. Certain precautions during the diagnosis and management of this condition could be taken that may allow appropriate care to be delivered to these patients while minimizing the risk of coronavirus infection.

Background: Citicoline is a drug used both in degenerative and in vascular cognitive decline; memantine is a drug used for the treatment of mild to moderate Alzheimer’s disease (AD). Our hypothesis is that their combined use could have enhanced action in patients having AD and mixed dementia (MD). We report the main tips from a recent study on the use of these drugs, the CITIMEM study. Methods: The study was retrospective and was performed on 126 patients aged 65 years old or older affected with AD or MD (mean age 80.7 ± 5.2 years old) who had been visited between 2015 and 2017 in four different centers for dementia all over Italy. Neuropsychological and functional tests were administered at baseline (T0), after 6 (T1), and 12 months (T2). The effects of combined treatment versus memantine alone on cognitive functions assessed by Mini-Mental State Examination (MMSE) and the possible onset of side effects or adverse events, as well as the influence on daily life functions and behavioral symptoms, were investigated. Results: Patients undergoing combined treatment showed a significant increase in MMSE vs. memantine alone, both at T1 (p=0.003) and T2 (p =0.000). Conclusion: The CITIMEM study confirms our hypothesis that the combined administration of memantine plus citicoline is safe and more effective than memantine alone on cognition in patients suffering from AD or MD.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that poses several challenges in terms of clinical diagnosis and investigation of molecular etiology. The lack of knowledge on the pathogenic mechanisms underlying ASD has hampered the clinical trials that so far have tried to target ASD behavioral symptoms. In order to improve our understanding of the molecular abnormalities associated with ASD, a deeper and more extensive genetic profiling of targeted individuals with ASD was needed. Methods: The recent availability of new and more powerful sequencing technologies (third-generation sequencing) has allowed to develop novel strategies for the characterization of comprehensive genetic profiles of individuals with ASD. In particular, this review will describe integrated approaches based on the combination of various omics technologies that will lead to a better stratification of targeted cohorts for the design of clinical trials in ASD. Results: In order to analyze the big data collected by assays such as the whole genome, epigenome, transcriptome, and proteome, it is critical to develop an efficient computational infrastructure. Machine learning models are instrumental to identify non-linear relationships between the omics technologies and, therefore, establish a functional informative network among the different data sources. Conclusion: The potential advantage provided by these new integrated omics-based strategies is better characterization of the genetic background of ASD cohorts, to identify novel molecular targets for drug development, and ultimately offer a more personalized approach in the design of clinical trials for ASD.

Introduction: Corona virus is a group of viruses that cause diseases in mammals and birds. In humans, these families of viruses can cause respiratory infections from a mild form to fatal. It is preferably called coronavirus. Formally, it is known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or 2019 novel coronavirus (2019-nCoV) and this disease is called coronavirus disease 2019 (COVID-19). SARS-CoV-2 is infectious in humans and the world health organization has announced COVID-19 as pandemic disease. Tocilizumab is a biological agent that inhibits the cytokine, interleukin 6 (IL-6 inhibitor). As SARS-CoV-2 infection leads to the development of cytokine storm syndrome, the drug, tocilizumab, seems to have a positive effect on patients with COVID-19. Aim: To analyze and review the possible effects and efficacy of the tocilizumab (monoclonal antibody against IL-6 receptors) in SARS-CoV-2 patients. Materials and Methods: A search was carried out for all recent review articles, which were used to study the SARS-CoV-2 disease and their characteristics. Furthermore, we have analyzed the most recent research articles on monoclonal antibody against IL-6 receptors (tocilizumab) and their possible clinical effects in COVID-19 and its’ clinical trials. Results: COVID-19 is a disease caused by SARS-CoV-2 infection. It is a life threatening condition, which can give rise to fatal outcomes if left untreated. However, there are no approved treatments for COVID-19 globally. Furthermore, we can conclude that SARS-CoV-2 is associated with the worsening of lung conditions, characterized by interstitial pneumonia with acute respiratory distress syndrome as a result of cytokine storm syndrome. According to available research data, tocilizumab, a recombinant humanized anti-human monoclonal antibody of IgG1Τ (gamma 1, kappa), can improve patient’s condition from cytokine storm syndrome by inhibiting the IL-6 (Interleukin 6) receptors. Conclusion: The rational use of the tocilizumab in severe and critically ill COVID-19 patients can prevent the development of irreversible lung injury and death of the patient. Three retrospective studies of Xiaoling Xu et al., Pan luo et al., and Paola Tonaiti et al. have shown the efficacy of tocilizumab in severe and critically ill COVID-19 patients. However, we need more randomized research studies with a significant number of patients which can confirm the promising results on tocilizumab treatment in COVID-19 patients. Moreover, ongoing clinical trails such as TOSCA, COVACTA results have not been published yet which are expected to give better and more significant results on tocilizumab’s effectiveness and safety.

