Israel Medical Association Journal

Background: Different clinical and sonographic parameters have been suggested to identify patients with retained products of conception. In suspected cases, the main treatment is hysteroscopic removal.

Objectives: To compare clinical, sonographic, and intraoperative findings in cases of hysteroscopy for retained products of conception, according to histology.

Methods: The results of operative hysteroscopies that were conducted between 2011 and 2016 for suspected retained products of conception were evaluated. Material was obtained and evaluated histologically. The positive histology group (n=178) included cases with confirmed trophoblastic material. The negative histology group (n=26) included cases with non-trophoblastic material.

Results: Patient demographics were similar in the groups, and both underwent operative hysteroscopy an average of 7 to 8 weeks after delivery/abortion. A history of vaginal delivery was more common among the positive histology group. The main presenting symptom in all study patients was vaginal bleeding, and the majority of cases were diagnosed at their routine postpartum/abortion follow-up visit. Sonographic parameters were similar in the groups. Intraoperatively, the performing surgeon was significantly more likely to identify true trophoblastic tissue as such than to correctly identify non-trophoblastic tissue (P < 0.001).

Conclusions: Suspected retained trophoblastic material cannot be accurately differentiated from non-trophoblastic material according to clinical, sonographic, and intraprocedural criteria. Thus, hysteroscopy seems warranted in suspected cases.

Background: Adverse drug events (ADEs) are a major cause of morbidity and mortality worldwide. Hence, identifying and monitoring ADEs is of utmost importance. The Trigger Tool introduced by the Institute of Healthcare Improvement in the United States has been used in various countries worldwide, but has yet to be validated in Israel.

Objective: To validate the international Trigger Tool in Israel and to compare the results with those generated in various countries.

Methods: A retrospective descriptive correlative analysis surveying four general hospitals in Israel from different geographical regions was conducted. Patient medical charts (n=960) were screened for 17 established triggers and confirmed for the presence of an ADE. Trigger incidence was compared to the actual ADE rate. Further comparison among countries was conducted using published literature describing Trigger Tool validation in various countries.

Results: A total of 421 triggers in 279 hospitalizations were identified, of which 75 ADEs in 72 hospitalizations (7.5%) were confirmed. In addition, two ADEs were identified by chart review only. Mean positive predictive value was 17.81% and overall sensitivity was 97%. We found 1.54 ADEs for every 100 hospitalization days, 7.8 ADEs per 100 admissions, and 1.81 ADEs for every 1000 doses of medication. Of the 77 ADEs identified, 22.7% were defined as preventable.

Conclusions: Our results support the Trigger Tool validity in Israel as a standardized method. Further studies should evaluate between hospital and region differences in ADE rate, in particular for the preventable events.

Background: Trabectedin is a marine-derived chemotherapy, which has received U.S. Food and Drug Administration approval for use in anthracycline-resistant advanced soft tissue sarcoma (STS), especially liposarcoma and leiomyosarcoma (L-sarcomas).

Objectives: To describe our 10 year real-life experience with trabectedin regarding safety and efficacy in a cohort of 86 patients.

Methods: In our study cohort, 46.51% were diagnosed with liposarcoma and 43.02% with leiomyosarcoma. A total of 703 cycles of trabectedin were given, with a median of five cycles per patient (range 1–59). Median overall survival was 13.5 months for the whole cohort, 11 months for liposarcoma patients (range 1–63), and 15 months for leiomyosarcoma patients (range 1–35).

Results: There was no statistically significant difference in progression free survival when stratified according to previous treatment lines given. Trabectedin exhibited a favorable safety profile, with only 22% requiring dose reductions. Grade 3 and higher toxicity was noted in 25% of the patients, mostly due to myelosuppression. There were no treatment-related deaths.

Conclusions: Trabectedin is a safe and effective drug for treating advanced STS. Our results reflect real-life data with patients receiving the drug as a third and even fourth line of treatment, or with a suboptimal performance status, yet achieving impressive clinical benefit rates and survival.

