Israel Medical Association Journal

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.

A 26-year-old female at 28 weeks of gestation with her fourth pregnancy presented with a 24-hour history of diffuse abdominal pain and distension. In addition, she had nausea, vomiting, and constipation. The pain did not respond to analgesics. She had poor prenatal care during her pregnancy. She had previously had three cesarean deliveries. The first cesarean delivery was due to non-progressive second stage of labor, the second was preterm due to abdominal pain and suspected uterine rupture, and the last was due to the previous cesarean deliveries. In her last previous pregnancy, she presented with recurrent milder abdominal pain, which resolved spontaneously.

On examination, she was afebrile, with normal blood pressure and heart rate. Her abdomen was distended, tympanic, and mildly tender to palpation with no tenderness on the cesarean scar and no peritoneal signs. Her laboratory testing was normal except for mild hypokalemia.

Contactin associated protein-like 2 (CASPR2) and leucine-rich glioma-inactivated protein 1 (LGI1) voltage gated potassium channel (VGKC) proteins are found in both the central and peripheral nervous systems [1]. Antibodies against these proteins are associated with encephalopathy, seizures, peripheral nerve hyper-excitability, autonomic dysfunction, hyponatremia, pain, and insomnia in varying severity and combination [1].

Morvan syndrome, first described in 1890, combines symptoms of peripheral nervous system (PNS), central nervous system (CNS), and autonomic nervous system dysfunction. It was later found to be associated with VGKC-complex antibodies, mainly against CASPR2 or LGI1 or both.

Our patient had a history of anti-LGI1 positive limbic encephalitis, which presented years later with anti-CASPR2 positive Morvan syndrome.

Ruxolitinib is an inhibitor of the cytosolic tyrosine kinase Janus kinase (JAK) family of proteins (JAK1/2), which is widely used to treat various myeloid neoplasms that are characterized by constant activation of the JAK-STAT signaling pathway.

Many side effects are associated with ruxolitinib, including anemia, thrombocytopenia, increased rate of infections (especially herpes zoster), and mild hypercalcemia noted in 15.4% of patients [1]. The possible mechanism causing hypercalcemia may involve altered bone and mineral metabolism with secondary hyperparathyroidism, as described for other kinase inhibitors [2].

Background: Myalgic encephalomyelits/chronic fatigue syndrome (ME/CFS) is an acquired disease with symptoms of fatigue and pain. In pathogenesis, the induction of autoantibodies (AAB) against G-protein coupled receptors (GPCR), such as β-adrenergic receptors (β-AdR), has been suspected. GPCR-AAB correlate with symptom severity and autonomic dysfunction in ME/CFS.

Objectives: To describe symptoms and treatment of a patient presenting with infection-triggered ME/CFS demonstrating that levels of β-AdR-AAB underlie modulation over time, correlating with the severity of symptoms.

Methods: At T1 and T2, GPCR-AAB were measured and questionnaires assessing symptom severity were completed. TSHDS-IgM-AAB were tested, and SF density was analyzed via skin probe.

Results: At T2, elevated levels of β-AdR-AAB were found, corresponding with an aggravation of fatigue and pain symptoms. Elevated TSHDS-IgM-AAB were found, which corresponded with reduced fiber density from the skin probe.

Conclusions: The levels of β-AdR-AAB in post-infectious ME/CFS can be modulated. Future studies might target interventions to reduce these AAB.

Background: Cannabis consumption is suspected of causing arrhythmias and potentially sudden death.

Objectives: To investigate prevalence and temporal relationships between cannabis use and onset of symptomatic arrhythmias among cancer patients using Belong.life, a digital patient powered network application.

Methods: Real-world data (RWD) were obtained through Belong.Life, a mobile application for cancer patients who use cannabis routinely. Patients replied anonymously and voluntarily to a survey describing their demographics, medical history, and cannabis use.

Results: In total, 354 cancer patients (77% female, 71% 50–69 years of age) replied: 33% were smokers and 49% had no co-morbidities. Fifteen had history of arrhythmias and two had a pacemaker; 64% started cannabis before or during chemotherapy and 18% had no chemotherapy. Cannabis indication was symptom relief in most patients. The mode of administration included oil, smoking, or edibles; only 35% were prescribed by a doctor. Cannabis type was delta 9-tetrahydrocannabinol > 15% in 43% and cannabidiol in 31%. After starting cannabis, 24 patients (7%) experienced palpitations; 13 received anti-arrhythmic drugs and 6 received anticoagulation. Eleven needed further medical investigation. Three were hospitalized. One had an ablation after starting cannabis and one stopped cannabis due to palpitations. Seven patients (2%) reported brady-arrhythmias after starting cannabis, but none needed pacemaker implantation.