Background: Nutrition plays a major role in the growth and well-being of children and forms the basis of their existence. A pandemic like COVID19 poses some serious questions and challenges in the minds of practicing pediatricians as to what support they should offer children, their parents and carers alleviating their anxiety about their children’s diet and nutrition, that is critical at this time of crisis. Although the evidence for pediatric nutrition and COVID19 is not strong, this article aims to critically look into pediatric nutrition during the COVID19 pandemic and bring the most recent evidence into the limelight to facilitate making the right choices with respect to pediatric nutrition. Methods: We performed a search on recent literature using the search terms “Covid19” + “Children” + “Nutrition” to analyze the current evidence supporting nutrition as a stimulant for covid19. A review article based on the above search results was written to highlight the importance of nutrition during this pandemic. Results: Strong recommendations remain unchanged for breastfeeding, healthy complementary feeding, use of supplemental formula where appropriate, oral nutritional supplements, zinc, n-3 & n- 6 fatty acids, and probiotics all have a certain role to play as a stimulant for Covid19 in children. Conclusion: Current evidence emphasizes the use of additional nutritional supplements, especially in the “at risk” groups, low socio-economic status and children with chronic medical problems. Paediatric nutrition should never be overlooked and “one size does not fit all” as every child is different and children’s individual nutritional needs vary. This review points to the importance of nutrition as a stimulant to covid19 in the pediatric population.

Backround: Radiation-induced oral mucositis consists of a series of relatively frequent side effects after head and neck cancer radiotherapy and has an adverse impact on both regular treatment process and the quality of life of patients. Objective: The purpose of the present review is to optimize the current management of radiation-induced oral mucositis in head and neck cancer patients. Methods: PubMed database research was performed on articles published since 2015 that demonstrated efficacy in the management of radiation-induced oral mucositis in head and neck cancer patients. The study selection included observational, prospective, comparative, randomized, double- blind, placebo-controlled or uncontrolled, and retrospective studies, as well as systematic reviews and metanalyses. Results: From the 931 citations obtained from the search, only 94 articles met the inclusion criteria, including mucosal protectants, anti-inflammatory agents, growth factors, and various miscellaneous and natural agents. Several methods, including both pharmacological and natural agents, have been proposed for the management of oral mucositis. In addition to the already known interventions with strong evidence, according to the Multinational Association of Supportive Care in Cancer and he International Society of Oral Oncology guidelines, further agents have been used. However, a great number of them lack clear evidence, which surely requires the design of more controlled clinical trials for a better assessment of the ideal methods. Conclusion: The management of oral mucositis constitutes an active area of research. In light of these results, it is aimed to illustrate those treatment strategies that are most effective regarding the treatment approach of oral mucositis.

