Israel Medical Association Journal

Background: Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of all non-Hodgkin lymphomas (NHL) and 80% of agressive lymphomas. Besides the traditional International Prognostic Index (IPI), some other factors may also influence the prognosis of DLBCL patients.

Objectives: To study how the genetic polymorphisms in the metabolic pathway influence the event-free and overall survivals and therapeutic responses in DLBCL.

Methods: The study was comprised of 51 patients (32 men, 19 women). The average age was 53.1 years. DLBCL was diagnosed between 2011 and 2016 and the average follow-up time was 3.78 years. These patients received 1–8 cycles (an average of 6.2 cycles) of rituximab, cyclophosphamide, doxorubicin, vincristin, prednisolon (R-CHOP) immunochemotherapy. Real-time polymerase chain reaction was used to determine the genetic polymorphisms of CYP2E1, GSTP1, NAT1, and NAT2 genes.

Results: Our results showed that the polymorphisms of CYP2E1, GSTP1, and NAT1 genes did not influence the prognosis of DLBCL patients significantly. In terms of the NAT2 gene, GG homozygous patients showed slightly better therapeutic response and survival results compared to those bearing an A allele; however, the differences were not statistically significant.

Conclusions: Our results could not confirm that genetic polymorphism in metabolic pathways has any predictive role in DLBCL. 

 

Background: Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights.

Objectives: To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries.

Methods: The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes.

Results: By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss > 7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH.

Conclusions: Recognition of C1-INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries.

Background: Circulating endothelial progenitor cells have an important role in the process of vascular repair. Impaired recruitment and function of endothelial progenitor cells is related to the pathophysiology of congestive heart failure. Endothelial progenitor cells have been shown to express the mineralocorticoid receptor. 

Objectives: To investigate the effect of mineralocorticoid receptor antagonists on endothelial progenitor cells in patients with heart failure. 

Methods: Twenty-four patients with compensated heart failure, who were not under mineralocorticoid receptor antagonist therapy, were recruited. Either eplerenone (n=8) or spironolactone (n=16) therapy was initiated. Circulating endothelial progenitor cell level, identified as the proportion of mononuclear cells expressing vascular endothelial growth factor receptor 2 (VEGFR-2), CD133, and CD34, was evaluated by flow cytometry at baseline and after 8 weeks. Following 7 days of culture, colonies were counted by microscopy and MTT assay was performed on randomly selected patients (n=12) to estimate viability.

Results: Both median CD34+/VEGFR2+ and median CD133+/VEGFR2+ increased significantly (P = 0.04 and 0.02, respectively). However, the number of colonies and viability of the cells after therapy (as assessed by the MTT assay) was not significantly different compared with the baseline. 

Conclusions: These preliminary results suggest that mineralocorticoid receptor blockade may enhance endothelial progenitor cells recruitment in patients with compensated heart failure.

Background: Chronic fatigue is common among patients with rheumatoid arthritis (RA), affecting quality of life. Osteoporosis is a prevalent co-morbidity in RA patients.

Objectives: To assess the effect of long-term treatment with tocilizumab on fatigue and bone mineral density (BMD) in RA patients with inadequate response to synthetic or biologic disease-modifying anti-rheumatic drugs. 

Methods: In this multicenter, open-label, non-controlled, single-arm study, patients ≥ 18 years of age received intravenous tocilizumab 8 mg/kg every 4 weeks for 96 weeks. The primary outcome was the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to weeks 24, 48, 72, and 96. BMD was assessed before and 96 weeks after treatment. 

Results: The study comprised 145 patients (mean age 53.4 ± 13.4 years, 83.4% women). Of these, 88 (60.7%) completed the 2 year treatment period. The mean FACIT-Fatigue score improved consistently starting from week 4 and showed a statistically significant increase of 5.0 ± 9.7, 6.8 ± 10.5, 7.3 ± 10.9, and 7.3 ± 10.4 from baseline to weeks 24, 48, 72, and 96, respectively (P < 0.0001). Mean BMD of femoral neck and total spine remained stable. Disease activity, acute phase reactants, and composite efficacy measures decreased during the study, while hemoglobin levels increased. Adverse events and serious adverse events were as expected for the known and previously described data.

Conclusions: Tocilizumab therapy for 2 years significantly and clinically decreased fatigue. BMD remained stable and no new safety issue was reported. 

 

Background: Previous studies have demonstrated the utility of exercise hemodynamics during right heart catheterization (RHC) in the diagnosis of diastolic dysfunction (DD). Little data exists regarding exercise hemodynamics during RHC in symptomatic systemic sclerosis (SSc) patients. 

Objectives: To assess the added diagnostic value of using exercise hemodynamics during RHC in assessment of patients with symptomatic SSc.

Methods: We performed 22 RHCs in 17 SSc patients with dyspnea and/or pulmonary arterial hypertension (PAH). Exercise was performed in 15 RHCs using isotonic arm exercises while holding a 1 kg weight in each hand. Measurements of pulmonary arterial pressure (PAP), pulmonary arterial wedge pressure (PAWP), and cardiac output (CO) were taken at rest and during peak exercise. 