Conclusions: RWD showed that in cancer patients using cannabis, the rate of reported symptomatic tachy- and brady-arrhythmias was significant (9%) but rarely led to invasive treatments. Although direct causality cannot be proven, temporal relationship between drug use and onset of symptoms suggests a strong association.

Background: The two cerebral hemispheres influence the immune response differently. While the left hemisphere enhances cellular immunity, the right hemisphere inhibits it.

Objectives: To determine whether immune and inflammatory markers correlated with stroke severity and hospitalization duration as a function of stroke side.

Methods: The study included 137 patients with unilateral ischemic stroke. The medical records were reviewed for demographic and clinical laboratory data, including C-reactive protein (CRP), white blood cell (WBC) count, its differential stroke side and stroke severity according to the National Institute of Health Stroke Scale (NIHSS), and length of hospital stay (LOS). We examined differences between right side (RS) and left side (LS) stroke on immune and inflammatory markers and compared correlations between these markers and NIHSS and LOS as a function of stroke side.

Results: RS stroke patients had higher CRP and monocytes than LS stroke patients. In RS stroke patients, CRP, total WBC, and lymphocyte levels positively correlated with both NIHSS and LOS, whereas levels of neutrophils were positively correlated with NIHSS alone. No correlations were found for LS stroke patients.

Conclusions: Immune-inflammatory markers correlated with stroke severity and LOS only in patients with RS stroke. Neuroimmunological processes influence short-term clinical outcomes after stroke, especially considering the differential effects of the hemispheres on immunity. Prospective studies that evaluate long-term clinical outcomes are needed. Testing the effects of anti-inflammatory treatments on prognosis of RS stroke patients should be considered.

Background: Fibromyalgia syndrome (FMS) is estimated to affect 2–4% of the general population. While FMS has some known environmental and genetic risk factors, the disorder has no clear etiology. A common coexisting disorder with FMS is small fiber neuropathy (SFN). High levels of serum immunoglobulin M (IgM) binding to trisulfated-heparin-disaccharide (TS-HDS) were recently found to be associated with SFN.

Objectives: To evaluate potential differences in anti-TS-HDS antibody titers in women with FMS compared to healthy controls.

Methods: In this cross-sectional study, we evaluated 51 female participants: 30 with a diagnosis of FMS and 21 healthy controls who had been recruited at the Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Israel. All of the participants were older than 18 years of age. Anti-TS-HDS IgM levels were measured in their sera using the enzyme immunoassay technique.

Results: The mean anti-TS-HDS IgM levels were significantly lower in the FMS group, compared with the control group (7.7 ± 5 vs. 13.2 ± 8.6 U/ml, respectively; P = 0.013).

Conclusions: There is a possible association between FMS and anti-TS-HDS IgM. This association might be the missing link for the coexistence of SFN and FMS, but further study should be performed to assess this association and this auto-antibody characteristic.

Background: Bicalutamide monotherapy (BMT) is an option for androgen deprivation therapy (ADT) in patients with low- and intermediate-risk prostate cancer (LIR-PC). Painful gynecomastia (PG) is a common side effect of BMT. Few therapeutic options are available for preventing BMT-induced PG.

Objectives: To assess the efficacy and side effects of single fraction (SF) prophylactic breast irradiation (PBI) to prevent painful gynecomastia (PG) in patients LIR-PC treated with BMT.

Methods: We reviewed the results of bilateral PBI in a prospective cohort of LIR-PC patients who received 150 mg bicalutamide daily as a first-line treatment for at least 12 months. A single fraction of 8 Gy was administered to both breasts by a stationary field of 10 × 10 cm, using 10–15 MeV electron beam. PBI was commenced on the same day as BMT, but prior to the first dose of bicalutamide. A radiotherapy treatment plan was designed to cover breast tissue by the 90% isodose line. Subsequent monthly physical examinations were scheduled for all patients during the first year of BMT to evaluate any PG symptoms.

Results: Seventy-six patients received BMT and PBI, 80% (61/76) showed no signs of PG; 20% (15/76) experienced mild gynecomastia. The main adverse effect of PBI was grade 1 radiation dermatitis.

Conclusions: PBI using a SF of 8 Gy is an effective, safe, and low-cost strategy for the prevention of BMT-induced PG in LIR-PC patients.

