Reviews on Recent Clinical Trials - Volume 13, Issue 2, 2018

Background: Dyspnea is a very common and well-known symptom in patients with advanced cancer, but it is often neglected by physicians. Moreover, despite the high frequency of dyspnea, few controlled studies have been conducted on cancer patients. In most cases, this ‘awareness of breathing with difficulty’ and its severity can only be judged by the patient. Moderate or severe dyspnea is described in 20-80% of patients with advanced cancer and breathlessness is considered a prognostic factor for shorter survival, either alone or associated with other parameters. Methods: I reviewed the literature and guidelines on the topic with the aims to focus on what is known and on future pathways to follow for the diagnosis and treatment of dyspnea. Results: There is no uniformity regarding the definition of dyspnea; consequently, there is still no general agreement about which tools are the best to use in clinical practice to detect the presence and severity of this symptom. In addition to the difficulty of assessing the symptom, a further limit concerns the management of dyspnea: a very limited number of therapies, both pharmacological and otherwise, are currently available that lead to satisfactory outcomes. Opioids such as morphine remain the cornerstone of treating dyspnea. Conclusion: Dyspnea is a complex, multidimensional symptom that results from an interaction between factors and their causes, perception and expression. The main target of assessment and management is the intensity of dyspnea, as expressed by the patient, rather than the objective parameters of the disease. Although dyspnea is a very common symptom, debilitating and often difficult to control, especially in the terminal phase of the disease, few controlled studies have been conducted on cancer patients. Dyspnea remains a well-known but neglected symptom in advanced and terminal cancer patients. Future studies should be conducted regarding the careful assessment and management of this symptom.

Background & Aims: Diverticular Disease (DD) is a common clinical condition with a dramatic increasing of the prevalence among industrialized countries. Based on the most used classification, DD may be divided into asymptomatic diverticulosis, symptomatic uncomplicated diverticular disease and complicated diverticular disease. Since recent studies pointed out the role of GUT microbiota imbalance in promoting diverticular formation and inflammation, we have designed a systematic review focusing on the possible role of probiotics in the management of this condition. Methods: According to PRISMA, we identified studies on DD patients treated with probiotics, by searching on Pubmed, Embase, Cochrane and ResearchGate. Results: 13 studies were included in this review based on our selection criteria: 3 double-blind randomized placebo-controlled, 6 open randomized, and 4 non-randomized open studies. Conclusion: This is the first systematic review providing an updated measure of evidence on the efficacy of probiotics in a different phase of DD. Even though the majority of studies are still preliminary, current data show a possible clinical application of certain probiotic strains in all stages of DD. Further investigation is then required to better understand when and how probiotics can be used in different phases of DD.

Background: Endoscopic ultrasound (EUS) has been used in the clinical arena for almost 35 years and it is now well-integrated in everyday hospital practice. Method: We conducted a systematic review of the available English-language articles. Objective: The purpose of this review is to summarize the relevant applications of operative EUS. Results: More than 5000 scientific papers published in the literature have demonstrated its high accuracy for the diagnosis and staging of a variety of benign and malignant conditions. The main indications of operative EUS, both diagnostic and therapeutic, are related to its ability to combine ultrasound imaging and safe and effective needle insertion into lesions originating from the gut wall and from organs nearby. In addition, technologic advancements of echoendoscopes with a therapeutic working-channel have allowed to perform several EUS-guided interventions, i.e. celiac plexus neurolysis, drainage of fluid collections, drainage of dilated biliary and pancreatic ducts, and vascular interventions.

Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disorder characterized by chronic inflammation, which can result in a multitude of systemic or organ-limited manifestations, including the skin, lungs, heart, and kidney. SLE nephritis is present in an average of 38% of patients at the time of diagnosis, and may occur as the initial presentation of disease with progression to End-Stage Renal Disease (ESRD) in roughly 10-20% of patients. Methods: A review of the current literature was undertaken to investigate the evolution of treatment of SLE nephritis based on randomized trials and robust observational studies. We aimed to provide a timeline of the development of current induction and maintenance therapy, as well as the development of novel targeted therapies, all leading to current guidelines. Results: Based on all available current data on standard of care therapies for SLE nephritis, there is at best a complete remission rate of 50-60%, and roughly 13-25% of patients experience periods of relapse during maintenance therapy for SLE nephritis. Therefore, the need for newer, targeted therapies has been the focus of many current, ongoing clinical trials. Conclusion: Standard induction and maintenance therapies at present are anti-proliferative and nonspecific, that is, interfering with the process of autoantigen presentation and activation of autoreactive leukocytes. However, newer agents with specific T-cell, B-cell, or proteasome targets are currently being investigated.

