Israel Medical Association Journal

Recurrent pericarditis is a state of repetitive inflammation of the pericardium with intervals of remission. The etiology of recurrent pericarditis is still largely unknown, yet most causes are presumed to be immune mediated. Genetic factors, including human leukocyte antigen (HLA) haplotypes, can be involved in dysregulation of the immune system and as a predisposition to several autoimmune conditions, including recurrent pericarditis. Several diseases are frequently associated with such manifestations. They include systemic lupus erythematosus, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. However, idiopathic recurrent pericarditis remains the most frequently observed clinical condition and the conundrum of this disease still needs to be solved.

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: 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: The MitraClip procedure is becoming an acceptable alternative for high-risk patients with mitral regurgitation (MR) due to functional (FMR) or degenerative (DMR) disease and suitable mitral anatomy.

Objectives: To evaluate the results of MitraClip at our institute in carefully selected patients.

Methods: We conducted a retrospective analysis of medical records and echocardiography data from January 2012 to December 2017.

Results: A total of 39 MitraClip procedures in 37 patients (aged 75 ± 12 years, 9 women) was performed. Twenty-four patients presented with FMR, 12 with DMR, and 1 with combined pathology. One-day post-procedure MR was moderate to low in 86.1% of patients, with immediate device success in 88.8%. MR at 1 year was moderate to low in 79% at 1 year. Survival at 1 year was 86% and at 2 years 69.4%. Peri-procedural (< 1 week) death and MitraClip failure occurred in one and three patients, respectively. New York Heart Association score improved to class 1 or 2 in 37% of patients at 1 year vs. one patient at baseline. Post-procedural systolic pulmonary pressure was reduced from 53 (range 48–65) to 43 (range 36–52) mmHg at 1 month with a subsequent plateau at follow-up, to 41 (34–57) mmHg at 6 months, and to 47 (38–50) at 12 months.

Conclusions: MitraClip in severe MR resulted in modest improvement in functional status and pulmonary pressure with a small risk of immediate procedural complications. Outcomes are encouraging considering the natural course of MR and the risks of surgical intervention.

Background: Access-site bleeding is a common complication of transfemoral transcatheter aortic valve implantation (TAVI). Percutaneous stent-graft implantation within the femoral artery may achieve hemostasis and avert the need for more invasive surgical vascular repair; however, failure to advance a guidewire antegradely via the injured vessel may preclude stent delivery. While retrograde stent-graft delivery from the distal vasculature may potentially enable percutaneous control of bleeding, this approach has not been reported.

Objectives: To assess the feasibility of a retrograde approach for stent-graft implantation in the treatment of access-site bleeding following transfemoral TAVI.

Methods: A prospective TAVI registry was analyzed. Of 349 patients who underwent TAVI, transfemoral access was used in 332 (95%). Access-site injury requiring stent-graft implantation occurred in 56 (17%). In four patients (7%), antegrade wiring across the site of vascular injury was not possible and a retrograde approach for stent delivery was used.

Results: Distal vascular access was achieved via the superficial femoral or profunda artery. Retrograde advancement of a polymer-coated 0.035” wire to the abdominal aorta, followed by stent-graft delivery to the common femoral artery, achieved hemostasis in all cases. During a median (interquartile range) follow-up period of 198 (618) days (range 46–2455) there were no deaths and no patient required additional vascular interventions.

Conclusions: A retrograde approach for stent-graft delivery is feasible and allows percutaneous treatment of a common femoral artery injury following TAVI in patients who are not suitable for the conventional antegrade approach.

Background: Methotrexate is the most frequently administered first-line treatment for rheumatoid arthritis (RA). The disease-modifying effects of methotrexate are mainly associated with enhanced release of free adenosine. The downstream anti-inflammatory effects of adenosine are mediated via its binding to adenosine receptor 2A (ADORA2A) and 3 (ADORA3). Many clinically important single nucleotide polymorphisms (SNPs) were reported in ADORA2A and ADORA3 genes.

Objectives: To investigate whether tagging ADORA2A and ADORA3 polymorphisms influences methotrexate treatment in RA.

Methods: In total, 212 RA patients treated with methotrexate were genotyped for tagging ADORA2A (rs2298383, rs8141793, rs2236624, rs5751876, rs35320474, and rs17004921) and ADORA3 SNPs (rs2298191, rs1544223, rs78594984, rs35511654, rs2229155, rs3393, and rs3394).

Results: RA patients who carried ADORA3 rs35511654 G allele showed a tendency toward better response to methotrexate treatment (P = 0.054). Carriers of ADORA2A polymorphic allele rs2298383 (P = 0.011), rs2236624 (P = 0.027), rs5751876 (P = 0.018), and rs35320474 (P = 0.026) were less likely to experience methotrexate induced adverse events. All associations remained significant after adjustment for clinical factors. The effects of these polymorphisms were also significant in haplotype analyses.

Conclusions: Polymorphisms in the ADORA2A gene may influence methotrexate treatment response and may be considered as a potential biomarker for methotrexate treatment in rheumatoid arthritis.

Background: Although women comprise only a minority of patients hospitalized due to violence-related injury, the circumstances of attacks against women may make their injuries more severe.

Methods: We conducted a retrospective study using data of 9173 patients with stabbing-related injuries from 19 trauma centers participating in the Israeli National Trauma Registry between 1 January 1997 and 31 December 2014. Male and female patients were compared in terms of demographic and circumstantial factors, clinical characteristics, and outcomes.

