Israel Medical Association Journal

Background: Lung cancer is the most common cause of cancer-related death.

Objectives: To identify changing patterns of lung cancer and its histologic subtypes among different population groups in Israel over a 25 year period.

Methods: Primary lung cancers, all types and all stages, diagnosed during 1990–2014 were recorded in the Israel National Cancer Registry database. Demographic information was retrieved from the National Population Register. Age-standardized rates for the different subgroups were calculated for each year. Joinpoint software was used to analyze trends in incidence.

Results: We identified 42,672 lung cancer cases. The most common histology was adenocarcinoma (34%), followed by squamous cell carcinoma (19%), large cell/not-otherwise-specified (19%), other histologies (15%), and small cell lung cancer (11%). The adenocarcinoma incidence rose from 25.7% to 48.2% during the examined period. Large cell/not-otherwise-specified incidence peaked around 2005–2006 and declined after. Lung cancer incidence increased significantly for the population overall and specifically in Arab females, followed by Jewish females and by Arab males. Adenocarcinoma and small cell lung cancer increased in Jewish females and in Arab males. A younger age of diagnosis was seen in Arab compared to Jewish patients.

Conclusions: Jewish females and Arab males and females living in Israel demonstrated a constant increase in lung cancer incidence, mostly in adenocarcinoma and small cell lung cancer incidence. In addition, a younger age of diagnosis in Arabs was noted. Smoking reduction interventions and screening should be implemented in those populations.

Background: Prophylactic cranial irradiation (PCI) exclusion in favor of brain magnetic resonance imaging (MRI) staging and surveillance in the management of small cell lung cancer (SCLC) is controversial yet accepted by some centers. The use of MRI suggests performing stereotactic radiosurgery (SRS) treatment for limited brain metastases. Data regarding SRS efficacy in this setting is limited.

Objectives: To assess intracranial objective response rate (iORR), progression-free survival (iPFS), intracranial failure patterns, overall survival (OS) and time-to-whole-brain radiation therapy (WBRT)/death, whichever occurred first (TTWD) with SRS in SCLC.

Methods: The study comprised 10 consecutive SCLC patients with brain metastases treated with SRS and followed-up at Davidoff Cancer center between Aug 2012 and March 2019. Brain MRI images were reviewed by a neuro-radiology specialist.

Results: iORR was 57% as assessed by response assessment in neuro-oncology brain metastases. Intracranial progression developed in 8 patients. Median iPFS was 4.0 months (95% confidence interval [95%CI] 1.7–7.2). In-site, off-site and combined pattern of intracranial failure was seen in 0, 5, and 3 patients, respectively; median number of new brain lesions following SRS was 4 (range, 1–12). SRS was performed 10 additional times in 6 patients (median number of lesions irradiated per round was 1, range 1–5). WBRT was administered in 3 patients. Median TTWD was 20.9 months (95% CI, 1.9–26.8). Median OS since SRS administration was 23.2 months (95% CI, 4.2–not reached).

Conclusions: MRI surveillance with multiple rounds of SRS may serve a reasonable alternative to PCI or therapeutic WBRT in SCLC. 

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: Determining the accuracy of interferon gamma-releasing assays (IGRAs) is difficult due to the lack of a gold standard test for diagnosing latent tuberculosis (LTB). 

Objectives: To analyze the guidelines used for interpreting IGRAs in determining prophylactic treatment management for latent tuberculosis (LTB) in Israel.

Methods: We analyzed the retrospective data of 367 subjects who were referred to our laboratory during the period 2007–2011 for QuantiFERON Test-Gold In Tube (QFT-GIT) tests because of suspected LTB. Demographics and clinical data were retrieved from a questionnaire at enrollment, and 166/367 (45%) were further interviewed by phone in order to complete follow-up information on prophylactic TB treatment. 

