Israel Medical Association Journal

Background: Nasal polyps are three-dimensional structures arising from the mucosa of the upper airway. Due to their complexity, the reliability of single-layer cell cultures and animal systems as research models is limited.

Objectives: To evaluate the feasibility of an ex vivo organ culture of human polyps, preserving tissue structure and function.

Methods: Nasal polyps were excised during routine endoscopic sinus surgery for chronic rhinosinusitis and polyposis. Fresh tissue samples were used for pathological evaluation and for the preparation of 250–500 µm sections, which were incubated in culture media. Tissue viability was assessed by visualisation of cilia motility, measurement of glucose uptake, and an infectivity assay. Cytokine secretion was evaluated by enzyme-linked immunosorbent assay and real-time polymerase chain reaction before and after the introduction of steroids.

Results: Polyp tissue viability was retained for 2–3 days as demonstrated by cilia motility, glucose uptake and preserved cellular composition. Tissue samples maintained their capacity to respond to infection by herpes simplex virus 1 and adenovirus. Introduction of dexamethasone to cultured tissue samples led to suppression of interferon-g production.

Conclusions: The ex vivo nasal polyp organ culture reproduces the physiological, metabolic, and cellular features of nasal polyps. Furthermore, it shows a preserved capacity for viral infection and response to drugs. This system is a useful tool for the investigation nasal-polyps and for the development of novel therapies.

Background: Older age is an independent predictor of worse outcome from traumatic brain injury (TBI). No clear guidelines exist for the management of TBI in elderly patients.

Objectives: To describe the outcomes of elderly patients presenting with TBI and intracranial bleeding (ICB), comparing a very elderly population (≥ 80 years of age) to a younger one (70–79).

Methods: Retrospective analysis of the outcomes of elderly patients presenting with TBI with ICB admitted to a level I trauma center.

Results: The authors analyzed 100 consecutive patients aged 70–79 and 100 patients aged 80 and older. In-hospital mortality rates were 9% and 21% for groups 70–79 and ≥ 80 years old, respectively (P = 0.017). Patients 70–79 years old showed a 12-month survival rate of 73% and a median survival of 47 months. In patients ≥ 80 years old, 12-month survival was 63% and median survival was 27 months (P = NS). In patients presenting with a Glasgow Coma Scale score of ≥ 8, the in-hospital mortality rates were 41% (n=5/12) and 100% (n=8/8). Among patients ≥ 80 years old undergoing emergent surgical decompression, in-hospital mortality was 66% (n=12/18). Survivors presented with a severe drop in their functional score. Survival was dismal in patients ≥ 80 years old who were treated conservatively despite recommended operative guidelines.

Conclusions: There is a lack of reliable means to evaluate the outcome in patients with poor functional status at baseline. The negative prognostic impact of severe TBI is profound, regardless of treatment choices.

Background: The frequency of increased high-sensitivity C-reactive protein (hs-CRP) and the time course of evolution of their levels in patients with acute idiopathic pericarditis (AIP) are not well established.

Objective: To assess the time course of evolution of hs-CRP levels and the possible clinical significance of maximal hs-CRP levels in patients with AIP

Methods: We retrospectively reviewed the medical files of 241 patients admitted to the hospital with a diagnosis of AIP between March 2006 and March 2017. Data on demographics, time of symptom onset, laboratory and imaging findings, and outcome were collected.

Results: Data on serum hs-CRP levels were available for 225 patients (age 18–89 years, 181 men). Fever, pleural effusion, and age were independently associated with hs-CRP levels. Major cardiac complications (MCC) (death, cardiac tamponade, cardiogenic shock, large pericardial effusion, ventricular tachycardia, pericardiocentesis, or pericardiectomy) were more common in patients with hs-CRP levels above the median compared to those below (21.2% vs. 4.5%, respectively, P < 0.001). Hs-CRP levels were independently associated with MCC (odds ratio [OR] 1.071, 95% confidence interval [95%CI] 1.016–1.130, P = 0.011). Hs-CRP levels were elevated in 76.0%, 92.3% and 96.0% of the patients tested <6 hours, 7-12 hours, and >12 hours of symptom onset, respectively (P = 0.003). The frequency of elevated hs-CRP among patients tested > 24 hours was 98.1%.

Conclusions: Hs-CRP levels rise rapidly among patients with AIP. Maximal hs-CRP levels are associated with MCC. A normal hs-CRP level is rare among patients tested > 24 hours of symptom onset.

Background: Tumor treating fields (TTFields) are low-intensity, intermediate frequency electric fields that affect proliferating cells. TTFields are FDA approved for treatment of newly diagnosed and recurrent glioblastoma. Combining TTFields with immunotherapy is a rational approach due to their different mechanisms of action (MOA) and to the ability of TTFields to induce immunogenic cell death. Conversely, TTFields may interfere with immune functions critical for effective T-cell responses.

