Israel Medical Association Journal

Background: Traditionally, transesophageal echocardiography (TEE) has been performed under moderate sedation and local pharyngeal anesthesia. Respiratory complications during the TEE can occur.

Objectives: To test the effectiveness of low-dose midazolam combined with verbal sedation during TEE.

Methods: The study comprised 157 consecutive patients who underwent TEE under mild conscious sedation. All patients received local pharyngeal anesthesia and low doses of midazolam combined with verbal sedation. The course of TEE and clinical characteristics of the patients were analyzed.

Results: The mean age was 64 ± 15.3 years, 96 males (61%). In 6% of the patients, low dose midazolam in combination with verbal sedation was insufficient and propofol was administrated. In women under 65 years of age with normal renal function, there was a 40% risk of low-dose midazolam being ineffective (P = 0.0018).

Conclusions: In most patients, TEE can be conducted easily using low-dose midazolam combined with verbal sedation. Some patients need deeper sedation with anesthetic agents like propofol. These patients tended to be younger, in good general health, and more often female.

Background: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia. Previous studies showed that rhythm and rate control strategies are associated with similar rates of mortality and serious morbidity. Beta blockers (BB) and calcium channel blockers (CCB) are commonly used and the selection between these two medications depends on personal preference.

Objectives: To compare real-time capability of BB and CCB for the treatment of rapid AF and to estimate their efficacy in reducing hospitalization duration.

Methods: We conducted a retrospective cohort study of 306 patients hospitalized at Soroka Hospital during a 5-year period with new onset AF who were treated by a rate control strategy.

Results: A significant difference between the two groups regarding the time (in hours) until reaching a target heart rate below 100 beats/min was observed. BB were found to decrease the heart rate after 5 hours (range 4–14) vs. 8 hours (range 4–18) for CCB (P = 0.009). Patients diagnosed with new-onset AF exhibited shorter duration of hospitalization after therapy with BB compared to CCB (median 72 vs. 96 hours, P = 0.012) in the subgroup of patients discharged with persistent AF. There was no significant difference between CCB and BB regarding the duration of hospitalization (P = 0.4) in the total patient population.

Conclusions: BB therapy is more potent for rapid reduction of the heart rate compared to CCB and demonstrated better efficiency in shortening the duration of hospitalization in a subgroup of patients. This finding should be reevaluated in subsequent research.

Background: Diabetes mellitus (DM) is one of the risk factors for progression from latent to active tuberculosis. However, the effect of DM on subsequent tuberculosis treatment is still inconclusive.

Objectives: To compare tuberculosis treatment outcomes and the rate of drug resistance of tuberculosis patients with or without DM.

Methods: This case-control study was conducted between 2005 and 2015 at the only tuberculosis ward in Israel. All 80 tuberculosis patients who had DM and were hospitalized during the study period were included in this study, as were a randomized sample of 213 tuberculosis patients without DM. Demographic, clinical, and laboratory data were collected from patient files in the hospital and clinics after discharge.

Results: Tuberculosis patients with DM were more often older and more likely to be Israeli citizens with a lower socioeconomic status than patients without DM. No statistically significant differences were found in clinical presentation, radiological findings, and sputum smear tests between the two groups. Culture converting times were prolonged in patients with DM compared to normoglycemic patients. Multidrug drug resistance tuberculosis was more common among normoglycemic tuberculosis patients than tuberculosis patients with DM (9.2% vs. 1.6%, P = 0.12). Treatment success rates were 76.2% and 83.1% for tuberculosis patients with or without DM, respectively (P = 0.18). DM was not statistically significant in the multivariate analysis predicting treatment success, which controlled for age, citizenship, compliance, addictions, and chronic diseases.

Conclusions: The presence of DM does not necessarily affect tuberculosis treatment outcomes as long as treatment compliance is optimal.

Background: Infants born very prematurely have functionally and structurally immature gastrointestinal tracts.

Objectives: To assess the safety and tolerability of administration of enteral recombinant human (rh) insulin on formula fed preterm infants and to assess whether enteral administration of rh-insulin enhances gastrointestinal tract maturation by reducing the time to reach full enteral feeding.

Methods: A phase 2, multicenter, double-blind, placebo-controlled, randomized study was conducted. Premature infants (26–33 weeks gestation) were randomized 1:1 to receive insulin 400 μU/ml mixed with enteral feeding or placebo added to their formula. The primary efficacy outcome measure was the number of days required to achieve full enteral feeding. Safety outcomes included adverse events and blood glucose levels.

Results: The study consisted of 33 infants randomized for the safety population and 31 for efficacy analysis. The mean time to full enteral feeding was 6.37 days (95% confidence interval [95%CI] 4.59–8.15) in the enteral rh-insulin treatment group (n=16) and 8.00 days (95%CI 6.20–9.80) in the placebo group (n=15), which represents a statistically significant reduction of 1.63 days (95%CI 0.29–2.97; P = 0.023). There was no difference in blood glucose levels between the groups and none of the participants experienced hypoglycemia. Adverse events occurred in 9/17 (53%) infants in the enteral rh-insulin group and 12/16 (75%) in the placebo group.

