Israel Medical Association Journal

Background: In 2019, 1 mg subcutaneous semaglutide was registered for the treatment of diabetes in Israel. Recognition of its effect on weight has led to its use as a treatment for obesity.

Objectives: To explore physicians’ pre-therapy considerations, therapy practices, and attitudes regarding subcutaneous semaglutide for weight loss.

Methods: A 22-item questionnaire was disseminated to physicians who prescribed semaglutide 1-mg for weight loss using an authorized off-label path.

Results: In total, 127 physicians completed the questionnaire. As for pretreatment requirements, in the absence of diabetes, 30% requested a minimal body mass index of 30 kg/m². Additional requirements were documented lifestyle-change effort (67%) and prior weight loss medication use (13%). Half of the physicians regarded calorie restriction, and 23% considered physical activity as necessary for weight loss while on therapy. As for dose, most physicians (78%) started with a 0.25-mg weekly injection, 57% doubled the dose monthly, and all others recommended doubling when side effects subsided. Regarding weight loss goal, 43% of the physicians set a personal goal with each patient while 26% limited the goal to 10% of initial weight. Fewer than 50% of physicians discussed treatment duration with their patients, and 52% of patients discontinued therapy in the first 3 months. The main reasons for discontinuation were price, lack of effect, and fear of long-term side effects.

Conclusions: The diverse approaches regarding off-label use of semaglutide for weight reduction highlight the necessity to guide physicians and standardize treatment regimen.

Background: Chronic fatigue is common among patients with rheumatoid arthritis (RA), affecting quality of life. Osteoporosis is a prevalent co-morbidity in RA patients.

Objectives: To assess the effect of long-term treatment with tocilizumab on fatigue and bone mineral density (BMD) in RA patients with inadequate response to synthetic or biologic disease-modifying anti-rheumatic drugs. 

Methods: In this multicenter, open-label, non-controlled, single-arm study, patients ≥ 18 years of age received intravenous tocilizumab 8 mg/kg every 4 weeks for 96 weeks. The primary outcome was the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to weeks 24, 48, 72, and 96. BMD was assessed before and 96 weeks after treatment. 

Results: The study comprised 145 patients (mean age 53.4 ± 13.4 years, 83.4% women). Of these, 88 (60.7%) completed the 2 year treatment period. The mean FACIT-Fatigue score improved consistently starting from week 4 and showed a statistically significant increase of 5.0 ± 9.7, 6.8 ± 10.5, 7.3 ± 10.9, and 7.3 ± 10.4 from baseline to weeks 24, 48, 72, and 96, respectively (P < 0.0001). Mean BMD of femoral neck and total spine remained stable. Disease activity, acute phase reactants, and composite efficacy measures decreased during the study, while hemoglobin levels increased. Adverse events and serious adverse events were as expected for the known and previously described data.

Conclusions: Tocilizumab therapy for 2 years significantly and clinically decreased fatigue. BMD remained stable and no new safety issue was reported. 

 

Background: Neoadjuvant chemo-radiation therapy (CRT) dosages in locally advanced non-small cell lung cancer (NSCLC) were traditionally limited to 45 Gray (Gy).

Objectives: To retrospectively analyze outcomes of patients treated with 60 Gy CRT followed by surgery.

Methods: A retrospective chart review identified patients selected for CRT to 60 Gy followed by surgery between August 2012 and April 2016. Selection for surgery was based on the extent of disease, cardiopulmonary function, and response to treatment. Pathological response after neoadjuvant CRT was scored using the modified tumor regression grading. Local control (LC), disease free survival (DFS), and overall survival (OS) were estimated by the Kaplan–Meier method.

Results: Our cohort included 52 patients: 75% (39/52) were stage IIIA. A radiation dose of 60 Gy (range 50–62Gy) was delivered in 82.7%. Surgeries performed included: lobectomy, chest-wall resection, and pneumonectomy in 67.3%, 13.4%, and 19.2%, respectively. At median follow-up of 22.4 months, the 3 year OS was 74% (95% confidence interval [CI] 52–87%), LC was 84% (95%CI 65–93), and DFS 35% (95%CI 14–59). Grade 4–5 postoperative complications were observed in 17.3% of cases and included chest wall necrosis (5.7%), bronco-pleural fistula (7.7%), and death (3.8%). A major pathologic regression with < 10% residual tumor occurred in 68.7% of patients (36/52) and showed a trend to improved OS (P = 0.1). Pneumonectomy cases had statistically worse OS (P = 0.01).

Conclusions: Major pathologic regression was observed 68.7% with 60 Gy neoadjuvant CRT with a trend to improved survival. Pneumonectomy correlated with worse survival.

Background: There is a wide treatment gap between evidence-based guidelines and their implementation in primary care.

Objective: To evaluate the extent to which physicians "literally" follow guidelines for secondary prevention of dyslipidemia and the extent to which they practice "substitute" therapeutic measures.