Background: Radiation therapy is stressful for both the patient and family. After a child's cancer diagnosis, parents face the burden of dealing with fear, their children's needs and the unfamiliarity of radiotherapy procedure. Introduction: This paper aims to present methods to alleviate the total psychological stress those children and parents feel during the radiation course. Methods: A literature search was performed until January 2020. Result: Previous publications suggest a multidisciplinary proactive approach involving health professionals, patient, family, and extended family to lessen the stress associated with radiation therapy. A well-trained, specialist, healthcare radiotherapy-pediatric staff can help, educate and communicate effectively with the family. Maintaining the same health staff during radiotherapy creates intimacy and reduces anxiety. All necessary age-appropriate information as well as a list available with the most important things about the care-giving should be clearly written and easily accessible. An information exchange system among all the health specialists involved must be developed. Friendly and playful specialists are crucial in familiarizing the child with the computed tomography (CT) machines and radiotherapy process. A tablet with an educating application or machine models installed in the waiting area can be useful. Creative arts therapy may be a positive intervention. Maintaining a normal routine is vital for the psychological well-being of parents and children. A social worker may assist in regaining a good mental state. Conclusion: With ongoing age-appropriate information and psychological support throughout the whole radiation period, both parents and children will be more optimistic, strong and encouraged to fight for the child’s and family’s well-being.

Background: Neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have been studied so far as prognostic factors of cardiovascular diseases. Their role interplayed with endothelial inflammation has emerged as optimal predictors for major cardiovascular disease events and prognostic factors for post-procedural outcomes. Methods: A review of the current literature was undertaken to investigate the relationship between NLR and PLR with percutaneous, cardiac surgery, and vascular surgery procedures. Results: Our findings show that perioperative NLR and PLR levels are significantly correlated with patient morbidity and mortality rates. Conclusion: These biomarkers have several attractive characteristics, as they are inexpensive and quickly available, and they can contribute to the early identification of patients at high risk for periprocedural adverse events.

Background: We performed a critical overview of published systematic reviews (SRs) of chemotherapy for advanced and locally advanced pancreatic cancer, and evaluated their quality using AMSTAR2 and ROBIS tools. Materials and Methods: PubMed and Cochrane Central Library were searched for SRs on 13th June 2020. SRs with meta-analysis which included only randomized controlled trials and that had assessed chemotherapy as one of the treatment arms were included. The outcome measures, which were looked into, were progression-free survival (PFS), overall survival (OS), and adverse events (AEs) of grade 3 or above. Two reviewers independently assessed all the SRs with both ROBIS and AMSTAR2. Results: Out of the 1,879 identified records, 26 SRs were included for the overview. Most SRs had concluded that gemcitabine-based combination regimes, prolonged OS and PFS, but increased the incidence of grade 3-4 toxicities when compared to gemcitabine monotherapy, but survival benefits were not consistent when gemcitabine was combined with molecular targeted agents. As per ROBIS, 24/26 SRs had 'high' risk of bias, with only 1/26 SR having 'low' risk of bias. As per AMSTAR2, 25/26 SRs had 'critically low', and 1/26 SR had 'low' confidence in the results. The study which scored 'low risk of bias' in ROBIS scored ‘low confidence in results’ in AMSTAR2. The inter- rater reliability for scoring the overall confidence in the SRs with AMSTAR2 and the overall domain in ROBIS was substantial; ROBIS: kappa=0.785, SEM=0.207, p<0.001; AMSTAR2: kappa= 0.649, SEM=0.323, p<0.001. Conclusion: Gemcitabine-based combination regimens can prolong OS and PFS but also worsen AEs when compared to gemcitabine monotherapy. The included SRs have an overall low methodological quality and high risk of bias as per AMSTAR2 and ROBIS respectively.

