Israel Medical Association Journal

Neuroendocrine tumors (NETs) are a group of rare, heterogenous neoplasms that maintain unique morphologic and clinical features of neuroendocrine neoplasia and account for approximately 0.5% of all newly diagnosed malignancies. NETs are divided into two groups based on their histopathological morphology: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Well differentiated NETs are classified as G1, G2, or G3 based on their proliferation rate, whereas NECs are highly proliferative and poorly differentiated by definition [1]. Neuroendocrine neoplasms can occur almost anywhere in the body; however, they are most often seen in the gastrointestinal tract, pancreas, and lungs [2]. The extrahepatic bile duct is one of the rarest primary sites for NETs, accounting for 0.1% to 0.2% of NETs of the gastrointestinal tract [3]. Signet ring cell bile duct NETs are extremely uncommon and have no established incidence and prognosis due to their rarity. There is sparse information available regarding these tumors, and only a few cases have been reported in the literature to date. In this report, we presented the clinical course and surgical management of a 31-year-old female patient with a Klatskin signet ring cell NET.

Biological therapies with monoclonal antibodies have revolutionized the management of many inflammatory and autoimmune diseases. Combining biological treatments is very rarely indicated and may theoretically result in severe adverse effects, specifically, an increased tendency toward infectious diseases. We present the case of a woman in whom combination therapy with canakinumab for familial Mediterranean fever (FMF) and mepolizumab for chronic eosinophilic pneumonia was successfully employed.

Germline pathogenic variants (PVs) in the RET proto-oncogene (OMIM 164761) are associated with a diverse phenotype based on the type of PV. Gain-of-function (GOF) PVs are associated with the highly penetrant multiple endocrine neoplasia type 2 (MEN2-OMIM 171400), which are hallmarked by an increased risk for developing medullary thyroid cancer (MTC), pheochromocytoma, and parathyroid adenomas. Loss-of-function (LOF) RET PVs are associated with incompletely penetrant Hirschsprung's disease (HSCR OMIM 142623), which are pathologically characterized by the absence of enteric ganglia affecting the distal colon and clinically manifest as neonatal intestinal obstruction. Despite anecdotal reports of familial clustering of neoplasms in HSCR families, mostly MEN2-associated tumors [1,2], HSCR is not considered to be associated with an increased risk for developing cancer [3]. We report on a family with an unusual multigenerational solid tumor phenotype and severe HSCR phenotype with a LOF RET PV.

Familial spastic paraparesis is a non-progressive disorder. However, clinical experience shows that after trauma, disease, surgery, or limb fracture that force a patient's long immobilization, a significant functional deterioration is observed. I describe two patients with Silver syndrome who experienced such functional deterioration after sustaining a simple fracture. A description of Silver syndrome and a biographical sketch of Dr. Silver, who explained the disorder in 1966, are given.

Background: Massive, non-compressible bleeding is a leading cause of preventable trauma mortality. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is a minimally invasive procedure in which a balloon catheter is maneuvered into the aorta to temporarily occlude large vessels and enable stabilization of the exsanguinating patient.

Objectives: To present experiences in assimilating REBOA at a single level 1 trauma center in Israel, to evaluate the technical aspects of the procedure, and to describe patient characteristics and outcomes.

Methods: This retrospective cohort study comprised civilians admitted with hemorrhagic shock to our trauma department who were treated with REBOA between November 2017 and July 2021. Descriptive statistics of the patients, characteristics of the injuries and patient outcomes are presented.

Results: The study included 22 patients (median age 30.1 years, 21 male). The mean systolic blood pressure (SBP) before REBOA inflation was 59.6 ± 11.4 mmHg, and the mean SBP measured after the procedure was 115.2 ± 26.3 mmHg. In 20 patients (91%), the SBP was normalized (> 90 mmHg) shortly after inflation of the balloon, and they survived the treatment in the trauma department; 15 (75%) survived the first 30 days. 

Conclusions: REBOA is an effective method for the initial resuscitation and hemorrhage control of patients with massive, non-compressible bleeding and is relatively easy to assimilate in a hospital. The achievement of immediate normalization of SBP enables medical personnel to correct physiological parameters and obtain accurate imaging before proceeding to the operating theater. 