Background: Metadoxine is composed of pyroglutamic acid and vitamin B6. Administrations of metadoxine are indicated in cases of acute alcohol intoxication or in chronic alcoholism. Objectives: To reference all available clinical trials investigating the effects of metadoxine on humans. A focus was put on alcohol intoxication and chronic alcoholism, alcohol abstinence and survival rates. Adverse events were also taken into consideration. Finally, potential roles of metadoxine in treating disorders of the central nervous system will be assessed. Methods: PRISMA guidelines were followed. Computerised literature searches were performed in July 2017 to retrieve all clinical trials investigating metadoxine from the MEDLINE®, the European Union Clinical Trials Register and the ClinicalTrials.gov databases, using the following equation: “metadoxine”. Inclusion criteria were all published clinical trials investigating metadoxine in humans, regardless of outcome measures. Exclusion criteria were articles not abstracted, in vitro studies, studies in rodents, retrospective studies and reviews. Results: Sixteen studies were included. Evidence suggests that metadoxine appears safe to use, as it rarely induced adverse events (reported in 7 out of the 7 studies measuring safety/tolerability). Moreover, metadoxine seems efficient in treating acute alcohol intoxication (2/2 studies) as well as improving liver functions following chronic alcoholism (4/5 studies). Finally, currently on-going clinical trials will reveal if metadoxine could be indicated in attention deficit and hyperactivity disorders as well as fragile X syndrome. Conclusion: Metadoxine appears safe to use and seems efficient to improve liver functions following alcohol-related diseases. Further clinical trials will be necessary to determine if metadoxine can be promising for treating brain disorders. PROSPERO registration number: CRD42017072964.

Background: The outcome of bone and soft tissue sarcomas (BST) after relapse has very poor prognosis with survival rates less than 39%. Unfortunately there are not many treatment options, but promising responses have been reported with ifosfamide, etoposide and carboplatin (ICE). Objective: Therefore, we planned a study for children with recurrent/refractory BST treated with ICE regimen to evaluate their demographic features, responses to treatment and outcome. Method: Patients with primary diagnosis of BST and treated with ICE regimen at the time of first or subsequent relapse, progression or unresponsive disease were selected for study. The files were retrospectively evaluated. Results: Thirty of sixty-six patients had metastatic disease at relapse. Patients received median 5 cycles of ICE and were followed-up median 16.3 months. Overall survival rates were 83% and 62% at 1st and 2nd year. The ORR to the regimen was 43%. Survival rates were significantly higher in good responders (3-year EFS and OS rates: 50% vs. 8% and 78% vs. 14%; p<0.0001 and p<0.0001). Survival rates for non-metastatic disease were 42% and 75% for EFS and OS and higher than patients with metastases at relapse (p<0.001 and p<0.0001). EFS and OS rates of patients with rhabdomyosarcoma were 42% and 69%. No grade 3 or 4 renal toxicity was documented. Conclusion: ICE combination improves the outcome of relapsed or refractory sarcomas and it might serve as second line treatment. Patients with no metastases at relapse would benefit more than others with metastatic disease.

Objective: Oxidative stress and Overproduction of pro-inflammatory cytokines are contributed in Rheumatoid Arthritis (RA) pathogenesis. N-acetylcysteine (NAC) is an antioxidant and antiinflammatory agent which demonstrated analgesic effects in some studies. This study is designed to assess the effects of oral NAC as an adjuvant therapy on the clinical outcomes of patients with active RA. Methods: In this randomized clinical trial, 51 RA patients with active RA were studied in 2 groups: NAC group (27 patients) received standard treatment of RA and 600 mg NAC twice a day for 12 weeks, and placebo group (24 patients) received the standard treatment of RA and placebo. Disease activity score (DAS28) was used to assess the activity of RA, Visual Analog Scale (VAS) for the severity of pain, Health Assessment Questionnaire (HAQ) for the patients' physical performance, and Global Health (GH) parameter for the patients' assessment of their disease activity. The number of tender and swollen joints and Erythrocyte Sedimentation Rate (ESR) were also determined for each patient. Data were analyzed using SPSS version 16.0 (Chicago, IL, USA). Results: After 12 weeks of intervention, there were no significant differences between two groups in DAS28 score and ESR (P values were 0.4 and 0.6, respectively). However, GH, VAS, and HAQ scores were improved significantly in the NAC group compared to the placebo group. Conclusion: Our findings indicate that oral administration of NAC may be associated with improving health status in RA patients and considered as an adjuvant therapy in these patients. Further studies with larger sample size, longer study duration and higher doses of NAC are needed to confirm the effects of oral NAC in RA patients.

