Israel Medical Association Journal

Background: Immunoglobulin G4-related disease (IgG4-RD) is a chronic, immune-mediated condition characterized by fibro-inflammatory lesions with lymphoplasmacytic infiltration. Diagnosis traditionally relies on histopathological findings, including the presence of IgG4+ plasma cells. However, due to challenges in biopsy accessibility, additional measures are needed to facilitate diagnosis.

Objectives: To identify additional parameters for characterizing IgG4-RD patients.

Methods: We compared several circulating factors between a cohort of patients with IgG4-RD disease seen at our hospital between 2017 and 2023 and healthy controls.

Results: Among 16 suspected patients, 13 were confirmed to have IgG4-RD, and 3 were classified as highly likely. Comparison with controls revealed differences in white blood cell count (WBC) (Folf change (FC) 1.46, P < 0.05), plasmablasts (FC 3.76, P< 0.05), plasmablasts CD38 (FC 1.43, P < 0.05), and CD27 (FC 0.66, P = 0.054), thus highlighting potential markers for IgG4-RD diagnosis. Treatments with steroids/rituximab tend to reduce plasmablast (FC 0.6) and IgG4 (FC 0.28) levels and to increase Gal-3 levels.

Conclusions: Levels of plasmablasts are a significant diagnostic feature in IgG4-RD. Healthy individuals have a lower level of plasmablasts. Elevated Gal-3 in serum of patients with IgG4-RD suggests a role in plasmablast activation. CD38/CD27 expression by plasmablasts emerges as a potential marker. Further research on a larger cohort is needed to confirm these findings.

A 65-year-old male with a medical history of diabetes mellitus, chronic kidney failure, and ulcerative colitis arrived at our facility with knee monoarthritis. The knee was tapped with 40 cc pus-like discharge [Figure 1A]. He was referred for a knee lavage with a working diagnosis of septic arthritis. The patient was afebrile, denied trauma, without neutrophilia on blood count.

Background: Primary central nervous system lymphoma (PCNSL) is a rare aggressive non-Hodgkin's lymphoma. There are limited data on the management of PCNSL outside of clinical trials.

Objectives: To report experience with three main high-dose methotrexate (HDMTX)-based protocols for PCNSL treatment at one medical center.

Methods: We conducted a retrospective review of the medical records of patients diagnosed with PCNSL who were treated at Soroka Medical Center between 2007 and 2019.

Results: The study included 36 patients, median age 64.9 years; 33 patients received a HDMTX backbone induction therapy, 21 (58.3%) received consolidation treatment in addition. In the entire cohort, 25 patients (75.7%) achieved complete remission (CR, CRu-unconfirmed), with mean progression-free survival (PFS) 32 ± 6.9 months and median overall survival (OS) 59.6 ± 12.4 months. More aggressive regiment such as combination of rituximab, HDMTX, cytarabine and thiotepa had better responses 5 (100%) CR, but also a higher incidence of side effects such as neutropenic fever 5 (100%). In subgroup analysis by age (younger vs. older than 60 years), the PFS was 24.2 vs. 9.3 months, and OS was 64.1 vs. 19.4 months, respectively.

Conclusions: A difference in CR and PFS favored a more aggressive protocol, but the toxicity of the multiagent combinations was significantly higher. The prognosis in younger was better than in older patients, with higher rates of CR, PFS, and OS, although not statistically significant. Overall treatment outcomes are encouraging; however, there is a real need for an adaptive approach for older patients and balancing among the effectiveness and side effects.

Background: Laparoscopic removal of ovarian dermoid cysts has been associated with increased risk for recurrence.

Objectives: To investigate the risk factors associated with recurrence of dermoid cysts.

Methods: We conducted a retrospective review of all women who underwent cystectomy for ovarian dermoid cysts by laparoscopy or laparotomy. At discharge, patients were instructed to undergo a yearly ultrasound exam. A follow-up telephone call was conducted to assess whether an additional surgery for dermoid cysts was required and whether ultrasound recurrence of dermoid cysts was suspected.

Results: The study cohort included 102 participants (92 [90.2%] operated by laparoscopy and 10 [9.8%] by laparotomy). The mean follow-up from the index surgery to the interview was 72.1 ± 38.2 months. The rates of recurrent surgery were similar among women who underwent laparoscopic cystectomy compared with laparotomy (5/92 [5.4%] vs. 1/10 [10.0%], respectively; P = 0.5), while the rates of reported ultrasound recurrence were significantly lower in the laparoscopy group compared with the laparotomy group (10/102 [10.9%] vs. 4/10 [40.0%], respectively; P = 0.03). Additional factors including age, cyst diameter, diagnosis of torsion, intraoperative cyst spillage, estimated blood loss, intraperitoneal adhesions, and postoperative fever were not associated with recurrence.