Results: The majority of subjects (116/166, 69.9%, P < 0.0001) were spared prophylactic treatment subsequent to QFT-GIT testing. Subjects with negative QFT-GIT and positive tuberculin skin test (TST) results who were BCG-vaccinated had the lowest treatment rates (6/68, 8.8%, P < 0.0001). Most BCG-vaccinated subjects with positive TST and negative QFT-GIT test results received treatment with anti-tumor necrosis factor-alpha (TNFα) (17/19, 89.5%, P = 0.004). We found more negative QFT-GIT test results in subjects who were receiving anti-TNFα or steroid and other immunosuppressive treatment prior to testing (11/11, 100%, P = 0.029; 22/26, 84.6%, P = 0.06; 15/17, 88%, P = 0.06, respectively). 

Conclusions: Deciding on LTB prophylactic treatment in Israel is highly influenced by QFT-GIT test results. QFT-GIT findings contribute to clinical decisions, but their interpretation must also consider the patient’s medical history and clinical characteristics. 

 

Background: Dyspnea may be a presenting symptom of type I food hypersensitivity, and bronchial hyper-reactivity, without known asthma, can coexist in patients with food allergy.

Objective: To evaluate airway involvement in young adult patients with food allergy and no asthma and compare the findings to those of patients with food allergy and asthma, with food allergy and allergic rhinitis, with asthma and no food allergy, and of apparently healthy controls.

Methods: The evaluation involved prick skin test to food (65 allergens) and inhalants (24 allergens), spirometry, methacholine inhalation challenge, and induced sputum for cell analysis. The five groups consisted of 18 patients with food allergy alone, 11 with food allergy and asthma, 13 with food allergy and allergic rhinitis, 10 with asthma alone, and 10 controls.

Results: Patients with food allergy alone were mainly (86%) skin sensitive to pollens. Those with either asthma or allergic rhinitis were mainly (95%) sensitive to mites. BHR was detected in 40% of the patients with food allergy alone, 55% of the patients with allergic rhinitis, and 100% of the patients with asthma. Cell counts in the sputum of patients with asthma and in those with food allergy and asthma showed higher eosinophil counts compared to those with food allergy and allergic rhinitis. Patients with food allergy and no asthma, regardless of BHR status, had mainly neutrophils in the sputum.

Conclusions: Patients with food allergy are highly likely to have concomitant asymptomatic BHR. Mite sensitivity in patients with food allergy predicts respiratory allergy (either asthma or allergic rhinitis). High eosinophil levels in the sputum of food allergy patients predict respiratory involvement.

Background: The anti-inflammatory effect of montelukast, a leukotriene receptor antagonist, in patients with bronchial asthma is not entirely clear. Basophils can release a variety of mediators, including histamine and leukotriens, which most likely play an active part in the late allergic response.

Objectives: To study the effect of montelukast (10 mg/day) on histamine and cysteinyl leukotriene release from basophils taken from 12 mild atopic asthmatic patients who were given the drug for 4 weeks.

Methods: Basophils were withdrawn at baseline, and after 48 hours, 1 week, and 4 weeks of therapy. Histamine was measured by a radioenzymatic method and leukotrienes by immunologic assay. Histamine and cysLT release was measured spontaneously and following stimulation with interleukin-3 and anti-immunoglobulin E. Spirometry and symptom score were measured before and during treatment.

Results: During the treatment with montelukast there were no significant changes in spontaneous, IL-3 and anti-IgE‑induced histamine release. cysLT release decreased significantly only after 4 weeks of treatment (from 2899 ± 550 pg/ml at baseline to 2225 ± 430 pg/ml at 4 weeks, P = 0.02).

Conclusions: Montelukast does not seem to affect the release of histamine from basophils but mildly inhibits the cysLT release seen after 4 weeks of treatment.

Background: It has been argued that arginine replacement in locus16 (Arg16) of ß₂ adrenergic receptor with glycin (Gly16) increases asthma severity, while glutamin replacement in locus 27 (Gln27) with glutamic acid (Glu27) decreases it. In addition, ethnic dependency of these polymorphisms has been described, but few studies investigated its relation to asthma severity in a non-anglosaxic population.