Methods: We performed a post hoc analysis of data collected in a prospective cluster randomized trial. The participants were 130 primary care physicians treating 7745 patients requiring secondary prevention of dyslipidemia. The outcome measure was physician "literal" adherence or "substitute" adherence. We used logistic regressions to evaluate the effect of various clinical situations on “literal” and “substitute” adherence.

Results: "Literal" adherence was modest for ordering a lipoprotein profile (35.1%) and for pharmacotherapy initiations (26.0%), but rather poor for drug up-titrations (16.1%) and for referrals for specialist consultation (3.8%). In contrast, many physicians opted for "substitute" adherence for up-titrations (75.9%) and referrals for consultation (78.7%). Physicians tended to follow the guidelines “literally” in simple clinical situations (such as the need for lipid screening) but to use "substitute" measures in more complex cases (when dose up-titration or metabolic consultation was required). Most substitute actions were less intense than the actions recommended by the guidelines.

Conclusions: Physicians often do not blindly follow guidelines, but rather evaluate their adequacy for a particular patient and adjust the treatment according to their assessment. We suggest that clinical management be evaluated in a broader sense than strict guideline adherence, which may underestimate physicians' efforts.
 

Background: An outbreak of respiratory illness caused by a novel swine-origin influenza virus (influenza A/H1N1 2009) that began in Mexico was declared a global pandemic by the World Health Organization in June 2009. The pandemic affected many countries, including Israel.

Objectives: To compare the course of chest radiographic and computed tomography findings in patients who survived and those who died following admission to the intensive care unit (ICU) or intubation due to severe laboratory-confirmed swine-origin influenza A/H1N1 2009.

Methods: We retrospectively reviewed the patient records (267 radiographs, 8 CTs) of 22 patients (10 males, 12 females) aged 3.5–66 years (median 34) with confirmed influenza A/H1N1 2009, admitted to the ICU and/or intubated in five major Israeli medical centers during the period July–November 2009. We recorded demographic, clinical, and imaging findings –including pattern of opacification, extent, laterality, distribution, zone of findings, and presence/absence of nodular opacities– at initial radiography and during the course of disease, and compared the findings of survivors and non-survivors. Statistical significance was calculated using the Wilcoxon (continuous variables) and Fisher's exact tests (categorical variables).

Results: The most common findings on the initial chest radiography were airspace opacities, which were multifocal in 17patients (77%) and bilateral in 16 (73%), in the lower or lower and middle lung zones in 19 patients (86%). Large airspace nodules with indistinct margins were seen in 8 patients (36%). Twelve patients survived, 10 died. Patients who died had multiple background illnesses and were significantly older than survivors (P = 0.006). Radiologic findings for the two groups were not significantly different.

Conclusion: Airspace opacities, often with nodular appearance, were the most common findings among patients with severeinfluenza A/H1N1 2009. The course of radiologic findings was similar in patients with severe influenza A/H1N1 2009 whosurvived and those who died.

Background: Occult breast cancer without clinically or mammographically detectable breast tumor is an uncommon presentation.

Objectives: To assess the role of breast MRI in women with metastatic carcinoma and an occult primary, and to define the MRI characteristics of the primary breast tumor.

Methods: This retrospective study evaluated 20 women with metastatic carcinoma of unknown origin who underwent breast MRI between 2000 and 2006. Four women were excluded, leaving 16 in the study group. Probability of malignancy was assessed according to BIRADS classification. MRI performance in detecting lesions and evaluating disease extent was assessed, with the gold standard being surgical or biopsy pathology.

Results: MRI detected suspicious lesions in 15 patients. Lesion size ranged from 0.4 to 7 cm (median 1.5 cm). MRI detected a single lesion in 6 patients (40%), multifocal disease in 3 (20%), multicentric disease in 4 (27%), and bilateral breast lesions in 2 (13%). In 13 patients MRI depicted the primary breast cancer. Initial treatment was surgical in nine; MRI correctly estimated disease extent in 6 (67%), underestimated disease extent in 1 (11%), and overestimated it in 2 (22%). Four patients had biopsy followed by chemotherapy; one had multicentric disease and one had multifocal disease. MR findings were false positive in two patients and false negative in one.

Conclusions: MRI is sensitive in detecting the primary tumor and beneficial in assessing tumor extent. Small size and multiple foci are common features. We suggest that bilateral breast MRI be part of the evaluation of women with metastatic carcinoma and an occult primary.
 

Background: Repaglinide, a new insulin secretagogue, is purported to be as effective as sulphonylurea but is less hypoglycemic-prone.

Objectives: To assess the efficacy of repaglinide and its proclivity for hypoglycemia in a post-marketing study.

