Israel Medical Association Journal

Background: Male breast cancer (MBC) is a rare disease that is poorly understood. Treatment protocols are widely extrapolated from breast cancer in women.

Objectives: To review the experience with MBC of a single center in Israel over a period of 22 years.

Methods: This single center retrospective study evaluated all patients diagnosed with MBC over a period of 22 years (1993–2015). Data were extracted from patient medical charts and included demographics, clinical, surgical, and oncological outcomes.

Results: The study comprised 49 patients. Mean age at diagnosis was 64.1 ± 13.5 years. The majority were diagnosed at early stages (1A–2A) (54.4%), 30.6% were stage 3B mostly due to direct skin and nipple involvement, and 59.2% of the patients had node negative disease. All of the patients were diagnosed with invasive ductal carcinoma and 30.6% had concomitant ductal carcinoma in situ. Estrogen receptor (ER) status was predominantly positive and luminal B (HER2-) was the most common subtype. Of the patients, 18.4% were BRCA carriers. The majority of patients underwent mastectomy. Radiotherapy was delivered to 46.9% and hormonal therapy to 89.8%. Chemotherapy was administered to 42.9%. Overall survival was 79.6% with a median survival of 60.1 (2–178) months; 5- and 10-year survival was 93.9% and 79.6%, respectively. Progesterone receptor (PR)-negative patients had a significantly improved overall survival.

Conclusions: MBC has increasing incidence. PR-negative status was associated with better overall survival and disease-free interval. Indications to radiotherapy and hormonal therapy need standardization and will benefit from prospective randomized control trials.

Background: The treatment of elderly patients with advanced stage ovarian carcinoma is challenging due to a high morbidity.

Objective: To evaluate the clinical course and outcome of elderly patients with advanced stage ovarian carcinoma receiving neoadjuvant chemotherapy (NACT).

Methods: A retrospective study of all patients with stage IIIC and IV ovarian carcinoma receiving NACT in one medical center (between 2005 and 2017). The study group criteria age was above 70 years. The control group criteria was younger than 70 years old at diagnosis. Demographics and treatment outcomes were compared between groups. Primary outcomes were progression-free survival (PFS) and overall survival (OS).

Results: Overall, 105 patients met the inclusion criteria, 71 patients (67.6%) were younger than 70 years and 34 patients (32.4%) older. Rates of interval cytoreduction were significantly higher in younger patients (76.1% vs. 50.0%, P = 0.01). Of those who underwent interval cytoreduction, no difference was found in rates of optimal debulking between groups (83.35% vs. 100%, P = 0.10). Using a Kaplan-Meier survival analysis, no significant differences were observed between groups in PFS or OS, P > 0.05. Among the elderly group alone, patients who underwent interval cytoreduction had significantly longer PFS than those without surgical intervention (0.4 ± 1.7 vs. 19.3 ± 19.4 months, P = 0.001).

Conclusions: Elderly patients with ovarian carcinoma who received NACT undergo less interval cytoreduction than younger patients, with no difference in PFS and OS. However, among the elderly, interval cytoreduction is associated with significantly higher PFS.

Background: Patients with right bundle branch block (RBBB) prior to transcatheter aortic valve implantation (TAVI) are at high risk for immediate post-procedural heart block and long-term mortality when discharged without a pacemaker.

Objectives: To test whether prophylactic permanent pacemaker implantation (PPI) is beneficial.

Methods: Of 795 consecutive patients who underwent TAVI, 90 patients had baseline RBBB. We compared characteristics and outcomes of the prophylactic PPI with post-TAVI PPI. Need for pacing was defined as  greater than 1% ventricular pacing.

Results: Forty patients with RBBB received a prophylactic PPI (group 1), and in 50 the decision was based on standard post-procedural indications (group 2). There were no significant differences in clinical baseline characteristics. One patient developed a tamponade after a PPI post-TAVI. A trend toward shorter hospitalization duration in group 1 patients was observed (P = 0.06). On long-term follow-up of 848 ± 56 days, no differences were found in overall survival (P = 0.77), the composite event-free survival of both mortality and hospitalizations (P = 0.66), or mortality and syncope (P = 0.65). On multivariate analysis, independent predictors of the need for pacing included baseline PR interval increase of 10ms (odds ratio [OR] 1.21 per 10 ms increment 95% confidence interval [95%CI] 1.02–1.44, P = 0.028), and the use of new generation valves (OR 3.92, 95%CI 1.23–12.46, P = 0.023).