Conclusions: Ultrasound recurrence of dermoid cysts is not uncommon and could be associated with the surgical approach.

Background: Acute appendicitis (AA) is one of the most common indications for emergency abdominal surgery.

Objective: To assess the diagnostic and prognostic value of serum bilirubin and liver enzyme levels in the management of acute appendicitis.

Methods: Consecutive emergency department patients referred for a surgical consult for suspected AA were prospectively enrolled in the study. Data regarding demographic, clinical and laboratory results were recorded. Receiver operating characteristic (ROC) curve was performed for all evaluated parameters. Clinical and laboratory markers were evaluated for diagnostic accuracy and correlation to the clinical severity, histology reports, and length of hospital stay.

Results: The study was comprised of 100 consecutive patients. ROC curve analysis revealed white blood cell count, absolute neutrophils count (ANC), C-reactive protein, total-bilirubin and direct-bilirubin levels as significant factors for diagnosis of AA. The combination of serum bilirubin levels, alanine transaminase levels, and ANC yielded the highest area under the curve (0.898, 95% confidence interval 0.835–0.962, P<0.001) with a diagnostic accuracy of 86%. In addition, total and direct bilirubin levels significantly correlated with the severity of appendicitis as described in the operative and pathology reports (P < 0.01). Total and direct bilirubin also significantly correlated with the length of hospital stay (P < 0.01).

Conclusions: Serum bilirubin levels, alone or combined with other markers, may be considered as a clinical marker for AA correlating with disease existence, severity, and length of hospital stay. These findings support the routine use of serum bilirubin levels in the workup of patients with suspected AA.

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: 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: In recent years, the role of intrapartum sonography has expanded in childbirth management, in subjective clinical situations such as arrested deliveries, or prior to instrumental deliveries.

Objectives: To assess the current use of intrapartum ultrasound by obstetricians in Israel.

Methods: An anonymous questionnaire was completed by 79 obstetricians in second- and third level- hospitals in Israel. The results were analyzed according to main subspecialty (sonography, delivery), experience and gender.

Results: A questionnaire was completed by 56 senior obstetricians and 23 interns with an average experience of 14.3 and 2.4 years, respectively. All obstetricians performed ultrasound examinations in the delivery room for basic indications such as fetal presentation during twin delivery and to rule out placenta previa. Sonographers consistently reported advanced indications as compared to senior members of delivery teams and interns in the assessment of prolonged first (52% vs. 14% vs. 14%) and second stage of labor (88% vs. 52% vs. 62%) and in assessment of fetal head station (60% vs. 30% vs. 22%), head progression during descent (48% vs. 23% vs. 11%), diagnosis of head position (88% vs. 68% vs. 60%), spine direction (92% vs. 59% vs. 53%) and asynclytism (41% vs. 20% vs. 29%).

Conclusions: Ultrasound is currently used by all physicians in the delivery room for basic indications. However, obstetric teams report a low use of advanced intrapartum ultrasound and prefer to rely on their clinical experience. Advanced intrapartum sonographic imaging should be an integral part of obstetric qualifications. A steep learning curve, along with high reproducibility, suggests that ultrasound devices will become a common tool in labor and delivery management.

Background: Stereotactic ablative radiation therapy (SABR) is the application of a very high radiation dose to a small treatment volume. It is the new standard of care in medically inoperable early-stage lung cancer. 

Objectives: To report the outcomes of SABR in stage I lung cancer at Sheba Medical Center since its introduction in 2009.

Methods: We conducted a retrospective chart review of patients with stage I lung cancer treated during the period 2009–2015. Survival status was retrieved from the electronic medical records and confirmed with the national registry. Local failure was defined as increased FDG uptake on PETCT scan within a 2 cm radius of the treated region. Toxicity was estimated from medical records and graded according to common toxicity criteria for adverse events (CTCAE) version 4.03. Overall survival and local control were estimated by the Kaplan-Meier method.

Results: During the study period 114 patients were treated for 122 stage I lung cancer lesions. Median follow-up time was 27 months (range 8.2–69.5 months), median age was 76 years. Eighty-two percent of the tumors were stage IA (size ≤ 3 cm). Median survival was 46 months; estimated 3 year overall survival was 59% (95%CI 47–69%) and local control was 88% (95%CI 78–94%). Toxicity included chest wall pain in 8.4% of patients, rib fracture in 0.9%, grade 1–2 pneumonitis in 12%, grade 3 in 12% and grade 5 (death) in 0.9%.

Conclusions: SABR has been successfully implemented at Sheba Medical Center for the treatment of stage I lung cancer in inoperable patients. It is associated with excellent local control, minor toxicity and an acceptable overall survival.