Background: Leukoplakia of the vocal cords may represent a pre-cancerous lesion of the larynx. The management of cases of recurrent leukoplakia with pathologically proven dysplasia is still controversial.

Objectives: To present a series of patients with recurrent vocal cord leukoplakia and to examine their malignant transformation rate in relation to the clinical characteristics, risk factors, and histological findings.

Methods: A retrospective cohort study was conducted between 1999 and 2017. The study comprised 52 patients with recurrent leukoplakia of the vocal cords who required ≥ 2 direct laryngeal procedures within a minimum of 3 months between each procedure. Malignant transformation rate over follow-up period, risk factors for malignant transformation, and interval to develop laryngeal squamous cell carcinoma were investigated.

Results: All patients presented with hoarseness. An average of three procedures per patient was performed (range 2–13). Ten male patients (19.2%) developed squamous cell carcinoma. Of these, four with severe dysplasia developed SCC within 19 months of the first direct laryngoscopy. In the six other patients, SCC developed within an average of 3.7 years. The follow-up period ranged from 9–253 months (mean 109 months). Heavy smoking and severe dysplasia in the first biopsy were found to be significant risk factors for developing squamous cell carcinoma, as was male gender.

Conclusions: We showed an increased malignant transformation rate in recurrent leukoplakia cases among heavy smokers and male patients. In addition, severe dysplasia at initial diagnosis was a risk factor for SCC development. Close follow-up of patients with recurrent leukoplakia is warranted.

Background: Recent studies have suggested that urgent cholecystectomy is the preferred treatment for acute cholecystitis. However, initial conservative treatment followed by delayed elective surgery is still common practice in many medical centers.

Objectives: To determine the effect of percutaneous cholecystostomy on surgical outcome in patients undergoing delayed elective cholecystectomy.

Methods: We conducted a retrospective analysis of all patients admitted to our medical center with acute cholecystitis who were treated by conservative treatment followed by delayed cholecystectomy between 2004 and 2013. Logistic regression was calculated to assess the association of percutaneous cholecystostomy with patient characteristics, planned surgical procedure, and the clinical and surgical outcomes.

Results: We identified 370 patients. Of these, 134 patients (36%) underwent cholecystostomy during the conservative treatment period. Patients who underwent cholecystostomy were older and at higher risk for surgery. Laparoscopic cholecystectomy was offered to 92% of all patients, yet assignment to the open surgical approach was more common in the cholecystostomy group (16% vs. 3%). Cholecystostomy was associated with significantly higher conversion rates to open approach (26% vs. 13%) but was not associated with longer operative time, hemorrhage, surgical infections, or bile duct or organ injuries.

Conclusions: Treatment with cholecystostomy is associated with higher conversion rates but does not include other major operative-related complications or poorer clinical outcome.

Background: Thymectomy is a reliable surgical method for treating patients with myasthenia gravis (MG) and benign tumors of the thymus. Despite the advantages of minimally invasive surgical approaches for resection of thymic neoplasms, there are still controversies regarding the superiority of one type of surgery over another.

Objectives: To report the results of our initial Israeli experience with robotic thymectomy in 22 patients with MG and suspected benign thymic tumors.

Methods: We retrospectively analyzed 22 patients (10 men, 12 women) who underwent robotic thymectomy by a left-sided (16) or right-sided approach (6) using the da Vinci robotic system at Assaf Harofeh Medical Center. Seven patients were diagnosed with MG before surgery and 14 had suspected benign thymic neoplasms.

Results: Average operative time was 90 minutes. There were no deaths or intraoperative complications. Postoperative complications occurred in two patients (dyspnea and pleural effusion). Median blood loss was 12.3 cc (range 5–35 cc), median hospital stay 2.9 days (range 2–5 days), and mean weight of resected thymus 32.1 grams. Seven patients had thymic hyperplasia, six a lipothymoma, one a thymic cyst. Seven each had thymomas in different stages and one had a cavernous hemangioma.