Background: Acute coronary syndrome (ACS) represents a spectrum of ischemic myocardial disease including unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). Various prognostic scores were developed for patients presenting with NSTEMI-ACS. Among these scores, the GRACE risk score offers the best discriminative performance for prediction of in-hospital and 6-month mortality. However, the GRACE score is limited and cannot be used in several ethnic populations. Moreover, it is not predictive of clinical outcomes other than mortality.

Objective: To assess the prognostic value of traditional cardiovascular risk factors and laboratory biomarkers in predicting 6-month major adverse cardiac and cerebrovascular events (MACCE), including hospitalization, recurrent percutaneous coronary intervention (PCI), stroke, and cardiovascular mortality in patients with NSTEMI treated with PCI.

Methods: This retrospective study included consecutive patients admitted with an initial diagnosis of NSTEMI to the cardiac intensive care unit (CICU) at the Tzafon Medical Center, Israel, between April 2015 and August 2018 and treated by PCI within 48 hours of admission.

Results: A total of 223 consecutive patients with NSTEMI treated by PCI were included in the study. Logarithm_ebrain natriuretic peptide (LogₑBNP), prior MI, and Hb levels were found to be significant predictors of any first MACCE. Only logₑBNP was found to be an independent predictor of a first MACCE event by multivariate logistic regression analysis.

Conclusions: LogₑBNP is an independent predictor of worse prognosis in patients with NSTEMI. Routine evaluation of BNP levels should be considered in patients admitted with NSTEMI.

Background: Despite its wide use, evidence is inconclusive regarding the effect of percutaneous endoscopic gastrostomy (PEG) in patients with chronic diseases and dementia among hospitalized patients with malnutrition.

Objectives: To examine the effect of PEG insertion on prognosis after the procedure.

Methods: This retrospective analysis of medical records included all adult patients who underwent PEG insertion between 1 January 2009 and 31 December 2013 during their hospitalization. For each PEG patient, two controls similar in age, sex, referring department, and underlying condition were randomly selected from the entire dataset of patients admitted. The effect of PEG on mortality and repeated admissions was examined.

Results: The study comprised 154 patients, 49 referred for PEG insertion and 105 controls (mean age 74.8 ± 19.8 years; 72.7% females; 78.6% admitted to internal medicine units). Compared to controls, the PEG group had a higher 2-year mortality rate (59.2% vs. 17.1%, P < 0.001) but the 2-year readmission rate did not differ significantly (44.9% vs. 56.2% respectively, P = 0.191). Regression analysis showed PEG was  associated with increased risk of the composite endpoint of death or readmission (hazard ratio 1.514, 95% confidence interval 1.016–2.255, P = 0.041). No specific characteristic of admission was associated with increased likelihood of death or readmission. Among readmitted patients, reasons for admission and baseline laboratory data, including albumin and cholesterol, did not differ between the PEG patients and controls.

Conclusions: In-hospital PEG insertion was associated with increased mortality at 2 years but had no effect on readmissions.

Background: Clinical investigations of long-term effects of coronavirus disease 2019 (COVID-19) are rarely translated to objective findings.

Objectives: To assess the functional capacity of individuals reported on deconditioning that hampered their return to their pre-COVID routine.

Methods: Assessment included the 6-minute walk test (6MWT) and the 30-second sit-to-stand test (30-STST). We compared the expected and observed scores using the Wilcoxon signed-rank test. Predictors of test scores were identified using linear regression models.

Results: We included 49 individuals, of whom 38 (77.6%) were recovering from mild COVID-19. Twenty-seven (55.1%) individuals had a 6MWT score lower than 80% of expected. The average 6MWT scores were 129.5 ± 121.2 meters and 12.2 ± 5.0 repeats lower than expected scores, respectively (P < 0.001 for both). The 6MWT score was 107.3 meters lower for individuals with severe COVID-19 (P = 0.013) and rose by 2.7 meters per each 1% increase in the diffusing capacity of carbon monoxide (P = 0.007). The 30-STST score was 3.0 repeats lower for individuals who reported moderate to severe myalgia (P = 0.038).

Conclusions: Individuals with long COVID who report on deconditioning exhibit significantly decreased physical capacity, even following mild acute illness. Risk factors include severe COVID-19 and impaired diffusing capacity or myalgia during recovery.

Background: Acute appendicitis (AA) is a medical emergency. The standard of care for AA had been surgical appendectomy. Recently, non-operative management (NOM) has been considered, mainly for uncomplicated AA.

Objectives: To evaluate AA NOM trends over two decades.