Conclusions: In patients with baseline pre-TAVI RBBB, no outcome differences were found with prophylactic PPI. On multivariate analysis, predictors of the need for pacing included baseline long PR interval, and the use of newer generation valves.

Background: The use of graphic depictions (pictorials) to represent medical conditions is an accepted method that can complement standard methodology of comprehensive geriatric assessment.

Objectives: To use the clinical pathway method to develop a comprehensive geriatric genogram assessment tool (CGGAT), which could supplement the written summary letter and recommendations.

Methods: We used the critical paths method to develop a tool to facilitate implementation of the comprehensive geriatric assessment recommendations. A multidisciplinary group of clinicians used the critical pathways method to develop a CGGAT.

Results: We used the CGGAT to depict the physical and functional status of patients and to complement the textual historical information, family dynamics, and current patient issues. CGGAT is a simple instrument that provides a visual structure and it can facilitate the sharing of information among team members, encourage interdisciplinary dialogue, enhance understanding and adherence on the part of patients and professionals, and reduce the burden on the clinicians who conduct the initial comprehensive geriatric assessment.

Conclusions: We showed the benefits and obstacles related to the adaptation of this new tool and provide recommendations for further development. 

Background: The need for postnatal monitoring of infants exposed to intrauterine beta blockers (BBs) has not been clearly defined.

Objectives: To evaluate infants exposed to intrauterine BBs in order to estimate the need for postnatal monitoring.

Methods: This retrospective case-control study comprised 153 term infants born to mothers who had been treated with BBs during pregnancy. Treatment indications included hypertension 76 mothers (49.7%), cardiac arrhythmias 48 (31.4%), rheumatic heart disease 14 (9.1%), cardiomyopathy 11 (7.2%) and migraine 4 (2.6%). The controls were infants of mothers with hypertension not exposed to BBs who were born at the same gestational age and born closest (before or after) to the matched infant in the study group.

Results: Compared to the control group, the infants in the study group had a higher prevalence of early asymptomatic hypoglycemia (study 30.7% vs. control 18.3%, P = 0.016), short symptomatic bradycardia events, other cardiac manifestations (P = 0.016), and longer hospitalization (P < 0.001). No life-threatening medical conditions were documented. The birth weight was significantly lower for the high-dose subgroup compared to the low-dose subgroup (P = 0.03), and the high-dose subgroup had a higher incidence of small-for-gestational-age (P = 0.02).

Conclusions: No alarming or life-threatening medical conditions were observed among term infants born to BB treated mothers. These infants can be safely observed for 48 hours after birth close to their mothers in the maternity ward. Glucose follow-up is needed, especially in the first hours of life.

Background: Anastomotic leakage (AL) is a major complication following colorectal surgery, with many risk factors established to date. The incidence of AL varies in the medical literature and is dependent on research inclusion criteria and diagnostic criteria.

Objectives: To determine the incidence of and the potential risk factors for AL following colorectal surgery at a single academic medical center.

Methods: We retrospectively reviewed all operative reports of colorectal procedures that included bowel resection and primary bowel anastomosis performed at Sheba Medical Center during 2012. AL was defined according to the 1991 United Kingdom Surgical Infection Study Group criteria. Data were assessed for leak incidence within 30 days. In addition, 17 possible risk factors for leakage were analyzed. A literature review was conducted.

Results: This cohort study comprised 260 patients, and included 261 procedures performed during the study period. The overall leak rate was 8.4%. In a univariate analysis, male sex (odds ratio [OR] 3.37, 95% confidence interval [95%CI] 1.21–9.43), pulmonary disease (OR 3.99, 95%CI 1.49–10.73), current or past smoking (OR 2.93, 95%CI 1.21–7.10), and American Society of Anesthesiologist score ≥ 3 (OR 3.08, 95%CI 1.16–8.13) were associated with an increased risk for anastomotic leakage. In a multivariate analysis, male gender (OR 3.62, 95%CI 1.27–10.33) and pulmonary disease (OR 4.37, 95%CI 1.58–12.10) were associated with a greater risk.

Conclusions: The incidence of AL in the present study is similar to that found in comparable series. Respiratory co-morbidity and male sex were found to be the most significant risk factors.