Objectives: To investigate non-anglosaxic ethnic influences on ß₂AR[1] polymorphisms and its correlations to asthma severity.

Methods: Sixty-six Israeli Jewish and Arab asthmatics who had near-fatal asthma and/or severe nocturnal asthma and/or steroid-dependency were investigated for genetic polymorphisms of ß₂AR and compared to matched controls. The Jewish patients included both Ashkenazi (of East European origin) and non-Ashkenazi (originating from the Middle East or North Africa). The results were compared with those of ethnically matched 113 non-asthmatic Israelis, and of non-asthmatic Anglo-Saxons described in the literature.

Results: We found no significant genetic differences between the asthmatics and their controls or between the various ethnic groups of our population. However, the prevalence of Glu27 was significantly lower in non-asthmatic Israelis compared to non-asthmatic Anglo-Saxons.

Conclusions: The genetic distribution of ß₂AR polymorphisms in severe Israeli asthmatics is not different from that of non-asthmatic Israelis and therefore its clinical impact on asthma is probably minimal.

The induced sputum technique allows sampling of the airways in a non-invasive manner and thus offers a unique opportunity to identify biomarkers of potential clinical utility in respiratory medicine. Sputum cells were originally examined in stained smears and the procedure was applied in both research and clinical settings from the 1950s through the 1970s. The cells, recovered from spontaneous coughing, were used to study lung cancer and respiratory infections and, later on, to diagnose Pneumocystis carinii pneumonia in patients infected with human immunodeficiency virus. The method was largely improved by the induction of sputum with aerosol of hypertonic saline and was extended to become part of the assessment of airway inflammation in bronchial asthma and chronic obstructive pulmonary disease. It was recently shown that induced sputum can be used to study interstitial lung diseases and, more specifically, sarcoidosis, non-granulomatous ILD[1], occupational lung diseases and other systemic diseases with lung involvement.

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Background: Musculoskeletal complaints represent the second most common reason for visits to a physician, second only to the common cold. The limited capability of medical treatment for musculoskeletal disease requires modification of communication with patients by attending to their perception of the disease.

Objectives: To assess patients’ satisfaction with care provided by their primary physicians, and the relationship of patients' satisfaction to their expectations of that care, perceptions of physician performance, and perceived severity of musculoskeletal disease.

Methods: Questionnaires were administered to 90 community-dwelling elderly patients (mean age 76+-8 years) presenting for follow-up appointments with their primary care physicians. Patients were asked to report on their satisfaction with the medical care provided by the primary physicians for musculoskeletal symptoms, their expectations of that care, their perceptions of their primary physicians' interaction (regarding competence, performance, and communication), and their perceptions of disease severity (based on the number of areas involved, pain frequency and intensity, and impact on daily activity). The effects on the degree of satisfaction were assessed with regard to demographic variables, co-morbidity, site involved, and response to recommended treatment.

Results: Most patients (> 85%) expressed overall satisfaction with their doctor's interpersonal skills. Fewer (76.9%) were satisfied with the amount of effort their doctors spend evaluating their musculoskeletal symptoms, the information received regarding their musculoskeletal symptoms (75%), the degree of pain relief (75%), and the degree of functional improvement (61.8%). Level of education and response to recommended treatment for musculoskeletal disease were the only parameters associated with degree of satisfaction (higher education P = 0.005, lower education P = 0.059, medication P = 0.008, rehabilitation P = 0.076). A high level of expectations (regarding physician's care and musculoskeletal disease treatment) was noted.

Conclusions: The high level of patient satisfaction with their primary physicians' care for musculoskeletal symptoms may reflect the overall tendency of the elderly population to be satisfied with its primary care physicians. However, their high level of expectations (related to perceived efficacy of medical treatment) and their unrealistic perceptions of disease may lead to disappointment and non-compliance with their doctor's recommendations. Management of musculoskeletal disease in the elderly should address the patients’ disease perceptions, as well as their therapeutic and functional needs.
 