Objectives: To evaluate the effects of TTFields on pivotal antitumoral T-cell functions.

Methods: T-cells from healthy donor peripheral blood (PB) or from viably dissociated human glioblastoma samples were cultured under normal or TTFields conditions, with or without superantigen stimulation. Multiparametric flow cytometry (8-color) was used to assess T-cell responses by monitoring select pivotal functions: proliferation (CFSE), IFNγ secretion, cytotoxic degranulation (CD107a), and activation/exhaustion (PD-1). Cellular viability was assessed in a dedicated assay. A chimeric antigen receptor (CAR) T-cell-based assay directly evaluated cellular cytotoxicity.

Results: Activated PB T-cells and tumor-infiltrating T-cells (TILs) preserved all monitored anti- tumoral functions under TTFields, apart from proliferation. This finding also applied specifically to PD-1 + TILs, comprised predominantly of tumor antigen-specific cells. Activated T-cells that attempted to proliferate under TTFields demonstrated decreased viability, in line with TTField MOA. Small or no reduction in viability was found in T-cells that did not attempt to proliferate, whether activated or resting.

Conclusions: All monitored anti-tumoral T cell functions, except for proliferation, were unhindered by TTFields. Our results support further investigation into combinations of TTFields with T-cell based immunotherapeutic approaches.

Background: Frozen section (FS) is often performed when histopathological evaluations are urgently required for implementation of therapeutic measures. In dermatology, this method is most commonly used to evaluate excision margins of tumors. FS are also routinely employed to differentiate toxic epidermal necrolysis from staphylococcal scalded skin syndrome. However, little is currently known about the performance of FS in the diagnosis of inflammatory dermatoses.

Objectives: To compare histopathological diagnoses in a series of patients with a clinical diagnosis of an inflammatory dermatosis for which FS and paraffin-section (PS) specimens were obtained on the same day.

Methods: We conducted a single-center retrospective analysis of 43 cases. All histological slides were reviewed by a single dermato-pathologist. Concordance was calculated between FS and PS.

Results: Patients were divided into three groups according to diagnosis: papulosquamous diseases (group I), drug eruptions (group II), and a heterogeneous group (group III) that included cases of bullous vasculitis and Sweet syndrome. Among the three groups, the results of FS and of PS were discordant only in five cases (5/43, 11.6%). Compared to PS, FS had a sensitivity of 92.9% [95% confidence interval (95%CI) 64.17–99.63%] and a specificity of 100% in group I, sensitivity of 90.9% (95%CI 57.12–99.52%) and specificity of 100% in group II, and sensitivity of 83.33% (95%CI 60.78–94.16%) and specificity of 100% in group III. The degree of agreement between the results of the FS and of the PS was almost perfect (kappa = 0.95, 0.93 and 0.85 respectively).

Conclusions: This study suggests that FS is a valid approach for the rapid diagnosis of inflammatory dermatoses. This method is as specific as PS, although it is less sensitive.

Background: Adjuvant radiotherapy for breast cancer reduces local recurrence and improves survival. In patients with left sided breast cancer, anterior heart position or medial tumor location may cause inadequate breast coverage due to heart shielding. Respiration gating using the Real-time Position Management (RPM) system enables pushing the heart away from the tangential fields during inspiration, thus optimizing the treatment plan.

Objectives: To compare breathing inspiration gating (IG) techniques with free breathing (FB), focusing on breast coverage.

Methods: The study comprised 49 consecutive patients with left sided breast cancer who underwent lumpectomy and adjuvant radiation. RPM was chosen due to insufficient breast coverage caused by an anterior heart position or medial lumpectomy cavity. FB and IG computed tomography simulations were generated for each patient. Breast (PTVbreast) and lumpectomy cavity (CTVlump) were defined as the target areas. Optimized treatment plans were created for each scan. A dosimetric comparison was made for breast coverage and heart and lungs doses.

Results: PTVbreast V95% and mean dose (Dmean) were higher with IG vs. FB (82.36% vs. 78.88%, P = 0.002; 95.73% vs. 93.63%, P < 0.001, respectively). CTVlump V95% and Dmean were higher with IG (98.87% vs. 88.92%, P = 0.001; 99.14% vs. 96.73%, P = 0.003, respectively). The cardiac dose was lower with IG. The IG left lung Dmean was higher. No statistical difference was found for left lung V20.

Conclusions: In patients with suboptimal treatment plans due to anterior heart position or medial lumpectomy cavity, RPM IG enabled better breast/tumor bed coverage and reduced cardiac doses.