Background: Transesophageal endoscopic ultrasound-guided fine-needle aspiration using a bronchoscope (EUS-B-FNA) allows clinicians to determine mediastinal staging and lung mass evaluation of lesions not accessible by endobronchial ultrasound (EBUS) or where endobronchial ultrasound-guided transbronchial needle aspiration might not be safe.

Objectives: To evaluate the safety, diagnostic accuracy, and feasibility of EUS-B-FNA.

Methods: The study comprised patients who underwent a pulmonologist-performed EUS-B-FNA of mediastinal lymph nodes and parenchymal lung lesions between June 2015 and September 2017 at the Carmel Medical Center, Haifa, Israel.

Results: EUS-B-FNA was performed in 81 patients. The transesophageal procedure was performed for easier accessibility (49.4%) and in high-risk patients (43.3%). The most frequently sampled mediastinal stations were left paratracheal and sub-carinal lymph nodes or masses (38.3% and 56.7%, respectively). There were no complications (e.g., acute respiratory distress, esophageal perforation, or bleeding). An accurate diagnosis was determined in 91.3% of cases.

Conclusions: Pulmonologist-performed EUS-B-FNA is safe and accurate for evaluating mediastinal and parenchymal lung lesions and lymphadenopathy. Diagnostic accuracy is high. EUS-B-FNA may allow access to sites not amenable to other forms of bronchoscopic sampling, or may increase diagnostic accuracy in patients where anatomic position predicts a low diagnostic yield.

Background: Crohn’s disease and ulcerative colitis are the two major classic presentations of inflammatory bowel diseases (IBD). Studies have shown a wide variation in the incidence and prevalence attributed to different geographic and ethnic populations.

Objectives: To assess the clinical characteristics of IBD among Arabs in Israel and to compare them to characteristics of IBD among Ashkenazi Jews.

Methods: This retrospective, comparative study compared the clinical characteristics of IBD among 150 Arabs from the Holy Family Hospital and the Nazareth Hospital EMMS, both located in Nazareth, Israel, to those of 97 age- and sex-matched Ashkenazi Jewish patients from Shaare Zedek Medical Center, Jerusalem, Israel.

Results: The Arab cohort, which included 106 patients (70%) with Crohn's disease and 44 (29%) with ulcerative colitis, was compared to 97 Ashkenazi patients (81% with Crohn's disease and 17% with ulcerative colitis) (P < 0.05). Alcohol consumption was found in both groups, but Arabs smoked more (46% vs. 12%, respectively, P < 0.05). Obstructive phenotype was lower in Arabs (10% vs. 32%, P < 0.05). 5-aminosalicylic acid and anti-tumor necrosis factor alpha were prescribed for the Arab and Ashkenazi groups (89% and 21%, respectively). The need for surgical intervention due to disease severity and/or complications was not significant (22% vs. 24%).

Conclusions: Despite similar reports of NOD2/CARD15 mutations, Crohn's disease is more common than ulcerative colitis within the Arab-Israeli population. Increased smoking rates may explain milder disease severities in Arabs, as reflected by lower obstructive pattern and frequent use of milder therapeutic modalities.

Background: Recurrent miscarriages are associated with a high prevalence of thrombophilia. Use of a calibrated automated thrombogram (CAT) can serve as a universal test for thrombophilia.

Objectives: To examine whether thrombin generation measured by CAT is elevated during the first trimester in women with unexplained recurrent miscarriages.

Methods: This study comprised 25 pregnant women with recurrent pregnancy loss referred for thrombophilia screening and treated with low-molecular-weight heparin (LMWH). Thrombin generation parameters were measured in women who had miscarriages or live births and who were diagnosed as positive or negative for thrombophilia.

Results: Of the pregnancies, 76% resulted in live birth and 24% ended in miscarriages. Among the women, 76% were positive for thrombophilia. Thrombin generation parameters between pregnancies that ended in miscarriage compared to live births were not significantly different, and CAT parameters failed to predict pregnancy outcome. Although the CAT parameters demonstrated a trend toward a hypercoagulable state in women with thrombophilia, there was no statistical significance (P > 0.05).

Conclusions: Women with unexplained pregnancy loss demonstrated similar thrombin generation in the first trimester, regardless of the pregnancy outcome. CAT parameters failed to predict pregnancy outcome in women with recurrent unexplained pregnancy loss. Our results should be interpreted with caution due to the small number of participants.

Background: Isolated fallopian tube torsion (IFTT) is a rare gynecological entity and its diagnosis is challenging.