Conclusions: Robotic thymectomy is a safe, technically effective surgical method for resection of thymic neoplasms. The advantages of this technique are safety, short hospitalization period, little blood loss, and low complications. We have included this surgical procedure in our thoracic surgery residency program and recommend a learning curve program of 10 to 12 procedures during residency.

Background: A cardiac restrictive filling patterns are associated with unfavorable prognoses. Cardiac interventions may change the natural history of patients.

Objectives: To investigate the prevalence of restrictive filling pattern in routine echocardiographic examinations and their association with morbidity and mortality.

Methods: The clinical and echocardiographic data of patients with newly diagnosed restrictive filling pattern were analyzed and summarized.

Results: Among 8000 patients who underwent an echocardiographic examination in our hospital in 2013, a restrictive filling pattern was identified in 256. Of these, 134 showed a restrictive filling pattern that was newly diagnosed. Mean age was 69 years. Hypertension, diabetes, and ischemic heart disease were found in 81%, 60%, and 53%, respectively. Left ventricular ejection fraction was 42% ± 16%. Severe valvular abnormalities were found in 18%. During follow-up (29 ± 15 months), 40% of patients died. The strongest predictor of mortality (73%) was moderate or more advanced aortic stenosis, P = 0.005. Renal failure was an important independent predictor of mortality (53%, P < 0.05). A very high E/E' ratio ≥ 20, was another independent mortality predictor (50%, P < 0.03). Patients who died were less likely to have undergone cardiac interventions than those who survived (26% vs. 45%, P < 0.03).

Conclusions: Prevalence of restrictive filling among echocardiographic studies is 3.2%. In a half of these, the restrictive filling pattern is a new diagnosis. Patients who are diagnosed with a new restrictive filling pattern have higher mortality rates. Patients with restrictive filling should be evaluated thoroughly for possible coronary artery or valvular heart disease.

Background: Mortality and decrease in function after hip fracture are significantly related to patient factors including age, gender, co-morbidities, and mental status. Several studies demonstrated ethnic disparities in incidence, mortality, and functional outcome after hip fractures in the United States.

Objectives: To assess the relationship between ethnicity and hip fracture incidence and outcomes of mortality, functional change, and perioperative complications in the Israeli population.

Methods: We reviewed our institutional hip fracture registry for all patients from 2014–2015. Patients with incomplete data, < 60 years of age, or pathologic and periprosthetic fractures were excluded. Our study comprised 693 patients. Ethnicity was based on country of birth. Specifically, for those born in Israel, the nationality of either Jewish or Arab was further dichotomized. Perioperative complications, mortality, and mobility status at 1 year follow-up were recorded. The ethnicities of 27,130 patients admitted to the medicine and surgical wards during the same time interval served as a control group for the hip fracture cohort.

Results: Immigrants from Europe and America had the highest incidence of hip fractures. Fracture types varied in incidence in groups with 70% of extracapsular hip fractures occurring in Arabs and immigrants from Eastern countries, compared to 60% in immigrants from Western countries and the former Soviet Union. Mortality, perioperative complications, and mobility at 1 year were similar in all ethnic groups.

Conclusion: Our study demonstrated significant differences in incidence and fracture characteristic among ethnicities, but no difference in patient outcome. These findings differed from the available North American studies.

Background: Correct diagnosis of cardiac masses is a challenge in clinical practice. Accurate identification and differentiation between cardiac thrombi and tumors is crucial because prognosis and appropriate clinical management vary substantially.

Objectives: To evaluate the diagnostic performances of cardiac magnetic resonance imaging (CMR) in differentiating between cardiac thrombi and tumors.

Methods: A retrospective review of a prospectively maintained database of all CMR scans was performed to distinguish between cardiac thrombi and tumors during a 10 year period in a single academic referral center (2004–2013). Cases with an available standard of reference for a definite diagnosis were included. Correlation of CMR differentiation between thrombi and tumors with an available standard of reference was performed. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy were reported.