Background: We compared the response rates, survival rates, and safety profile of epidermal growth factor receptor (EGFR) inhibitors with non-targeted chemotherapy and older EGFR inhibitors when used to treat advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. Methods: We searched PubMed, Cochrane Central Register of Controlled Trials, and clinicaltrial.- gov for randomized controlled trials published until 11-Feb-2020. Treatment outcomes were compared between EGFR inhibitor and pooled comparator; a subgroup analysis compared outcomes between EGFR inhibitor and non-targeted chemotherapy, and between newer and older EGFR inhibitors. Results: Twenty-one studies with 4,250 unique patients were included. Significantly higher objective response rate (ORR) (odds ratio (OR) 2.28; 95% CI 2.00-2.61), higher disease control rate (DCR) (OR 2.3; 95% CI 1.88-3.06), and longer progression-free survival (PFS) (Hazard ratio (HR) 0.56; 95% CI 0.52-0.60) were observed in the EGFR inhibitor group compared to the pooled comparator group. Subgroup analysis revealed that the ORR, DCR, and PFS were significantly higher with EGFR inhibitors than non-targeted chemotherapy, and only PFS (and not ORR and DCR) was significantly longer with newer EGFR inhibitors than the older EGFR inhibitors. Overall survival (OS) was not significantly different between EGFR inhibitors and pooled comparator (HR 0.91; 95% CI 0.83-1.00) as well as in either of the subgroup analyses. Adverse events ≥ grade 3 and treatment discontinuation were significantly higher with non-targeted chemotherapy compared to the EGFR inhibitors. Conclusion: The benefits of prolongation of ORR, DCR, and PFS might not imply significantly improved OS after therapy with EGFR inhibitors when compared with non-targeted chemotherapy or older EGFR inhibitors.

Background: A recent survey reported an association between fibromyalgia and overactive bladder. Objective: To carry out the first systematic case-controlled study to compare the level of overactive bladder symptoms in a group of fibromyalgia patients and a group of matched controls. Methods: The symptom-bother OAB-q8 questionnaire and Revised Fibromyalgia Impact Questionnaire (FIQR) were administered to 27 patients who fulfilled the revised diagnostic criteria for fibromyalgia of the American College of Rheumatology and to 26 healthy controls who had no history of suffering from fibromyalgia or any other rheumatological or neurological illness. Results: The groups were matched in respect of age, sex and ethnicity. None of the 53 subjects was taking medication, which might cause urinary urgency, none was suffering from, or had recently suffered from, a urinary tract infection and none had undergone a previous operative procedure on the lower urinary tract. Twenty-five (93%) patients had evidence of an overactive bladder during the previous four weeks, compared with five (19%) of the control group (p < 0.001). In terms of symptom severity, the mean (standard error) OAB-q8 score was 24.4 (1.5) in the fibromyalgia patients and 10.8 (4.5) in the controls (p < 0.001). Furthermore, the total OAB-q8 and FIQR scores were positively correlated (rs = 0.727, p < 0.001). Conclusion: This systematic controlled study confirms that fibromyalgia is associated with overactive bladder symptoms. The relatively high prevalence of 93% indicates that overactive bladder is an important urological association of fibromyalgia and should be routinely assessed in these patients.

Background: The topical routes of administering drugs have certain visible advantages, such as the direct application of a drug to the site of action and persistence of action for a prolonged duration. More stability and better application property of gel allow its use for topical application. Objectives: To determine and compare antibacterial efficacy of commercially available different dental gels. Methods: For the evaluation of the antibacterial efficacy of commercially available different antiseptic gels on Streptococcus mutans and Lactobacillus acidophilus, well-diffusion method was used. To assess the antibacterial efficacy after incubation in an appropriate culture medium, diameter of zone of inhibition was measured. Results: Maximum zone of inhibition was found with Cure next gel (40 mm,40mm) followed by Hexigel (30 mm, 21mm), Mucopain (17 mm, 17mm), and Dologel (7 mm, 16mm) against S. mutans and L. acidophilus, respectively. Analysis of variance (ANOVA) and Post Hoc Test were used to analyze results statistically. The difference between commercially available different dental gels was statistically significant (P < 0.001) at a 5%. Conclusion: In the present study, it was observed that Curenext gel was more effective, followed by Hexigel, Mucopain gel, and Dologel on S. Mutans and L. Acidophilus.