Background: Severe asthma affects up to 20,000 citizens of Israel. Novel biological therapies, which individually have been proven to reduce asthma morbidity in clinical trials, have become available in recent years. Comparative data among different drugs are scarce.

Objectives: To describe and compare the clinical outcomes of biological therapies in severe asthma patients treated at Shamir Medical Center.

Methods: We conducted a cohort study based on a review of cases treated with monoclonal antibodies for severe asthma at our center. Data were extracted for demographics, eosinophil count, lung function (FEV1), exacerbation rate, and median dose of oral prednisone. Between-drug comparison was conducted by repeated measures ANOVA.

Results: The cohort included 62 patients receiving biological therapy. All biologic drugs were found to reduce exacerbation rate [F(1, 2) = 40.4, P < 0.0001] and prednisone use [F(1, 4) = 16, P < 0.001] significantly. ANOVA revealed no difference of efficacy endpoints between the different drugs. Eosinophil count was significantly reduced post-biologic treatment in the anti-interleukin-5 agents (P < 0.001) but not under treatment with omalizumab and dupilumab.

Conclusions: All of the biological therapies were effective for improving clinical outcomes. None of the agents was clearly superior to any other. These data emphasize the need for severe asthma patients to be seen by pulmonary medicine specialists and offered, where appropriate, biological therapies.

Background: Data regarding risk factors for superficial thrombophlebitis (STP) cases presenting to a hospital is limited.

Objectives: To investigate and stratify clinical and laboratory risk factors for STP

Methods: We conducted a retrospective case control study comparing patients presenting to the emergency department with STP and age- and gender-matched controls. We collected data on multiple risk factors and five blood indices.

Results: The study comprised 151 patients and matched controls. Patients with STP were more likely to have varicose veins (43.7% vs. 5.3%, P < 0.001), recent immobilization (14.6% vs. 1.3%, P < 0.001), obesity (36.4% vs. 18.5%, P = 0.001), a history of venous thromboembolism (VTE) or STP (27.2% vs. 0.7%, P < 0.001), and inherited thrombophilia (9.3% vs. 1.3%, P = 0.002). Following multivariate analysis, all five risk factors remained significant, with a history of VTE or STP associated with the largest risk (odds ratio [OR] 35.7), followed by immobilization (OR 22.3), varicose veins (OR 12.1), inherited thrombophilia (OR 6.1), and obesity (OR 2.7). Mean platelet volume was higher (8.5 vs 7.9 fl, P = 0.003) in STP cases.

Conclusions: A history of VTE or STP, immobilization, varicose veins, inherited thrombophilia, and obesity serve as independent clinical risk factors for STP presenting to hospital.

Hypereosinophilia is defined as the absolute eosinophilic count of above 1500 cells/µL in the peripheral blood on two separate tests taken during one month and/or the pathological confirmation of hypereosinophilia. There are many conditions that are associated with increased eosinophil counts including: parasitic infections, drug reactions, eosinophilic granulomatosis with polyangiitis, allergic reactions, drug reaction with eosinophilia and systemic symptoms (DRESS), primary immunodeficiencies (PID), eosinophilic gastrointestinal diseases (EGID), familial hypereosinophilia, and neoplasms [1]. Molecular classification may be an adjuvant in the classification of hypereosinophilia [2]. Our patient presented with hypereosinophilia as part of a paraneoplastic syndrome.

Background: The hepatobiliary system is a sterile micro-environment. Bacterial infection in this system is most commonly associated with anaerobes as well as gram-positive and gram-negative bacteria. Biliary infections with Staphylococcus aureus are poorly characterized.

Objectives: To depict the clinical characteristics and outcome of patients with S. aureus infection of the hepatobiliary system.

Methods: Medical records of patients with bile cultures positive for S. aureus from January 2006 to November 2020 were extracted from the computerized database of a hospital in Israel.