Conclusions: Our trial demonstrated that administration of enteral rh-insulin as supplement to enteral nutrition significantly reduced time to achieve full enteral feeding in preterm infants with a gestational age of 26–33 weeks.

Background: Adherence to treatment by adolescents and adults with cystic fibrosis (CF) is often poor.

Objectives: To assess the impact of a focused clinical intervention on adherence in individual patients, including help in problem-solving key barriers to adherence. To implement a patient-centered problem-solving intervention using CF My Way tools. To identify and overcome a selected barrier to adherence.

Methods: Medication possession ratios (MPRs), number of airway clearance sessions, forced expiratory volume (FEV₁), body mass index (BMI), and health-related quality of life (HRQoL) were measured before and after the intervention.

Results: Sixteen patients with CF, aged 23.4 ± 6.7 years, participated. MPR increased for colistimethate sodium and tobramycin inhalations from a median of 21 (range 0–100) to 56 (range 0–100), P = 0.04 and 20 (range 0–100) to 33.3 (range 25–100), P = 0.03, respectively. BMI standard deviation score rose from -0.37 to -0.21, P = 0.05. No significant improvements were found in FEV₁, airway clearance, or HRQoL scores.

Conclusions: The CF My Way problem-solving intervention increased adherence to medical treatments by removing barriers directly related to the needs and goals of young adults with CF

Background: There is a lack of real-life clinical data for biosimilar etanercept, an anti-TNF blocking fusion protein. We describe the comparable efficacy and safety of originator and biosimilar etanercept in rheumatoid arthritis (RA) patients in a real-life clinical setting. Our data confirm that a biosimilar etanercept can be safely used as first-line treatment as well as in patients switched from a previous originator compound.

Objectives: To compare the efficacy and safety of originator and biosimilar etanercept in a cohort of RA patients attending two Italian hospitals.

Methods: The study involved 81 consecutive adult RA patients treated for at least 6 months with originator or biosimilar etanercept and considered their clinical and laboratory data, concomitant medications, and adverse events at baseline, and after 3 and 6 months of treatment.

Results: Group 1 included 51 patients taking originator etanercept; group 2 included 30 taking biosimilar etanercept, including 19 who had been switched from the reference product. Despite a significant baseline difference in clinical disease activity, one-way analysis of variance showed that the two groups were clinically comparable after 6 months of treatment, and the same was true when only those receiving etanercept as first-line biological treatment were considered. Nine patients discontinued the treatment due to inefficacy or adverse events, which were never serious and were only reported in group 1.

Conclusions: The efficacy and safety profiles of originator and biosimilar etanercept are comparable in RA patients in a real-life clinical setting. Further studies are needed to confirm these preliminary findings

Background: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA.

Objectives: To evaluate SC tocilizumab in a real-life clinical setting.

Methods: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed.

Results: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively.

Conclusions: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.

Background: The main acquired resistance mechanism to first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant non-small cell lung cancer (NSCLC) is the propagation of T790M clones, which can be detected in circulating tumor DNA (ctDNA).

Objectives: To analyze osimertinib outcomes according to T790M testing method.

Methods: The study comprised 33 consecutive patients with advanced EGFR mutant NSCLC who were diagnosed with a T790M mutation after progression on first- or second-generation EGFR TKIs and treated with osimertinib. The patients were divided into groups A (diagnosed by tumor testing) and B (by ctDNA testing). Osimertinib outcomes were compared between the groups.

Results: Objective response rate with osimertinib comprised 54% and 62% in groups A and B, respectively (P = 0.58). Median progression-free survival (PFS) with osimertinib was 8.9 months (95% confidence interval [95%CI] 1.8–17.5) and 9.1 months (95%Cl 5.3–12.6) in groups A and B, respectively (log-rank test 0.12, P = 0.73). Median overall survival (OS) was 13.8 months (95%CI 4.9–25.5) and 13.8 months (95%Cl 7.7–27.7) in groups A and B, respectively (log-rank test 0.09, P = 0.75). T790M testing technique did not affect PFS (hazard ratio [HR] 1.16, 95%CI 0.50–2.69, P = 0.73) or OS (HR = 1.16, 95%CI 0.45–3.01, P = 0.76). The proportion of patients diagnosed by ctDNA grew from 56% in 2015 to 67% in 2016–2017.

Conclusions: Our study provides a ctDNA validation for the purpose of T790M testing in EGFR mutant NSCLC.

Background: Guillain-Barré syndrome (GBS) is an autoimmune disease of the peripheral nervous system with a typical presentation of acute paralysis and hyporeflexia. Intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) are treatments that have proven to expedite recuperation and recovery of motor function.

Objectives: To describe our experience at one tertiary medical center treating GBS with IVIG and to compare the efficacy of IVIG as the sole treatment versus combined therapy of IVIG and plasma exchange.

Methods: We reviewed the records of all patients diagnosed with GBS and treated with IVIG at the Sheba Medical Center from 2007 to 2015 and collected data on patient demographics, disease onset and presentation, and treatments delivered. The motor disability grading scale (MDGS) was used to evaluate the motor function of each patient through the various stages of the disease and following therapy.

