Israel Medical Association Journal

Background: Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights.

Objectives: To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries.

Methods: The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes.

Results: By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss > 7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH.

Conclusions: Recognition of C1-INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries.

Background: Circulating endothelial progenitor cells have an important role in the process of vascular repair. Impaired recruitment and function of endothelial progenitor cells is related to the pathophysiology of congestive heart failure. Endothelial progenitor cells have been shown to express the mineralocorticoid receptor. 

Objectives: To investigate the effect of mineralocorticoid receptor antagonists on endothelial progenitor cells in patients with heart failure. 

Methods: Twenty-four patients with compensated heart failure, who were not under mineralocorticoid receptor antagonist therapy, were recruited. Either eplerenone (n=8) or spironolactone (n=16) therapy was initiated. Circulating endothelial progenitor cell level, identified as the proportion of mononuclear cells expressing vascular endothelial growth factor receptor 2 (VEGFR-2), CD133, and CD34, was evaluated by flow cytometry at baseline and after 8 weeks. Following 7 days of culture, colonies were counted by microscopy and MTT assay was performed on randomly selected patients (n=12) to estimate viability.

Results: Both median CD34+/VEGFR2+ and median CD133+/VEGFR2+ increased significantly (P = 0.04 and 0.02, respectively). However, the number of colonies and viability of the cells after therapy (as assessed by the MTT assay) was not significantly different compared with the baseline. 

Conclusions: These preliminary results suggest that mineralocorticoid receptor blockade may enhance endothelial progenitor cells recruitment in patients with compensated heart failure.

Background: Previous studies have demonstrated the utility of exercise hemodynamics during right heart catheterization (RHC) in the diagnosis of diastolic dysfunction (DD). Little data exists regarding exercise hemodynamics during RHC in symptomatic systemic sclerosis (SSc) patients. 

Objectives: To assess the added diagnostic value of using exercise hemodynamics during RHC in assessment of patients with symptomatic SSc.

Methods: We performed 22 RHCs in 17 SSc patients with dyspnea and/or pulmonary arterial hypertension (PAH). Exercise was performed in 15 RHCs using isotonic arm exercises while holding a 1 kg weight in each hand. Measurements of pulmonary arterial pressure (PAP), pulmonary arterial wedge pressure (PAWP), and cardiac output (CO) were taken at rest and during peak exercise. 

Results: Normal resting RHC (PAP 22 ± 3 mmHg, PAWP 11 ± 3 mmHg) was found in seven cases. Of these, exercise induced elevation in PAP was found in three (38 ± 7 mmHg), and exercise induced elevation in PAWP was found in four (24 ± 6 mmHg). Elevated resting PAP was found in 15 (41 ± 11 mmHg) with minor changes in exercise. Of the 22 RHCs, elevation of the PAWP was found in 11 (50%), half of which were in response to exercise. 

Conclusions: In symptomatic SSc patients, exercise hemodynamics provides important information on diastolic dysfunction that is not available with non-invasive testing. Findings on exercise RHC can explain patient symptoms in up to 50% of cases. Earlier and more accurate diagnosis of patient symptoms can aid in tailoring the correct therapy for each.

In this article, we offer a brief summary of the report from the Task Force for the Promotion of the Status of Women in Medicine in Israel. The task force, formed by the Israel Medical Association in 2013, published a comprehensive report in May 2015 dedicated to the promotion of equal opportunities for female doctors in the Israeli healthcare system and in the academic world. The aim of this paper is to present the work of the task force and to highlight its main principles and recommendations against the backdrop of the gender revolution in the Israeli healthcare system and worldwide.

Background: Several types of human papillomavirus (HPV) have been found to be associated with oral squamous cell carcinoma (OSCC). Still, the significance of HPV infection and its relationship to patient prognosis remains an important matter of debate.

Objectives: To investigate the incidence of HPV infection in OSCC patients in northern Israel populations to determine its role in the etiology and prognosis of OSCC.

Methods: OSCC tissues were gathered from the pathology departments at Rambam and Padeh medical centers in northern Israel. HPV DNA typing and immunohistochemistry for p16INK4A antibodies were conducted to evaluate their incidence in OSCC tissues. Statistical analysis regarding its expression in the different sub-populations (Jews, Arabs, Druze) was conducted using chi-square and Fisher’s exact tests.