Results: We analyzed the results of 28 cases that were found in the database. The mean age of study patients was 62.2 ± 19 years. Hypertension, dyslipidemia, chronic kidney disease, diabetes, and benign prostatic hypertrophy were the most common co-morbidities (57.1%, 32.1%, 25%, 25%, and 25%, respectively). Fourteen of the methicillin-resistant S. aureus (MRSA) bile cultures (82.3%) were a result of primary S. aureus biliary infections (no other source for S. aureus infection) and the remainder were of a secondary infection. Eight of the MRSA cultures (47.1%) were from hospital acquired infections. Increased hospital mortality in patients with S. aureus hepatobiliary infection was associated with hypertension (P = 0.04), bedridden status (P = 0.01), and nursing home residence (P = 0.003).

Conclusions: Hepatobiliary infection with S. aureus can manifest in a variety of ways. S. aureus should be especially considered in patients who are bedridden, present with hypertension, or live in nursing homes because of their association with in-hospital mortality resulting from this entity.

Background: Patients with autoimmune disease (AID) and coronavirus disease 2019 (COVID-19) could have higher mortality due to the co-morbidity and the use of immunosuppressive therapy.

Objectives: To analyze the risk factors and outcomes of patients with AID and COVID-19 versus a control group.

Methods: A prospective cohort study included patients with and without AID and COVID-19. Patients were paired by age and sex. Clinical, biochemical, immunological treatments, and outcomes (days of hospital stay, invasive mechanical ventilation [IMV], oxygen at discharge, and death) were collected.

Results: We included 226 COVID-19 patients: 113 with AID (51.15 ± 14.3 years) and 113 controls (53.45 ± 13.3 years). The most frequent AIDs were Rheumatoid arthritis (26.5%), systemic lupus erythematosus (21%), and systemic sclerosis (14%). AID patients had lower lactate dehydrogenas, C-reactive protein, fibrinogen, IMV (P = 0.027), and oxygen levels at discharge (P ≤ 0.0001) and lower death rates (P ≤ 0.0001). Oxygen saturation (SaO₂) ≤ 88% at hospitalization provided risk for IMV (RR [relative risk] 3.83, 95% confidence interval [95%CI] 1.1–13.6, P = 0.038). Higher creatinine and LDH levels were associated with death in the AID group. SaO₂ ≤ 88% and CO-RADS ≥ 4 were risk factors for in-hospital mortality (RR 4.90, 95%CI 1.8–13.0, P = 0.001 and RR 7.60, 95%CI 1.4–39.7, P = 0.016, respectively). Anticoagulant therapy was protective (RR 0.36, 95%CI 0.1–0.9, P = 0.041)

Conclusions: Patients with AID had better outcomes with COVID-19 than controls. Anticoagulation was associated with a lower death in patients with AID.

Background: Solid organ transplant recipients (SOTRs) are at increased risk for both skin and internal malignancies (IM). The risk of IM after the occurrence of non-melanoma skin cancer (NMSC) has been studied in the general population but very little is known about this association in SOTRs.

Objectives: To evaluate the risk of IM following a prior diagnosis of post transplantation NMSC in SOTRs.

Methods: This single center retrospective cohort study included a study population of 329 SOTRs from Rabin Medical Center who had a post-transplant diagnosis of skin malignancy, internal malignancy, or both from 2012 to 2018.

Results: In total, 135 (41.03%) SOTRs were diagnosed with IM without a preceding diagnosis of NMSC while only 42 (12.76%) patients diagnosed with IM had a preceding diagnosis of NMSC. SOTRs with a diagnosis of NMSC showed a significantly decreased risk of developing subsequent IM (hazard ratio [HR] 0.64, 95% confidence interval [95%CI] 0.44–0.94, P = 0.02) compared to those without a prior NMSC diagnosis. Liver and lung transplant patients showed a significantly decreased risk of developing subsequent IM after a diagnosis of NMSC (HR 0.09 and 0.43, respectively). When stratified by type of IM, only patients who were diagnosed with a hematological malignancy had a significantly lower risk of developing this malignancy if they had a prior NMSC (HR 0.26).

Conclusions: The findings of this study suggest a protective effect of NMSC on subsequent IM in the organ transplant population.