Results: In this study, 101 consecutive patients underwent CMR for suspicious cardiac masses documented on transthoracic or transesophageal echocardiography. CMR did not detect any cardiac pathology in 17% (17/101), including detection of anatomical variants and benign findings in 18% (15/84). Of the remaining 69 patients, CMR diagnosis was correlated with histopathologic result in 74% (51/69), imaging follow-up in 22% (15/69), and a definite CMR diagnosis (lipoma) in 4% (3/69). For tumors, diagnostic accuracy, sensitivity, specificity, PPV, and NPV were 96.6%, 98%, 86.6%, 96.2%, and 96.6%, respectively. For thrombi, the results were 93.6%, 86.7%, 98.04%, 92.9%, and 97%, respectively.

Conclusions: CMR is highly accurate in differentiating cardiac thrombi from tumors and should be included in the routine evaluation of cardiac masses.

Background: Nail-patella syndrome (NPS) is characterized by changes in the nails, knees, and elbows, as well as the presence of iliac horns detected by X-ray of the pelvis. A higher occurrence of psychiatric disorders has also been suggested in NPS. Heterozygous mutations in the gene encoding the LIM-homeodomain transcription factor (LMX1B) are identified in most patients with typical clinical findings of NPS.

Objective: To report on the association between NPS and schizophrenia.

Methods: Genomic DNA were isolated from a patient's venous blood and collected on ethylenediaminetetraacetic 5% with the Gentra Puregene Blood Kit. All exons and flanking regions of the LMX1B gene (LMX1B: NM_001174146.1) were amplified by standard polymerase chain reaction and analyzed by direct DNA sequencing with BigDye Terminators on an ABI 3100 sequencer. Sequence chromatograms were analyzed using SeqScape software version 1.1. Mutation analysis and characterization of variants was performed with the Alamut Software Version 2.1.

Results: We report a patient presenting to the psychiatry department with schizophrenia. Clinical examination revealed characteristic findings consistent with NPS. Since NPS was suspected, based on clinical findings, sequencing of all coding exons of LMX1B gene was completed. Results revealed a novel heterozygous mutation in the proband: c.546_547insACCG(het); p.Glu183Thrfs*11.

Conclusions: Based on LMX1B expression in brain regions that are implicated in neuropsychiatric illness, and especially in the development of dopaminergic neurons, we hypothesize that schizophrenia may be part of the clinical spectrum of NPS.

Background: Family physicians and internal medicine specialists play an essential role in treating cancer patients. Modern technological advances in radiotherapy are not widely appreciated by primary care physicians. Bone metastases are a frequent complication of cancer. Palliative radiation therapy, as a component of modern advances in radiation treatments, should not subject normal bodily structures to excessive doses of irradiation. The sacrum is a common destination site for bone metastases, yet its concave shape along with its proximity to the rectum, intestines, and femoral heads creates treatment-planning challenges.

Objectives: To investigated whether the volumetric modulated arc therapy (VMAT) technique is preferable to more conventional radiation strategies.

Methods: The study comprised 22 patients with sacral metastases who were consecutively treated between 2013 and 2014. Two plans were generated for the comparison: three-dimensional (3D) and VMAT.

Results: The planning target volume (PTV) coverage of the sacrum was identical in VMAT and 3D planning. The median values for the rectal dose for 3D and VMAT were 11.34 ± 5.14 Gy and 7.7 ± 2.76 Gy, respectively. Distal sacral involvement (S4 and S5) was observed in only 2 of 22 cases, while the upper pole of the rectum ended at the level above S3 in just 3 cases.

Conclusions: Radiation therapy continues to be an integral component of the palliative armamentarium against painful metastases. Radiation oncologist, in conjunction with referral physicians, can tailor treatment plans to reflect the needs of a given patient.

Background: A dental appliance for obstructive sleep apnea (OSA) is recommended for patients who cannot adjust to continuous positive airway pressure (CPAP) treatments.



Objectives: To describe patients with extremely severe OSA who were successfully treated with a dental appliance and to compare their characteristics with the relevant literature to identify clinical features associated with a good outcome.