Background: Cardiac damage caused by oncological therapy may manifest early or many years after the exposure.

Objectives: To determine the differences between sub-acute and late-onset cardiotoxicity in left ventricular ejection fraction (LVEF) recovery as well as long-term prognosis.

Methods: We studied 91 patients diagnosed with impaired systolic function and previous exposure to oncological therapy. The study population was divided according to sub-acute (from 2 weeks to ≤ 1 year) and late-onset (> 1 year) presentation cardiotoxicity. Recovery of LVEF of at least 50% was defined as the primary end point and total mortality was the secondary end point.

Results: Fifty-three (58%) patients were classified as sub-acute, while 38 (42%) were defined as late-onset cardiotoxicity. Baseline clinical characteristics were similar in the two groups. The mean LVEF at presentation was significantly lower among patients in the late-onset vs. sub-acute group (28% vs. 37%, respectively, P < 0.001). Independent predictors of LVEF recovery were trastuzumab therapy and a higher baseline LVEF. Although long-term mortality rates were similar in the groups with sub-acute and late-onset cardiotoxicity, improvement of LVEF was independently associated with reduced mortality.

Conclusions: Our findings suggest that early detection and treatment of oncological cardiotoxicity play an important role in LVEF recovery and long-term prognosis.

Background: A patient`s individual chance of being diagnosed with cardiovascular disease can be determined by risk scores.

Objectives: To determine the risk score profiles of patients presenting with a first acute coronary event according to pre-admission risk factors and to evaluate its association with long-term mortality.

Methods: The research was based on a retrospective study of a cohort from the 2010 and 2013 Acute Coronary Syndrome Israeli Surveys (ACSIS). Inclusion criteria included first event and no history of coronary heart disease or cardiovascular disease risk equivalent. The Framingham Risk Score, the European Systematic COronary Risk Evaluation (SCORE), and the American College of Cardiology/American Heart Association/ (ACC/AHA) risk calculator were computed for each patient. The risk profile of each patients was determined by the three scores. The prognostic value of each score for 5 year survival was evaluated.

Results: The study population comprised 1338 patients enrolled in the prospective ACSIS survey. The ACC/AHA score was the most accurate in identifying patients as high risk based on pre-admission risk factors (73% of the subjects). The Framingham algorithm identified 53%, whereas SCORE recognized only 4%. After multivariate adjustment for clinical factors at presentation, we found that no scores were independently associated with 5 year mortality following the first acute coronary event.

Conclusions: Patients with first acute coronary event had a higher pre-admission risk scores according to the ACC/AHA risk algorithm. No risk scores were independently associated with 5 year survival after an event.

Background: About half of all patients with heart failure are diagnosed with heart failure preserved ejection fraction (HFpEF). Until now, studies have failed to show that medical treatment improves the prognosis of patients with HFpEF.

Objectives: To evaluate changes in exercise capacity of patients with HFpEF compared to those with heart failure with reduced ejection fraction (HFrEF) following an exercise training program.

Methods: Patient data was retrieved from a multi-center registry of patients with heart failure who participated in a cardiac rehabilitation program. Patients underwent exercise testing and an echocardiogram prior to entering the program and were retested6  months later.

Results: Of 216 heart failure patients enrolled in the program, 170 were diagnosed with HFrEF and 46 (21%) with HFpEF. Patients with HFpEF had lower baseline exercise capacity compared to those with HFrEF. Participating in a 6 month exercise program resulted in significant and similar improvement in exercise performance of both HFpEF and HFrEF patients: an absolute metabolic equivalent (MET) change (1.45 METs in HFrEF patients vs. 1.1 in the HFpEF group, P = 0.3).

Conclusions: An exercise training program resulted in similar improvement of exercise capacity in both HFpEF and HFrEF patients. An individualized, yet similarly structured, cardiac rehabilitation program may serve both heart failure groups, providing safety and efficacy.

Background: Limited information exists about detailed clinical characteristics and management of the small subset of Brugada syndrome (BrS) patients who had an arrhythmic event (AE).

Objectives: To conduct the first nationwide survey focused on BrS patients with documented AE.

Methods: Israeli electrophysiology units participated if they had treated BrS patients who had cardiac arrest (CA) (lethal/aborted; group 1) or experienced appropriate therapy for tachyarrhythmias after prophylactic implantable cardioverter defibrillator (ICD) implantation (group 2).