Background: The coronavirus disease-2019 (COVID-19) pandemic had enormous impact on many aspects of our society, including huge medical, social, and economic challenges.

Objective: To evaluate the impact of the first wave of the COVID-19 pandemic and the related movement restrictions on the incidence of hip fractures in different age groups.

Methods: This single center retrospective observational study included all patients over 60 years old admitted to our hospital with the diagnosis of hip fracture during March and April 2020. Exclusion criteria were periprosthetic or pathologic fractures and multitrauma. We collected the same data on all patients with hip fractures admitted during March and April of 2018 and 2019.

Results: Mean patient age increased from 81.7 to 85.0 years. Only two of 49 patients tested positive for COVID-19. The data show a decrease of 38% in fracture load, but a striking decrease of 85% and 59% among sexagenarians and septuagenarian, respectively. There was no decrease among nonagenarians. Early mortality, both at 30 days and 90 days, was twice as common during the pandemic. However, stratification by age group demonstrated that the risks of early mortality were the same as previous years. Mean waiting time for surgery decreased from 27.5 to 18.9 hours. Patient discharge to home over a rehabilitation facility increased from 9% to 17%.

Conclusions: The COVID-19 pandemic affected the epidemiology of hip fractures in the elderly. The incidence of fractures and age distribution were significantly different from other years. Discharge destinations were also affected. The management of hip fracture patients was not compromised.

Background: Consent rates for organ donation remain one of the most important factors determining the number of organs available for transplantation. Trauma casualties constitute a substantial part of the deceased organ donor pool and have unique characteristics that distinguish them from the general donor population. However, this group has not been extensively studied.

Objectives: To identify donor factors associated with positive familial consent for solid organ donation among trauma casualties.

Methods: This retrospective study included all trauma casualties who were admitted to the Rabin Medical Center, Beilinson hospital, during the period from January 2008 to December 2017, who were potential organ donors. Data collected included demographic features, the nature of the injury, surgical interventions, and which organs were donated. Data was collected from the Rabin Medical Center Trauma Registry.

Results: During the study period 24,504 trauma patients were admitted and 556 died over their hospital course. Of these 76 were potential donors, of whom 32 became actual donors and donated their organs. Two factors showed a statistically significant correlation to donation, namely female gender (P = 0.018) and Jewish religion of the deceased (P = 0.032).

Conclusions: Only a small group of in hospital trauma deaths were potential solid organ donors (13.7%) and less than half of these became actual donors. Consent rates were higher when the deceased was female or Jewish

Background: Otogenic cerebral sinus vein thrombosis (CSVT) is a rare but severe complication of otitis media in children. To date, the role of prothrombotic evaluation is still controversial.

Objectives: To report the clinical manifestations, prothrombotic evaluation, and current management of CSVT.

Methods: We performed a retrospective study of nine pediatric patients with otogenic CSVT who underwent prothrombotic evaluation between 2008 and 2018.

Results: Prominent clinical features included persistent otorrhea (88.8%), signs of mastoiditis (88.8%), high fever ≥ 38.3°C (100%), a classic spiking fever pattern (55.5%), and neurological signs (55.5%). A subperiosteal abscess (66.6%) was the most common otitis media complication associated with mastoiditis and CSVT. No microorganism was identified in 55.5% of patients. Cultures collected from ear secretions had a low yield (6.25%). However, PCR assays had a high detection rate (100%; n=3). The prothrombotic evaluation demonstrated an abnormal LAC–dRVVT ratio (6/9), elevated Factor VIII (5/8) (and a combination of both in four patients), antiphospholipid antibodies (2/8), and high homocysteine levels (1/5).The surgical intervention of choice included one-sided mastoidectomy with myringotomy and ventilation-tube placement on the affected side (77.7%). There were no mortalities and no long-term sequela except chronic otitis media (22.2%).

Conclusions: Our findings demonstrate good outcomes for otogenic CSVT treatment with intravenous antibiotics, anticoagulation, and conservative surgical intervention, which supports the current trend in management. The prothrombotic evaluation revealed transient inflammation-related risk factors but did not alter management. Further prospective multicenter studies are needed to determine its relevance