Results: The study included 82 patients: 53 men and 29 woman; median age 62.1 years; 54 Jews, 25 Arabs, and 3 Druze. The overall incidence of HPV expression was 45% (n=37). The median age of HPV-positive patients was 53 years vs. 65.8 in the negative group (P < 0.001). The 5 year overall survival of HPV-positive patients was not significantly higher than HPV-negative patients. A significant association was found between P16 expression and overall survival (log-rank P = 0.001).

Conclusions: HPV infection in OSCC was not found to be significant in this study; however, P16 expression in the tumor tissue was found to be a positive prognostic factor for better survival.

Background: Previous surveys demonstrated variations in the clinical practices relating to the treatment and screening of maternal thyroid dysfunction.

Objectives: To study the current practices in the management of subclinical hypothyroidism (SCH) and thyroid nodules during pregnancy of obstetricians/gynecologists (OB/GYNs) and endocrinologists in Israel.

Methods: An electronic questionnaire was sent by email to all members of the Israeli Endocrine Society and the Israel Society of Obstetrics and Gynecology. Questionnaires included demographic data and clinical scenarios with questions regarding the screening and management of pregnant women with SCH, hypothyroxinemia, and a palpable thyroid nodule. The questionnaire for OB/GYNs was slightly modified.

Results: We received 90 responses from endocrinologists and 42 responses from OB/GYNs. Among endocrinologists, 39% would repeat a thyroid-stimulating hormone (TSH) test of 2.9 mU/L with normal free thyroxine and treat with thyroxine if the second result was above 2.5 mU/L. Among OB/GYNs, 73% would manage a woman with SCH at the beginning of her pregnancy by themselves and only 22% would start thyroxine after a first TSH result above 2.5 mU/L. Concerning screening, 57% endocrinologists and 71% OB/GYNs recommended screening for thyroid dysfunction in every woman at the beginning of her pregnancy. Among endocrinologists, 54% would order an ultrasound for a palpable thyroid nodule and perform a fine needle aspiration only for suspicious lesions.

Conclusions: The medical approach to thyroid disease in pregnant women remains a matter of controversy. Our results support the need for larger and prospective clinical studies.

Background: Diabetic ketoacidosis (DKA) as the first presentation of type 1 diabetes mellitus (T1DM) is a serious complication that is preventable.

Objectives: To identify risk factors for DKA at presentation of T1DM to delineate high-risk Israeli populations that could benefit from preventative measures.

Methods: Data for this multicenter retrospective study were collected from the medical files of three pediatric diabetes centers representing three districts in Israel. Inclusion criteria were diagnosis of T1DM, age at diagnosis ≤ 17 years, permanent residency in Israel, and documentation of the presence or absence of DKA at presentation.

Results: The study population included 607 patients of whom 438 met the inclusion criteria. The mean age at diagnosis was 9.1 ± 4.5 years. DKA was present at diagnosis in 156/438 patients (35.6%). The incidence of DKA was different among the three diabetes centers (P = 0.04). The DKA group was significantly younger than the non-DKA group (8.4 ± 4.5 vs. 9.5 ± 4.4, respectively, P = 0.008). DKA was significantly associated with maternal origin (Ashkenazi Jewish origin [lower] vs. non-Ashkenazi, P = 0.04) and with paternal education level (academic [lower] vs. non-academic education, P = 0.04). Stepwise logistic regression showed that maternal Ashkenazi Jewish origin has a protective effect on DKA (odds ratio [OR] 0.4, 95% confidence interval [95%CI] 0.21–0.74, P = 0.004) and that younger age is an independent risk factor (OR 1.06, 95%CI 1.01–1.1, P = 0.02).

Conclusions: A diabetes educational program targeting high-risk population groups may reduce the prevalence of DKA nationwide.

Background: The distribution of pathology and clinical characteristics of lacrimal gland diseases are different in different areas of the world.

Objectives: To evaluate the incidence rate, patient characteristics, and indications for surgical intervention of lacrimal gland lesions in a tertiary care center in Israel.