Background: Colorectal cancer is one of the most common malignancies in the United States, with a large proportion of patients presenting with metastatic disease or developing a recurrence. Systemic chemotherapy is the mainstay of therapy in this setting. There is a clear benefit in the addition of bevacizumab or cetuximab (for rat sarcoma [RAS] wild type tumors) to oxaliplatin- and irinotecan-based regimens which can be considered for first-line therapy. However, many significant questions remain as to which agent reflects best practice. Objective: Our review aimed to elucidate the benefit of adding bevacizumab and cetuximab to initial therapy for metastatic colorectal cancer based on primary tumor location and a variety of other disease- and patient-related factors, addressing the paucity of evidence that currently exists in this area and contributing to current literature and clinical practices. Methods: The primary endpoints of the study were first Progression-Free Survival (PFS) and Overall Survival (OS). Secondary endpoints included best response to first- and second-line therapies, Treatment- Related Adverse Events (TRAEs), second PFS, cost of therapy, and an assessment of other patient- and disease-related factors affecting PFS and OS. Results: While there were trends towards improved OS in patients with left-sided primary tumors (n=57) compared to those with right-sided disease (n=23), there were no significant differences between the two groups in either primary endpoint. While no differences were found for patients with left- or right- sided tumors stratified by add-on agent, these analyses were limited by the small number of patients receiving cetuximab with first-line therapy (n=4). However, the bevacizumab cohort (n=76) was sizable enough to provide ample data and produce clinically relevant results. Add-on therapy with bevacizumab in our study achieved impressive survival outcomes in both left-sided (median first PFS = 13 months, 95% CI 11-15 months; median OS = 37 months, 95% CI 21-53 months) and right-sided (median first PFS = 13 months, 95% CI 9-17 months; median OS = 37 months, 95% CI 22-52 months) disease. Conclusion: These results raised questions regarding the true significance of primary tumor location when selecting bevacizumab or cetuximab for first-line therapy, particularly the current thought of using cetuximab for left-sided tumors. While the superiority of bevacizumab over cetuximab in rightsided disease remained evident upon comparison of our analysis with historical controls, survival outcomes with the agent in our analysis appeared to be similar to that of cetuximab in CRYSTAL, FIRE- 3, and CALGB/SWOG 80405 in left-sided disease. Further study is required to determine if bevacizumab truly does produce similar outcomes to cetuximab in left-sided primary tumors.

Background: To evaluate the usefulness of Arnica compositum (AC) + Acidum nitricum (AN) + Hekla lava (HL) ointment in Emergency Medicine Department (EMD) as alternative nonpharmacological local treatment of patients with symptomatic calcific periarthritis of the shoulder (CPS) and to compare the effectiveness of this mixture against AC ointment alone. Methods: A series of 41 consecutive patients (20 women, 19 men, median age 49 years, range 25-80 years) with non-traumatic painful unilateral CPS were randomly assigned to receive local treatment with AC+AN+HL ointment mixture (Group A, cases, N=21) or AC ointment alone (Group B, controls, N=20). The radiological Gartner classification of the CPS, and the quantification of pre- and post-treatment pain intensity using a Visual Analogue Scale (VAS) were obtained. The orthopedic evaluation of Shoulder Motion (SM) was also performed. The use of painkillers was reported as a number of doses needed. Results: Age, gender distribution, Gartner type, main calcification size, baseline VAS (VAS-0) and degree of SM did not differ (p=NS) between Groups. After 3-day therapy, the reduction of pain in Group A (4.5±2.5) was superior to that observed in Group B (2.7±2.6) (p =0.03). The same result was observed in the improvement of SM in Group A (69.4±24.9) than in Group B (51.1±21.1) (p =0.015). No local or general adverse effects were noted. The number of doses of paracetamol was similar, but Group A patients used less ibuprofen (p =0.007). Conclusion: Local administration of the AC+AN+HL ointment mixture, which in our pilot study was superior to AC alone, could be safely suggested as an alternative uneventful treatment of patients with CPS.

Background: Diabetic ketoacidosis (DKA) is a serious complication of diabetes seen commonly in autoimmune Type 1 diabetes mellitus (DM), however patients with Type 2 diabetes are also at risk. Diabetic ketoacidosis may be precipitated by the catabolic stress of acute illness such as trauma, surgery, or infections. Recent studies have suggested that sodium-glucose cotransporter-2 (SGLT-2) inhibitors precipitate DKA in Type 2 diabetes. We present a case series of four patients on SGLT-2 inhibitors who presented with DKA. Methods: Medical records were reviewed and patients who were admitted with diabetic ketoacidosis in the last one year at our institute were identified. The charts of such patients were reviewed and we were able to identify 4 patients who were admitted with DKA and were on SGLT-2 inhibitors at the time of admission for the management of their diabetes. Results: The age group of the four patients was between 45-65 years. Interestingly, all four patients were female. The admission blood glucose levels of these patients ranged from 203 to 400(mg/dl). The pH at the time of admission was in the acidotic range with anion gap ranging from 19 to 24. Two of these four patients had symptoms of a localized infection at the time of admission, which was confirmed by laboratory and radiological evaluation. Three of these patients required management in the intensive care unit. Conclusion: Ketoacidosis is a rare but serious side effect of SGLT2 inhibitors. It is being increasingly reported as these drugs are now commonly being prescribed in the primary care setting. Awareness that DKA can occur in the setting of relative euglycemia is critical to recognize this life-threatening complication of diabetes. More research is needed to better understand the underlying pathophysiology and precipitating factors leading to ketoacidosis in SGLT-2 inhibitor treated patients.