Methods: We conducted a retrospective cohort study based on Israel’s National Hospital Discharges Database (NHDD). Inclusion criteria were AA admissions from 1 January 2000 to 31 December 2019, with either primary discharged diagnosis of AA, or principal procedure of appendectomy. Predefined groups were children (5 ≤ 18 years) and adults (≥ 18 years). We compared the last decade (2010–2019) with the previous one (2000–2009).

Results: The overall AA incidence rate over two decades was 126/100,000/year; higher in children 164/100,000/year than 113/100,000/year in adults. Surgery was the predominant AA treatment in 91.9%; 93.7% in children and 91.1% in adults. There was an increase in AA NOM rates when comparing the previous decade (5.6%) to the past decade (10.2%); 3.2% vs. 9.1% in children and 6.8% vs. 10.7% in adults, respectively. Annual trends revealed a mild increase in AA NOM rates. Delayed appendectomy (within 90 days of AA NOM) was 19.7% overall; 17.3% in adults and 26.3% in children.

Conclusions: There was an increase in AA NOM rates during the last decade in the overall population. Since 2015, there has been a noticeable increase in AA NOM rates, probably associated with World Society of Emergency Surgery Jerusalem guidelines. Surgery is still the predominant treatment for AA despite the increasing trend in NOM.

Background: Anal squamous cell carcinoma (ASqCC) is a rare malignancy, traditionally treated with combined chemoradiation, with a continuous infusion of 5-fluorouracil (5-FU) and mitomycin C (MMC). Replacing intravenous (IV) 5-FU with oral capecitabine (oral fluoropyrimidine) has been reported as a non-inferior treatment option. However, these data are scarce, with variable results.

Objectives: To examine the outcome of patients with ASqCC treated with either IV 5-FU or capecitabine concomitantly with radiation therapy. To compare treatment side effects, local recurrence, and general outcome.

Methods: We reviewed charts of patients who were diagnosed with stage I–III ASqCC. All participating patients received chemoradiation at the Assuta Medical Center between 2011 and 2019.

Results: In this study, 43 patients with ASqCC were eligible; 14 received 5-FU and 29 were treated with capecitabine. Basic characteristics were similar between the two groups, with longer follow-up for the 5-FU group. Six months following treatment, 100% (13/13 with adequate follow-up) of the 5-FU group had complete clinical response, compared to 84% in the capecitabine group (21/24), P = 0.143. The local recurrence incidence was higher in the 5-FU group at 23% (7, 10, 26 months following therapy, and none in the capecitabine group (P = 0.088). Although local and hematological toxicities were similar between groups, one patient receiving capecitabine died during chemoradiotherapy.

Conclusions: Oral capecitabine demonstrated non-inferior disease control in ASqCC treated with chemoradiotherapy. We recommend oral capecitabine over continuous IV 5-FU in locally and locally advanced ASqCC. Close monitoring of side effects is required to reduce major toxicity.

Background: Omega-3 fatty acids promote fertility in males and females and constitute an important factor in the normal development of the fetus.

Objectives: We investigated the effect of omega-3 supplements during ovulation induction treatment in women with polycystic ovary syndrome (PCOS)-related infertility.

Methods: A randomized, double-blind study was conducted for 60 treatment cycles in 34 women with PCOS-related oligo/anovulation referred to the fertility clinic at the Bikur Cholim/Shaare Zedek Medical Center in Jerusalem, who underwent ovulation induction with clomiphene citrate (50 mg). Seventeen women (mean age 33.9 ± 0.9 years) received omega-3 supplements (3 × 600 mg/day) and 17 received placebo capsules (mean age 32.7 ± 0.9 years) for a maximum of two cycles. We recorded their characteristics and data from their serial hormonal blood tests and ultrasound examinations. We also conducted both univariate and multivariate analyses. The primary endpoint was conception.

Results: There were clinical pregnancies in 8/30 (26.7%) treatment cycles for women receiving omega-3 supplements versus 4/30 (13.3%) cycles with placebo. Among overweight/obese women (body mass index [BMI] 25–35), there were clinical pregnancies in 8/27 cycles (29.6%) versus 1/19 (5.3%) with placebo (P < 0.04). For overweight/obese PCOS women, omega-3, lower BMI rates, and higher values of the endometrium’s thickness increased the odds of becoming pregnant. No harmful side effects from the omega-3 treatment were reported.

Conclusions: Omega-3 supplements demonstrated beneficial effects for fertility in women diagnosed with PCOS. Among the overweight/obese participants, the increased clinical pregnancy rate was significant.