Methods: All biopsied or surgically removed lacrimal gland lesions at the Goldschleger Eye Institute from 2009 to 2015 were identified. The following data were collected: age, gender, indications for surgical intervention, diagnosis, treatment, and prognosis.

Results: We evaluated 28 lacrimal gland biopsies from 26 patients (11 men, 15 women). Mean age at biopsy was 47.5 years old. The most common presenting symptoms were: eyelid swollenness (57.14%), ptosis (32.14%), and proptosis (10.71%). All patients underwent computed tomography and magnetic resonance imaging. In 28 cases, infiltrations of the lacrimal gland were found. In nine cases infiltration of muscles or orbital extension were found. The most common pathologies were non-specified inflammation (44.82%), lymphoma (20.68%), and immunoglobulin G4-related disease (10.34%). The treatment was diverse according to the patient diagnosis. Prognosis of lacrimal gland disease was good; however, in five patients the systemic disease progressed.

Conclusions: Lesions of the lacrimal gland comprise a wide variety of pathological findings that require different treatment strategies. Lacrimal gland biopsies enable physicians to precisely recognize the pathology; therefore, it is important to consider this surgical method in any patient with lesions in the lacrimal gland.

Background: Two types of growth curves are commonly used to diagnose fetal growth disorders: neonatal birth weight (BW) and sonographic estimated fetal weight (EFW). The debate as to which growth curve to use is universal.

Objectives: To establish sonographic EFW growth curves for the Israeli population and to assess whether the use of the BW growth curves currently adapted in Israel leads to under-diagnosis of intrauterine growth disorders.

Methods: Biometric data collected during a 6 year period was analyzed to establish sonographic EFW growth curves between 15–42 weeks of gestation for the Israeli population. Growth curves were compared to previously published sonographic EFW growth curves. A comparison with the Israeli BW growth curves was performed to assess the possibility of under-diagnosis of intrauterine growth disorders.

Results: Out of 42,778 sonographic EFW studies, 31,559 met the inclusion criteria. The sonographic EFW growth curves from the current study resembled the EFW curves previously published. The comparison of the current sonographic EFW and BW growth curves revealed under-diagnosis of intrauterine growth disorders during the preterm period. Four percent of the fetuses assessed between 26–34 weeks would have been suspected of being growth restricted; 2.8 percent of the fetuses assessed between 30–36 weeks would have been suspected of having macrosomia, based on the BW growth curves.

Conclusions: New Israeli sonographic EFW growth curves resemble previously published sonographic EFW curves. Using BW growth curves may lead to the under-diagnosis of growth disorders. We recommend adopting sonographic EFW growth to diagnose intrauterine growth disorders.

Background: Invasive cervical cancer is caused by human papillomavirus (HPV).

Objectives: To describe the prevalence and genotype distribution of HPV types in women at risk for cervical neoplasia.

Methods: Our study summarized HPV types detected in 6654 samples that were sent to the serology laboratory from cervical clinics in northern Israel between 2006–2014. The HPV test was performed during investigation of atypical squamous cells of undetermined significance (ASCUS) results on Pap tests or due to complaints suggestive of cervical neoplasia. HPV types were classified as high risk (HPV-HR) and low risk (HPV-LR).

Results: Of the samples, 46.4% (3085/6654) were HPV-HR positive. Of women with cervical intraepithelial neoplasia 2-3 (CIN 2-3) or cancer, 292/318 (91.8%) and 137/145 (94.5%), respectively, were HPV-HR positive. HPV 16 and HPV 18 were detected in 11.8% of the total samples and in 48.2% and 64.9% of the women with CIN 2-3 and with cancer, respectively. HPV was negative in 8/145 (5.5%) and 26/318 (8.2%) of women with cervical cancer and CIN 2-3, respectively.

Conclusions: This study shows the prevalence of HPV types in women at risk for cervical neoplasia. The sensitivity of all HPV types for CIN 2-3 and cervical cancer was 91.8% and 94.5%, respectively; and of HPV-HR types, 89% and 92.4%, respectively. Triage of HPV-HR types should be considered in women with ASCUS because HPV-HR types were discovered in only 36.7%. The distribution of HPV types in our population is similar to that reported for other developed countries.