 

Background: Atherosclerosis is a systemic disease. Nevertheless, the role of specific biomarkers as indicators for both coronary and carotid diseases is debatable.

Objectives: To evaluate the association of biomarkers with coronary and carotid disease.

Methods: We studied 522 consecutive patients with stable angina. All underwent coronary angiography and carotid duplex study on the same day. Patients with no apparent carotid plaques were evaluated for carotid intima-media thickness (CIMT) using an automated system that sampled over 100 samples in each carotid artery. Biochemical markers of cardiovascular disease risk were obtained at the time of coronary angiography, including serum lipid levels, hemoglobin A1C (HbA1c), white blood cell count, fibrinogen and high sensitivity C-reactive protein (hs-CRP).

Results: The mean age of the patients was 66 ± 11; 73% were males. Significant carotid stenosis was associated with higher hs-CRP (9.4 ± 17 vs. 6.3 ± 13 mg/L, P = 0.001), while high HbA1c (6.7 ± 1.6 vs. 5.8 ± 0.8%, P < 0.001) and low high density lipoprotein levels (40 ± 9 vs. 47 ± 14 mg/dl, P < 0.001) were linked with advanced coronary artery disease severity. In contrast, CIMT was not related to any of the biomarkers evaluated.

Conclusions: Although atherosclerosis is considered a systemic disease, different biomarkers are associated with coronary and carotid artery disease. Identifying the specific biomarkers for each disease is important for both prevention and for exposing the underlying pathophysiologic mechanism.

 

Background: Intra-articular corticosteroid injection (IACI), a common procedure in juvenile idiopathic arthritis, is usually associated with anxiety and pain. In a previous study, we concluded that nitrous oxide (NO₂) provides effective and safe sedation for such procedures. Following the introduction of medical clowns in our hospital, we added them as an integral part of the team performing IACI.

Objectives: To prospectively evaluate the effect of a medical clown on pain perception during intra-articular corticosteroid injection for juvenile idiopathic arthritis using NO₂ conscious sedation.

Methods: Patients scheduled for IACI first met and interacted with the medical clown. During the procedure, the rheumatologist and the medical clown worked in parallel to create distraction. NO₂ was administered. The patient, parent, physician, medical clown and nurse completed a visual analog scale (0–10) for pain. Change in heart rate ≥ 15% was recorded to evaluate physiologic response to pain and stress.

Results: A total of 46 procedures were performed in 32 children: 23 girls, 9 boys, with a mean age of 10.9 ± 3.6 years. The median visual analog scale pain score for the patients, parents, physicians, medical clown and nurses was 2, 2, 1, 1 and 1, respectively. Five patients had increased heart rate and experienced increased pain.

Conclusions: Active participation of a medical clown during IACI with nitrous oxide for juvenile idiopathic arthritis further decreases pain and stress and results in a positive patient experience. 

Background: Claudication is one of the sequelae of peripheral arterial disease (PAD). To date, no effective treatment has been found for this condition.

Objectives: To investigate a new device to treat PAD. The device administers pre-programmed protocols of oscillations to the foot.

Methods: Fifteen patients aged 40–70 years who suffered from intermittent claudication secondary to PAD were recruited to an open prospective study. Each patient was treated once for 30 minutes. The following parameters were evaluated: pain-free and maximal walking distances, skin blood flux by laser-Doppler, skin temperature, ankle-brachial and toe-brachial indices, transcutaneous oxygen pressure (tcpO₂) and transcutaneous carbon dioxide pressure (tcpCO₂). Non-parametric signed-rank test was applied for testing differences between baseline assessment and post-treatment assessments for quantitative parameters.

Results: Mean pain-free walking distance was 122 ± 33 m and increased to 277 ± 67 m, after the treatment session (P = 0.004). Mean maximal walking distance was 213 ± 37 m and it increased to 603 ± 77 m (P < 0.001). Foot skin perfusion also improved, as demonstrated by an increase in tcpO₂ by 28.6 ± 4.1 mmHg (P < 0.001), a decrease in tcpCO₂ by 2.8 ± 1.3 (P = 0.032), and up to twofold improvement in blood flux parameters, and an increase in skin temperature by 1.9 ± 0.5°C (P < 0.001). Ankle-brachial index increased by 0.06 ± 0.01 (P = 0.003) and toe-brachial index by 0.17 ± 0.02 (P < 0.001).

Conclusions: Preprogrammed oscillations applied to the foot had a positive effect on microcirculation, tissue oxygenation and CO₂ clearance; they had a smaller though significant effect on arterial blood pressure indices, and the change in the arterial-brachial index correlated with the change in the pain-free walking distance.