Results: Normal resting RHC (PAP 22 ± 3 mmHg, PAWP 11 ± 3 mmHg) was found in seven cases. Of these, exercise induced elevation in PAP was found in three (38 ± 7 mmHg), and exercise induced elevation in PAWP was found in four (24 ± 6 mmHg). Elevated resting PAP was found in 15 (41 ± 11 mmHg) with minor changes in exercise. Of the 22 RHCs, elevation of the PAWP was found in 11 (50%), half of which were in response to exercise. 

Conclusions: In symptomatic SSc patients, exercise hemodynamics provides important information on diastolic dysfunction that is not available with non-invasive testing. Findings on exercise RHC can explain patient symptoms in up to 50% of cases. Earlier and more accurate diagnosis of patient symptoms can aid in tailoring the correct therapy for each.

Background: Male infertility is solely responsible for approximately 20% of all infertility in couples. Various factors have been proposed as having a negative effect on sperm quality; however, the reasons for the global decline in sperm parameters during the last few decades are still controversial. 

Objectives: To investigate the fluctuations of semen parameters (sperm concentration, motility, and morphology) in three sperm quality groups and to examine the trends of those parameters in the same men over time. 

Results: Our data showed deterioration in all semen parameters assessed in the group of men originally considered as having normal semen values according to the 2010 criteria of the World Health Organization. In contrast, we found significant improvement over time in all semen parameters in the group of men with severe oligo-terato-asthenozoospermia. 

Conclusions: Our results suggest that, although there were changes in sperm quality over time in the groups assessed, the clinical significance is negligible and does not necessarily justify a change in the therapeutic approach to infertility or sperm cryopreservation. 

 

Background: Right hydronephrosis secondary to acute appendicitis is an under-reported phenomenon with only several case reports published.

Objectives: To assess the incidence of this phenomenon in our database of patients diagnosed with acute appendicitis.

Methods: Data were collected on 1092 patients who underwent surgery due to acute appendicitis between 2003 and 2007 in our tertiary medical center. The data entailed demographic, surgical, and hospitalization parameters including ultrasound or computed tomography examinations and presence of right hydronephrosis prior to surgery.

Results: Out of 1092 patients, appendicitis was eventually diagnosed in 87.4% of the patients. Only 594 (54%) had preoperative imaging performed prior to surgery (ultrasound or computed tomography). Out of these 594 patients, 21 (3.5%) had a new right hydronephrosis diagnosed and all had appendicitis with 15/21 (71%) having a retrocecal appendix. Of those with retrocecal appendix, 10 were pregnant women (48%). Erythrocyturia was present in 15/21 patients (71%) and in 10/11 of patients (91%) after excluding those who were pregnant. No significant differences were seen in patients with hydronephrosis regarding age, hospitalization, and surgery time. In all patients, an ultrasound was performed 2 weeks after surgery demonstrating the disappearance of hydronephrosis. Median follow-up time was 41.7 months (range 14.8–118.4 months).

Conclusions: Our study shows that 3.5% of our cohort had right hydronephrosis secondary to acute appendicitis. Although this presentation is very rare, physicians should be aware of this phenomenon and the risk for delayed diagnosis and treatment of acute appendicitis.

Background: Controlled ovarian hyperstimulation (COH) followed by oocyte retrieval is a leading option for fertility preservation before chemotherapy, yet this procedure causes excessive serum levels of estradiol (E2), which are often detrimental for cancer patients. Aromatase inhibitors are often used in breast cancer patients during COH to prevent elevated levels of E2.

Objectives: To describe our experience with COH for oocyte cryopreservation in non-breast cancer patients using aromatase inhibitors.

Methods: Of the five patients treated, two had an aggressive abdominal desmoid tumor, one had endometrial carcinoma, one had uterine sarcoma, and one patient had a brain oligodendroglioma. In all cases the treating oncologist suggested an association between estrogen and possible tumor progression. All patients were treated with a standard in vitro fertilization antagonist protocol combined with aromatase inhibitors, similar to the protocol used for breast cancer patients.

Results: The average duration of treatment was 10.5 days, mean peak E2 was 2348 pmol/L, mean number of oocytes aspirated was 17.3, and a mean of 14.6 embryos/oocytes were cryopreserved.

Conclusions: COH with aromatase inhibitors is apparently effective in non-breast cancer patients and spares exposure to high E2 levels.

Background: Accurate pulse oximetry reading at hospital admission is of utmost importance, mainly for patients presenting with hypoxemia. Nevertheless, there is no accepted or evidence-based protocol for such structured measuring.

Objectives: To devise and assess a structured protocol intended to increase the accuracy of pulse oximetry measurement at hospital admission.

Methods: The authors performed a prospective comparison of protocol-based pulse-oximetry measurement with non-protocol based readings in consecutive patients at hospital admission. They also calculated the relative percentage of improvement for each patient (before and after protocol implementation) as a fraction of the change in peripheral capillary oxygen saturation (SpO₂) from 100%.