Results: The cohort comprised 31 patients: 25 in group 1, 6 in group 2. Group 1: 96% male, mean CA age 38 years (range 13–84). Nine patients (36%) presented with arrhythmic storm and three had a lethal outcome; 17 (68%) had spontaneous type 1 Brugada electrocardiography (ECG). An electrophysiology study (EPS) was performed on 11 patients with inducible ventricular fibrillation (VF) in 10, which was prevented by quinidine in 9/10 patients. During follow-up (143 ± 119 months) eight patients experienced appropriate shocks, none while on quinidine. Group 2: all male, age 30–53 years; 4/6 patients had familial history of sudden death age < 50 years. Five patients had spontaneous type 1 Brugada ECG and four were asymptomatic at ICD implantation. EPS was performed in four patients with inducible VF in three. During long-term follow-up, five patients received ≥ 1 appropriate shocks, one had ATP for sustained VT (none taking quinidine). No AE recurred in patients subsequently treated with quinidine.

Conclusions: CA from BrS is apparently a rare occurrence on a national scale and no AE occurred in any patient treated with quinidine.

Background: Idiopathic membranous nephropathy (IMN) is one of the most common causes of nephrotic syndrome (NS) in Caucasian adults. Most patients have good renal prognosis, but 30–40% may progress to end stage renal disease (ESRD). 

Objectives: To evaluate the efficacy and safety of immunosuppressive treatment (IST) in high-risk patients.

Methods: All IMN patients diagnosed by kidney biopsy from 2004–2010 were included. Clinical and laboratory data were collected at each follow-up visit. Risk assessment for renal progression classified patients as high risk if: 24 hour protein excretion > 6 g/day, estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, and severe disabling or life-threatening clinical symptoms of NS were present.

Results: Among 290 biopsies, 37 patients (12.7%) were IMN. They were allocated to the high-risk IST group (n=16) or low-risk supportive treatment (ST) group (n=21) according to the likelihood of developing renal failure. Mean follow-up was 47 ± 17.3 months. Complete and partial remission rate was 68.7% for high-risk IST vs. 90.4% for low-risk ST. In the high-risk IST group, eGFR was significantly lower at 30 months (65.5 ± 28.6 vs. 85.3 ± 21.6 at baseline, P < 0.05). Four high-risk patients reached ESRD. In the low-risk ST group, eGFR remained stable at 30 and 60 months. 

Conclusions: This study showed a high remission rate for IMN. IST with prednisolone and cyclophosphamide provided favorable renal outcomes in most high-risk patients. The very high remission rate obtained in the low-risk patients confirms the adequacy of supportive treatment in this group.

Upper extremity deep vein thrombosis (UEDVT) is defined as thrombosis of the deep venous system (subclavian, axillary, brachial, ulnar, and radial veins), which drains the upper extremities. It can be caused by thoracic outlet anatomic obstruction, such as Paget–Schroetter syndrome, (primary) or by central intravenous catheters (secondary). UEDVT may be asymptomatic or present with acute severe pain and arm swelling. Clinical suspicion should be confirmed by diagnostic imaging procedures such as duplex ultrasound, computed tomography scan, or magnetic resonance imaging. UEDVT is managed by anticoagulant treatment. In addition to that, early thrombolysis aimed at preventing post-deep vein thrombosis syndrome and thoracic outlet decompression surgery should be given to patients with primary UEDVT. Anticoagulation without thrombolysis is the treatment of choice for patients with catheter-related thrombosis. Mandatory functioning catheters can remain in place with anticoagulant treatment. All other catheters should be immediately removed. The management of patients with UEDVT requires an experience multidisciplinary team comprised of internists, radiologists, hematologists, and vascular surgeons. Understanding the risk factors for the development of UEDVT, the diagnostic procedures, and the treatment modalities will improve the outcome of those patients.

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: Computed tomography (CT) brain perfusion is a relatively new imaging method that can be used to differentiate patients following epileptic seizures in the setting of acute neurological deficits (e.g., hemiparesis, hemiplegia, hemianopsia, aphasia) who arrive at the emergency room with a suspected stroke.

Objectives: To evaluate brain perfusion changes in patients who had an epileptic seizure.

Methods: We retrospectively identified 721 patients who presented at our stroke center between 2012 and 2015 with a suspected acute stroke and underwent examination thorough a stroke protocol, including cerebral CT perfusion (CTP) and CT angiography (CTA) within 8 hours from the onset of symptoms. 

Results: Out of 721 patients, 25 presented with ictal electroencephalography (EEG) findings within 24–72 hours from symptom onset without evidence of vascular occlusion on CTA. While 15 patients had to be excluded from the study due to concomitant brain pathology, we found a specific reduction in cerebral blood volume and cerebral blood flow occurring at the ictal zone, which was identified by a post hoc EEG investigation. 

Conclusions: Our study shows that CTP is an easily accessible tool in emergency department setting for the detection of changes in blood flow dynamics among postictal patients. Thus, we propose the use of CTP in emergency settings to discriminate between postictal changes and acute vascular events.