Results: Women were found to have greater injury severity according to the Injury Severity Scale (ISS) – 18% vs. 11% of severe (ISS 16+) injuries – requiring more hospital resources. Injuries that contributed most to injury severity in the female population were head and severe abdominal trauma. Women also sustained injuries to more body sites than men; however, regression analysis showed that the contribution of this factor to the overall difference in injury severity was less important than the injured sites. Regression analysis among severely injured patients pointed at injury to lower extremities as an independent factor related to female mortality. Different from men, among women the stabbing injuries to the upper extremities were not a protective factor in terms of mortality.

Conclusions: There are significant differences in the injury profiles of male and female stabbing victims, which can be explained by the different circumstances of the injury event.

Background: Gender differences in adolescent idiopathic scoliosis (AIS) have been documented in curve progression, response to bracing, and outcomes of surgical treatment. However, limited information is available about the relation between gender and scoliosis curve patterns and radiographical characteristics.

Objectives: To evaluate the effect of gender on curve pattern and compare clinical and radiographical characteristics between male and female patients with AIS.

Methods: We conducted a retrospective review of prospectively collected data that compared clinical and radiographical characteristics between male and female surgical candidates. Demographic and clinical data including age at presentation, gender, family history of scoliosis, brace treatment history, clinical coronal balance, shoulder asymmetry, and hump size were recorded. All patients graded their pain with the use of a visual analogue scale (VAS) on a scale from 0 to 10. Radiographs of the spine were reviewed to determine the type of curve according to the Lenke classification, Cobb angle, thoracic kyphosis angle, and the Risser sign. Radiologic coronal balance was recorded. Curve flexibility was determined by measuring the thoracic and lumbar curves magnitude on side bending radiographs

Results: The study included 163 patients with AIS including 35 males and 128 females patients. Although a trend toward more flexible major thoracic curves in females was noticed, there was no statistically significant difference between the 2 groups.

Conclusions: In this study we were not able to demonstrate any clinical nor radiological statistical differences between male and female patients who are candidate for surgical treatment.

Background: A history of childhood sexual abuse (CSA) has been linked to a variety of physical and psychiatric illnesses, including ischemic heart disease and post-traumatic stress disorder (PTSD).

Objectives: To determine the prevalence of past CSA and re-traumatization among hospital psychiatric consultations and to determine whether a CSA group in a hospital setting shared characteristics with community samples described in the literature.

Methods: We divided 228 consecutive psychiatric consultations into two groups. One group comprised patients with a past history of CSA while the other group had no such history. Both groups were further divided into a subgroup that presented with features of re-traumatization.

Results: In the cohort, 38% described a history of CSA. Twenty patients were identified as presenting with features of re-traumatization. There were significant differences between the two groups. The patients with a history of CSA were more likely to have arrived at the emergency department (ED) during the preceding 12 months with a diagnosis of PTSD, personality disorder, and substance use disorder. There was a greater proportion of patients in the CSA group who had grown up in an ultra-Orthodox Jewish household and who currently identified as being secular.

Conclusions: The characteristics of the patients with past CSA in this study are similar to community-based samples, except for a significant gender difference. To the best of our knowledge, this study is the first to investigate CSA history during hospital ED psychiatric consultations. A history of CSA should be considered during psychiatric consultations in a general hospital ED admission.

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: Unilateral renal agenesis is a rare finding. There are no large-scale studies reporting this finding in early pregnancy.

Objectives: To evaluate the incidence of unilateral renal agenesis (URA) and of associated anomalies diagnosed by early prenatal trans-vaginal sonography.

Methods: We performed a retrospective chart review of all 59,382 trans-vaginal scans performed at 14–16 weeks gestation by a single operator at different clinics during the period 1994–2013.

Results: The incidence of URA was 1:1212 (49/59382 cases). Associated anomalies were diagnosed in 22 cases (45%). Renal anomalies were diagnosed in 22.4%. Extra-renal anomalies (with exclusion of a single umbilical artery or nuchal edema as isolated findings) were diagnosed in 24.5%. Ambiguous genitalia were diagnosed in 8.2%.

Conclusions: URA is a rare finding in early trans-vaginal sonography. Associated anomalies are very common and should be sought.

Background: Burn injury pathophysiology is characterized by severe catabolic state and poor glycemic control. A tight glycemic control protocol using insulin for burn victims has yielded inconsistent mortality and morbidity outcomes.

Objectives: To compare the effect of standard and tight glycemic control protocols on mortality and hypoglycemia events in critical care burn patients.

Methods: We conducted a case-control study of burn victims admitted to the burn intensive care unit between 2005 and 2011. Patients were assigned to either a standard or a tight glycemic control protocol.

Results: Of the 38 burn patients in the study, 28 were under a tight glycemic control protocol. No differences in glucose area-under-the-curve per day levels were observed between the groups (148.3 ± 16 vs. 157.8 ± 16 mg/dl in the standard and tight glycemic control protocol groups respectively, P < 0.12). The hypoglycemic event rate was higher in the tight glycemic control protocol group (46.4% vs. 0%, P < 0.008). No difference in mortality rate was noted (67.9% vs. 50%, P < 0.31). Mortality-independent risk factors found on multivariate analysis included total body surface area (adjusted hazard ratio [AHR] 1.039, 95% confidence interval  [95%CI] 1.02–1.06, P < 0.001), white blood cell count on admission (AHR 1.048, 95%CI 1.01–1.09, P < 0.02) and surgery during hospitalization (AHR 0.348, 95%CI 0.13–0.09, P < 0.03).

Conclusions: The tight glycemic control protocol in burn patients was associated with higher rates of hypoglycemic events, and no association was found with improved survival in the acute setting of burn trauma care.