Methods: The clinical, management, and outcome data of three patients with an apnea-hypopnea index (AHI) of > 80 who showed clinical improvement following treatment with a dental appliance were collected retrospectively from sleep laboratory reports in Israel over a period of 3 years. 



Results: The patients included one man and two women, aged 33, 56, and 61 years, respectively. The diagnosis of OSA was based on clinical examination and polysomnography. AHI values at presentation were 83, 81, and 84, respectively. Treatment with a dental appliance (Herbst® or MDSA®) was proposed due to patient noncompliance with CPAP. Follow-up polysomnography with the dental appliance revealed a reduction in the AHI to 1.7, 10.7, and 11, respectively. All patients had supine OSA and a retrognathic mandible, both of which have been found to be associated with a good prognosis for treatment with a dental appliance.



Conclusions: Dental appliances may be considered an appropriate second-choice option to treat severe OSA in patients who are noncompliant with CPAP. This study helps physicians identify patients with extremely severe OSA who are suitable for dental appliance treatment. Well-designed large-scale studies are needed to reach definitive conclusions. 

Background: Williams syndrome (WS) is a neurogenetic syndrome characterized by a variety of medical conditions and cognitive deficits along with distinct psychiatric and behavioral characteristics. To the best of our knowledge, no studies to date have comprehensively reported the prevalence of medical, cognitive deficits, and psychiatric disorders in one cohort of people with WS in one study.

Objectives: To detail the prevalence of the various clinical features of WS in a large nationwide Israeli cohort. To examine potential risk factors for attention deficit hyperactivity disorder (ADHD) in WS.

Methods: We investigated the effects of cardiovascular anomalies, intellectual quotient (IQ), and phonophobia (fear of sounds) on the likelihood of ADHD. The study included 80 participants with WS (mean age 7.76 years). Relevant medical information from medical records was obtained retrospectively. In addition, IQ testing and psychiatric assessments using structured tools were conducted. The association between ADHD and cardiovascular anomalies, IQ, and phonophobia was analyzed using a logistic regression.

Results: Supravalvular aortic stenosis and supravalvular pulmonary stenosis are the prevalent cardiovascular anomaly in WS. Phonophobia and ADHD are the most prevalent psychiatric diagnoses in people with WS. Phonophobia was significantly associated with the risk for ADHD in WS participants.

Conclusions: Our findings regarding the type and prevalence of medical, cognitive, and psychiatric characteristics in WS correspond to results in previous publications. We also showed a potential link between phonophobia and ADHD that merits further research.

Background: Vitamin D deficiency and insufficiency have been reported in fibromyalgia. However, to the best of our knowledge, only one study has evaluated the role of 25-hydroxyvitamin D [25(OH)D] supplementation on fibromyalgia symptoms.

Objectives: To analyze the effects of 3 months of 25(OH)D supplementation on symptoms of fibromyalgia.

Methods: This study included 11 female patient. Demographic and clinical data, tender points, visual analog scale results, and pre- and post-serum levels of 25(OH)D supplementation were analyzed. The levels of 25(OH)D were measured by a radioimmunologic test.

Results: Patients with fibromyalgia diagnosis and 25(OH)D values ≤ 30 ng/ml were recruited to receive 50,000 IU of oral vitamin D once every week for 3 months. The disease was diagnosed based on the American College of Rheumatology criteria. The median age of all patients was 48.5 (28–67) years and 63.4% were Caucasian. Disease duration varied from 1–10 years. The 25(OH)D levels increased significantly after 3 months, 18.4 (15.5–25.8) ng/ml vs. 33.8 (28–58) ng/ml, P = 0.01. Interestingly, an improvement of visual analog scale scores was observed at 3 months, 90 (0–100) vs. 30 (0–80), P = 0.002. Eight patients (72.2%) responded that they experienced a very significant improvement in symptoms. In addition, a trend for reduction of the number of tender points was observed after 3 months, 17 (11–18) vs. 10 (0–18), P = 0.07.

Conclusions: The 25(OH)D levels and disease symptoms in patients with fibromyalgia and vitamin D deficiency/insufficiency seem to improve with vitamin D supplementation.