Background: Inflammatory mediators, including cytokines and reactive oxygen species. are associated with the pathology of chronic liver disease. Hepatocytes are generally considered as targets but not producers of these important mediators.

Objectives: To investigate whether cells of hepatocellular lineage are a potential source of various cytokines we estimated the expression and secretion of tumor necrosis factor alpha, transforming growth factor beta 1 and interleukins I beta, 6 and 8 in the culture of well-differentiated human HepG2 cells treated for 24 hours with ethanol, acetaldehyde and lipopolysaccharide. Lipid peroxidation damage, glutathione content and glutathione perox­idase, catalase and superoxide dismutase activity were also determined.

Methods: HepG2 cells were treated for 24 hours with ethanol (50 mM), acetaldehyde (175 ìM) and LPS (1 ìg/ml). TNF-á, TGF­-â, L-1â, IL-6 and IL-8 mRNA were determined by reverse transcriptase polymerase chain reaction and secretion by en­zyme-linked immunoassay. Lipid peroxidation damage, glutathione content and antioxidant enzyme activities were determined spectrophotometrically.

Results: Exposure to ethanol for 24 hours induced the expression of TNF-á and TGF- â1. secretion of IL-1â and TGF-â₁ and decreased catalase activity. Acetaldehyde markedly increased TNF-á and IL-8 expression, stimulated IL-1â and IL-8 secretion, increased lipid peroxidation damage and decreased catalase activity, while LPS exposure induced the expression of TNF-á. TGF- â₁, IL-6 and IL-8, the secretion of TGF-â₁, IL-1â, IL-6 and IL-8, and a decrease in catalase activity. No change in GSH, GSHPx or SOD was found in any experimental condition.

Conclusions: The present studies confirm and extend the notion that hepatocytes respond to ethanol, acetaldehyde and LPS-producing cytokines. Oxidative stress produced by the toxic injury plays an important role in this response through up­regulation of inflammatory cytokines.

Background: Both diagnostic and therapeutic options in the management of iatrogenic false aneurysms have changed dramatically in the last decade, with surgery being required only rarely.

Objective: To describe our experience, techniques and results in treating pseudoaneurysms at a large medical center with frequent arterial interventions. We emphasize upper limb lesions.

Materials and Methods: We reviewed the data of all consecutive patients diagnosed by color-coded duplex Doppler between August 1992 and July 1998 as having upper limb and lower limb pseudoaneurysms (mainly post- catheterization). We accumulated 107 false aneurysms (mainly post- catheterization lesions): 5 were upper limb lesions and 102 were groin aneurysms.

Results: In the lower limb cases 94 of the 102 lesions were not operated upon (92.1%). Seventy lower limb cases were treated non-operatively by ultrasound-guided compression obliteration with a 95.7% success rate (67 cases). Two cases were treated by  percutaneous thrombin injection (2%) and 23 by observation only (22.5%). Altogether 12 patients underwent surgery (11.2%): 4 upper extremity and 8 lower extremity cases. None of the lower limb group suffered serious complications regardless of treatment, but all five upper limb cases did, four of them necessitating surgical intervention. Three of the five upper limb cases had a grave outcome with severe or permanent or neurological damage.

Conclusion: Most post- catheterization pseudoaneurysms can be managed non-surgically. False aneurysms in the upper extremity are rare, comprising less than 2% of all lesions. However, upper extremity pseudoaneurysms present a potentially more serious complication and require early diagnosis and prompt intervention to minimize the high complication rate and serious long-term sequelae. Prevention can be achieved by proper puncture technique and site selection, and correct post-procedure hemostatic compression with or without an external device. Some upper limb lesions are avoidable if the axillary artery is not punctured.