Results: A total of 460 patients were recruited during a 6 month period. Implementation of a structured measurement protocol significantly changed saturation values. The SpO₂ values of 24.7% of all study participants increased after protocol implementation (ranging from 1% to 21% increase in SpO₂ values). Among hypoxemic patients (initial SpO₂ < 90%), protocol implementation had a greater impact on final SpO₂ measurements, increasing their median SpO₂ readings by 4% (3–8% interquartile range; P < 0.05). Among this study population, 50% of the cohort improved by 17% of their overall potential and 25% improved by 50% of their overall improvement potential. As for patients presenting with hypoxemia, the median improvement was 31% of their overall SpO₂ potential.

Conclusions: Structured, protocol based pulse-oximetry may improve measurement accuracy and reliability. The authors suggest that implementation of such protocols may improve the management of hypoxemic patients.

Background: Sonographic assessment of the fetal kidneys is an integral part of the prenatal anatomical survey.

Objectives: To evaluate the fetal renal to abdominal (RTA) ratio throughout pregnancy and to investigate whether this ratio can be a potential diagnostic landmark for congenital anomalies of the kidney and urinary tract (CAKUT).

Methods: Measurements of the anterior-posterior diameters of the fetal kidney and fetal abdomen (APAD) were obtained prospectively. The RTA was calculated as the ratio between them in in two groups: normal population vs. CAKUT cases. RTA in CAKUT cases was compared to RTA in a normal population.

Results: The study group was comprised of 210 women. The mean gestational age for the fetuses was 31 ± 5.6 weeks (range 14–40 weeks). Fetal RTA ratio was found to be 0.28 ± 0.03 throughout pregnancy from early second trimester to term, with high reproducibility of measurements. During the study period the RTA was evaluated in nine cases referred for suspected CAKUT. All cases demonstrated a different ratio according to the renal anomaly. High ratio was observed in one case of overgrowth syndrome (Beckwith Wiedenmann syndrome; 0.47), three cases of infantile polycystic kidney (0.45–0.47), and three cases of a solitary kidney (0.31–0.35), while cases of dysplastic kidneys revealed a low ratio (0.14–0.18).

Conclusions: Prenatal RTA ratio is constant throughout gestation. An abnormal ratio should lead to meticulous renal investigation to rule out kidney disease.

Background: Previous surveys demonstrated variations in the clinical practices relating to the treatment and screening of maternal thyroid dysfunction.

Objectives: To study the current practices in the management of subclinical hypothyroidism (SCH) and thyroid nodules during pregnancy of obstetricians/gynecologists (OB/GYNs) and endocrinologists in Israel.

Methods: An electronic questionnaire was sent by email to all members of the Israeli Endocrine Society and the Israel Society of Obstetrics and Gynecology. Questionnaires included demographic data and clinical scenarios with questions regarding the screening and management of pregnant women with SCH, hypothyroxinemia, and a palpable thyroid nodule. The questionnaire for OB/GYNs was slightly modified.

Results: We received 90 responses from endocrinologists and 42 responses from OB/GYNs. Among endocrinologists, 39% would repeat a thyroid-stimulating hormone (TSH) test of 2.9 mU/L with normal free thyroxine and treat with thyroxine if the second result was above 2.5 mU/L. Among OB/GYNs, 73% would manage a woman with SCH at the beginning of her pregnancy by themselves and only 22% would start thyroxine after a first TSH result above 2.5 mU/L. Concerning screening, 57% endocrinologists and 71% OB/GYNs recommended screening for thyroid dysfunction in every woman at the beginning of her pregnancy. Among endocrinologists, 54% would order an ultrasound for a palpable thyroid nodule and perform a fine needle aspiration only for suspicious lesions.

Conclusions: The medical approach to thyroid disease in pregnant women remains a matter of controversy. Our results support the need for larger and prospective clinical studies.

Background: Coronary artery disease (CAD) has known risk factors. Individual risks related to specific ethnicities are complex and depend on genetic predisposition and lifestyle.

Objectives: To compare the nature and prevalence of risk factors in Arab and non-Arab ethnic patients with symptomatic obstructive CAD referred for coronary angiography.

Methods: CAD, defined as coronary angiography with a ≥ 50% narrowing in ≥ 1 vessel, was diagnosed in 1029 patients admitted to a medical center between April 2014 and October 2015. Patients were divided into two groups according to ethnic origin: Arab vs. non-Arab. Demographics, clinical presentation, and coronary risk profiles were compared.

Results: The diagnosis of CAD was made during ST-elevation myocardial infarction (STEMI) in 198 patients (19%) who arrived at the clinic, 620 (60%) with unstable angina/non-STEMI, and 211 (21%) with stable angina. Patients with symptomatic CAD and Arab ethnicity were 47% more prevalent than non-Arab patients presenting with CAD. The Arab patients were appoximately 5 years younger, 50% more likely to be active smokers, 25% more likely to be obese, and more likely to have a family history of CAD. Other coronary risk factors were similar between the two groups.

Conclusions: Smoking and obesity, which are potentially modifiable CAD risk factors, stood out as major risk factors, in addition to genetic disposition, among Arab and non-Arab patients with symptomatic CAD. Screening and educational interventions for smoking cessation, obesity control, and compliance to treatment of co-morbidities should be attempted in order to decrease CAD in the Arab population.