Results: MDGS improvement from admission until discharge was statistically significant (P < 0.001), as was the regainment of motor functions at 3 and 12 months follow-up compared to the status during the nadir of the disease. The effectiveness of second-line treatment with IVIG following PLEX failure and vice versa was not statistically significant (P > 0.15).

Conclusions: The majority of patients included in this study experienced a significant and rapid improvement of GBS following treatment with IVIG. Combined therapy of PLEX and IVIG was not proven to be effective in patients who encountered a failure of the first-line treatment.

Background: Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of all non-Hodgkin lymphomas (NHL) and 80% of agressive lymphomas. Besides the traditional International Prognostic Index (IPI), some other factors may also influence the prognosis of DLBCL patients.

Objectives: To study how the genetic polymorphisms in the metabolic pathway influence the event-free and overall survivals and therapeutic responses in DLBCL.

Methods: The study was comprised of 51 patients (32 men, 19 women). The average age was 53.1 years. DLBCL was diagnosed between 2011 and 2016 and the average follow-up time was 3.78 years. These patients received 1–8 cycles (an average of 6.2 cycles) of rituximab, cyclophosphamide, doxorubicin, vincristin, prednisolon (R-CHOP) immunochemotherapy. Real-time polymerase chain reaction was used to determine the genetic polymorphisms of CYP2E1, GSTP1, NAT1, and NAT2 genes.

Results: Our results showed that the polymorphisms of CYP2E1, GSTP1, and NAT1 genes did not influence the prognosis of DLBCL patients significantly. In terms of the NAT2 gene, GG homozygous patients showed slightly better therapeutic response and survival results compared to those bearing an A allele; however, the differences were not statistically significant.

Conclusions: Our results could not confirm that genetic polymorphism in metabolic pathways has any predictive role in DLBCL. 

 

Background: Diagnosis of abdominal lymphadenopathy is challenging when not accompanied by peripheral lymphadenopathy. Computed tomography-guided core-needle biopsy has largely replaced open procedures in recent years, but this approach is limited by access to the anatomic region and the amount of tissue acquired.

Objective: To demonstrate the feasibility of the laparoscopic approach in obtaining abdominal lymph node biopsies and to evaluate the diagnostic adequacy of the technique.

Methods: We reviewed the data of patients who underwent laparoscopic lymph node biopsy between 2014 and 2014 in our department. Demographics, intra-operative parameters and postoperative course were examined, as were histological reports. Postoperative complications were categorized according to the Clavien-Dindo(CD) classification.

Results: Between 2004 and 2014, 57 laparoscopic biopsies were performed for intra-abdominal lymphadenopathy. One case was a repeated attempt due to limited histologic material. The mean age was 49.5 ± 19.6 years. There were two conversions to open laparotomy, one due to small bowel injury and the other due to a sizable mass. Overall, 56 cases had full clinical data: 48 cases (85.7%) had CD=0, six (10.7%) had CD=1, one postoperative severe complication (CD=3) and one mortality (CD=5), which was related to preexisting hepatic insufficiency. Mean hospital stay was 1.6 days. Overall, adequate tissue samples were acquired in 96.7% and only 3 of these cases resulted in inconclusive diagnoses.

Conclusions: Laparoscopic lymph node biopsy is a viable alternative to the currently available methods of tissue retrieval. It provides an access for nodes which are inaccessible percutaneously, and may allow a superior diagnostic yield.

Background: Cannabidiol (CBD)-based treatments for several diseases, including Tourette’s

syndrome, multiple sclerosis, epilepsy, movement disorders and glaucoma, are proving to be beneficial and the  scientific clinical background of the drug is continuously evolving. 

Objectives: To investigate the short-term effect of CBD-enriched hemp oil for relieving symptoms and improving the life quality (QOL) in young girls with adverse drug effects (ADRs) following human papillomavirus (HPV) vaccine. 

Methods: In this anecdotal, retrospective, “compassionate-use”, observational, open-label study, 12 females (age 12–24 years) with severe somatoform and dysautonomic syndrome following HPV vaccination were given sublingual CBD-rich hemp oil drops, 25 mg/kg per day supplemented by 2–5 mg/ml CBD once a week until a maximum dose of 150 mg/ml CBD per day was reached over a 3 month period. Patients’ quality of life was evaluated using the medical outcome short-form health survey questionnaire (SF-36).

Results: Two patients dropped out due to iatrogenic adverse events and another two patients stopped the treatment early due to lack of any improvement. SF-36 showed significant benefits in the physical component score (P < 0.02), vitality (P < 0.03) and social role functioning (P < 0.02) after the treatment. The administration of hemp oil also significantly reduced body pain according to the SF-36 assessment. No significant differences from the start of treatment to several months post-treatment were detected in role limitations due to emotional reactions (P = 0.02).

Conclusions: This study demonstrated the safety and tolerability of CBD-rich hemp oil and the primary efficacy endpoint. Randomized controlled trials are warranted to characterize the safety profile and efficacy of this compound.