Methods: The study group comprised 688 patients, aged 26–95 years, clinically diagnosed with non-insulin-dependent type 2 diabetes. The patients were divided into three groups based on previous therapy: a) sulphonylurea-treated (group 1, n=132); b) metformin with or without sulphonylurea where sulphonylurea was replaced with repaglinide. (group 2, n=302); and c) lifestyle modification alone (drug-naïve) (group 3, n=254). At initiation of the study, all patients were transferred from their current treatment to repaglinide. Only patients in group 2, with combined sulphonylurea plus metformin, continued with metformin plus repaglinide. Fasting blood sugar, hemoglobin A1c and weight were measured at study entry and 4–8 weeks following repaglinide therapy. A questionnaire documented the number of meals daily and the presence of eating from fear of hypoglycemia.

Results: The fasting blood sugar level of the entire cohort dropped from 191 ± 2.4 to 155 ± 2.0 mg/dl (P < 0.0001); HbA1c from 8.8 ± 0.1 to 7.7 ± 0.1% (P < 0.0001). The drop of HbA1c in groups 1, 2 and 3 respectively were: 1.04 ± 0.22% (P < 0.0001), 1.14 ± 0.24% (P < 0.0001), and 1.51 ± 0.31% (P = 0.0137). Weight dropped from 81 ± 0.7 to 80.2 ± 0.7 kg (P < 0.0001), and eating from fear of hypoglycemia from 157 to 97 (P < 0.001). The daily number of meals decreased from 2.9 ± 0.4 to 2.4 ± 0.4 (P < 0.001). No serious adverse reactions occurred during the study.

Conclusions: Repaglinide is an effective oral hypoglycemic agent taken either as monotherapy or combination therapy. There is less eating to avoid hypoglycemia, fewer meals consumed, and weight loss.
 

Background: Repaglinide, a new insulin secretagogue, is purported to be as effective as sulphonylurea but is less hypoglycemic-prone.

Objectives: To assess the efficacy of repaglinide and its proclivity for hypoglycemia in a post-marketing study.

Methods: The study group comprised 688 patients, aged 26–95 years, clinically diagnosed with non-insulin-dependent type 2 diabetes. The patients were divided into three groups based on previous therapy: a) sulphonylurea-treated (group 1, n=132); b) metformin with or without sulphonylurea where sulphonylurea was replaced with repaglinide. (group 2, n=302); and c) lifestyle modification alone (drug-naïve) (group 3, n=254). At initiation of the study, all patients were transferred from their current treatment to repaglinide. Only patients in group 2, with combined sulphonylurea plus metformin, continued with metformin plus repaglinide. Fasting blood sugar, hemoglobin A1c and weight were measured at study entry and 4–8 weeks following repaglinide therapy. A questionnaire documented the number of meals daily and the presence of eating from fear of hypoglycemia.

Results: The fasting blood sugar level of the entire cohort dropped from 191 ± 2.4 to 155 ± 2.0 mg/dl (P < 0.0001); HbA1c from 8.8 ± 0.1 to 7.7 ± 0.1% (P < 0.0001). The drop of HbA1c in groups 1, 2 and 3 respectively were: 1.04 ± 0.22% (P < 0.0001), 1.14 ± 0.24% (P < 0.0001), and 1.51 ± 0.31% (P = 0.0137). Weight dropped from 81 ± 0.7 to 80.2 ± 0.7 kg (P < 0.0001), and eating from fear of hypoglycemia from 157 to 97 (P < 0.001). The daily number of meals decreased from 2.9 ± 0.4 to 2.4 ± 0.4 (P < 0.001). No serious adverse reactions occurred during the study.

Conclusions: Repaglinide is an effective oral hypoglycemic agent taken either as monotherapy or combination therapy. There is less eating to avoid hypoglycemia, fewer meals consumed, and weight loss.

Background: According to studies from different countries, the prevalence of natural rubber latex sensitization in healthcare workers ranges from 2.9 to 17%.

Objective: To estimate the prevalence of NRL-specific IgE antibodies in healthcare workers in Israel.

Methods: Three hundred healthcare workers, mostly from a major pediatric tertiary care facility, and 15 non-healthcare workers completed a questionnaire on signs and symptoms of NRL allergy and other respiratory and food allergies. NRL-specific IgE antibodies were assayed with the DPC AlaSTAT-ELISA method.

Results: Seventy of the 300 workers (23.3%) reported symptoms of NRL allergy: hand eczema and pruritus in 63, upper respiratory tract and ocular symptoms in 10, shortness of breath in 2, and generalized rash in 6. None had anaphylaxis due to latex exposure. There was a significant correlation of symptoms of NRL allergy with atopy and job category (nurses, laboratory technicians, nurse assistants and dental medicine workers), but not with gender, age, or years of employment. The in vitro tests for specific IgE antibodies against NRL were positive (≥0.70 IU/ml) in five workers (1.66%).

Conclusions: This is the first study of the prevalence of NRL-specific IgE antibodies in healthcare workers in Israel. Our 1.66% sensitization rate is much lower than that reported for healthcare workers in other countries. This difference may be due to our inclusion of a study population with a relatively low exposure to latex gloves (pediatricians compared to surgeons). Further studies are needed in this and other high risk populations in Israel.  

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NRL = natural rubber latex