Aim: This cross-sectional case-control study evaluated the serum carnitine level in children with urinary tract infection (UTI). Background: Acute pyelonephritis (APN) is a common bacterial infection of the upper urinary tract in children which may also lead to renal damage and tubular atrophy. Activation of inflammatory mediator bedside alterations in the cytokines and generation of reactive oxygen species (ROS) play a striking role in the development of tissue damage after pyelonephritis. L-carnitine as one of the most potent natural antioxidant agents by inhibition of lipid peroxidation may protect cells and tissues from damage. Methods: A total of 30 children with UTI (as a case group) and 30 healthy children (as a control group) which matched in terms of age and sex were enrolled in this study. All children were evaluated and compared with respect to age, sex, weight, body mass index (BMI) and serum carnitine level. Serum carnitine level was determined using serum carnitine ELISA kit. Results: Demographic and clinical data such as age, sex, weight and BMI were not statistically significant between the two groups. The serum carnitine levels were significantly lower in the case group with UTI than the control group. Mean serum carnitine concentration in the case group and in the control group was 36.56 ± 9.87 μmol/l and 62.8±21.35, respectively (P = 0.001). Conclusion: According to our study, it could be concluded that low serum L-carnitine level is linked to UTI in children. Therefore, further studies are needed to confirm our results.

Background: Although epidemic, novel coronavirus (SARS-CoV-2) infection rarely affects the pediatric population. However, in the last months, an increasing number of Italian pediatricians have reported the occurrence of erythema pernio-like in children following a flu-like syndrome, after the outbreak of SARS-CoV-2 infection. Objective: The study aims to report cutaneous manifestation of SARS-CoV-2 infection in 4 adolescents. Methods: Observational study reporting 4 adolescents with skin lesions, 2 weeks after the occurrence of a flu-like syndrome. Results: Fourteen days after a flu-like syndrome, adolescents exhibited skin lesions to toes and feet. These lesions were rounded, with blurred limits, with a 5-15 mm diameter, red-violaceous- bluish colored, sometimes resulting in bullous lesions in correspondence of the central or apical portion, which tended to be covered with blackish crusts after evolution. Lesions were also accompanied by pain of variable intensity and evolved within two or three weeks to self-resolution without particular sequelae. In two patients, pharyngeal and nasal swabs were negative for SARSCoV- 2 infection, at the presentation of skin lesions. After 2 months from clinical manifestations, patients were tested positive for SARS-CoV-2 antibodies. Conclusions: In the pediatric and adolescent population, the occurrence of an erythema pernio-like after a flu-like syndrome could be associated with SARS-CoV-2 infection.

Background: Balloon dilation and atherectomy have several limitations in the treatment of heavily calcific coronary lesions. Introduction: Intravascular lithotripsy (IVL) is a state-of-the-art system that modifies severe calcific coronary plaques efficiently. In this paper, we report our experience with IVL in the context of a calcific in-stent chronic total occlusion. Case Summary: A 75-year-old gentleman whose status was post percutaneous coronary intervention, with the deployment of two overlapping bare-metal stents in the mid-left anterior descending artery (LAD) 20 years ago, was admitted to our cardiac center for the elective intervention of in-stent chronic total occlusion (CTO) of LAD, which was performed using an antegrade wire escalation (AWE) technique. After recanalization of the CTO body, optical coherence tomography pullback confirmed a very high calcium score. Balloon dilatation attempts failed, so we proceeded with shockwave lithotripsy with successful full expansion of the 3.5-mm IVL balloon followed by a straightforward stent delivery. The procedure was complicated by distal wire perforation, which was handled in a timely manner with coil embolization. The patient’s postoperative course was uneventful. Conclusion: This case illustrates the feasibility and effectiveness of IVL that powerfully cracks coronary calcium while minimizing vessel wall trauma in the context of heavily calcific in-stent CTO. In our case, coronary perforation occurred in a small-caliber side branch, which was identified in a timely manner before hemodynamic compromise and treated successfully straight away with coil embolization.