Objectives: To compare clinical characteristics, sonographic findings, surgical management, and outcomes of women with surgically verified IFTT compared to those diagnosed with adnexal torsion.

Methods: A retrospective case-control study in a university hospital was conducted. Thirty-four women with surgically verified IFTT between March 1991 and June 2017 were compared to 333 women diagnosed with adnexal torsion within the same time period.

Results: Both groups presented primarily with abdominal pain, which lasted longer prior to admission among the IFTT group (46.8 ± 39.0 vs. 30.0 ± 39.4 hours, P < 0.001). Higher rates of abdominal tenderness with or without peritoneal signs were found in the adnexal torsion group (90.3% vs. 70.6%, P < 0.001). Sonographic findings were similar; however, an increased rate of hydrosalpinx was found among the IFTT group (5.9% vs. 0.0%, P = 0.008). Suspected adnexal torsion was the main surgical indication in only 61.8% of IFTT cases compared with 79.0% in the adnexal torsion group (P = 0.02). Salpingectomy with or without cystectomy was more commonly performed in the IFTT group (35.3% vs. 1.5%, P < 0.001). The leading pathological findings among the IFTT group were hydrosalpinx and paraovarian cysts.

Conclusions: The clinical signs and symptoms of IFTT and adnexal torsion are similar. Although sonographic imaging demonstrating a paraovarian cyst or hydrosalpinx may be helpful in diagnosing IFTT, it is rarely done preoperatively.

Background: Ophthalmic pathologies may further complicate the sensory input of patients with congenital hearing loss; however, data on children with coexisting impairment of vision and hearing is outdated, from before universal implementation of hearing screening programs.

Objectives: To examine the different ophthalmic pathologies among children with congenital sensorineural hearing loss (SNHL) before or after the introduction of a universal newborn hearing screening program (UNHSP).

Methods: Retrospective cohort study was conducted of 91 children diagnosed with congenital SNHL between 2005 and 2016 in a tertiary pediatric hospital. All patients completed an ophthalmologic examination, including assessment of visual acuity, refraction, ocular motility, slit lamp examination, and indirect funduscopy. Radiological assessment and genetic analysis were offered to all caregivers.

Results: Average age at diagnosis was 4.1 years. Nineteen children (21%) were diagnosed with an ophthalmic condition, of which the most common were refractive pathologies. Diagnosis of an ophthalmic pathology was twice as likely in the pre-UNHSP era (14 children, 27%) compared to the post-UNHSP era (5 children, 13%). Out of 91 children, 57 (63%) underwent a computed tomography scan and/or magnetic resonance imaging. Imaging was positive for structural abnormalities in 23 children (40%). There was no correlation between imaging and ophthalmic conditions. Genetic analysis was performed in 67 patients (74%).

Conclusions: The ophthalmic assessment of babies and children with congenital SNHL may yield in significant numbers of children with concomitant ophthalmic pathologies. Implementation of a UNHSP allows early diagnosis and treatment of coexisting ophthalmic and hearing conditions.

Background: Benign rolandic epilepsy or benign childhood epilepsy with centrotemporal spikes (BCECTS) is a common childhood epileptic syndrome. The syndrome resolves in adolescence, but 1–7% of patients have an atypical presentation, some of which require aggressive medical treatment. Early treatment may prevent complications and neurocognitive deterioration. Variants include Landau-Kleffner syndrome (LKS) and electrical status epilepticus during sleep (ESES).

Objectives: To determine data driven identification of risk factors and characterization of new subtypes of BCECTS based on anontology. To use data mining analysis and correlation between the identified groups and known clinical variants.

Methods: We conducted a retrospective cohort study comprised of 104 patients with a diagnosis of BCECTS and a minimum of 2 years of follow-up, between the years 2005 and 2017. The medical records were obtained from the epilepsy service unit of the pediatric neurology department at Dana–Dwek Hospital, Tel Aviv Sourasky Medical Center. We developed a BCECTS ontology and performed data preprocessing and analysis using the R Project for Statistical Computing (https://www.r-project.org/) and machine learning tools to identify risk factors and characterize subgroups.

Results: The ontology created a uniform and understandable infrastructure for research. With the ontology, a more precise characterization of clinical symptoms and EEG activity of BCECTS was possible. Risk factors for the development of severe atypical presentations were identified: electroencephalography (EEG) with spike wave (P < 0.05), EEG without evidence of left lateralization (P < 0.05), and EEG localization (centrotemporal, frontal, or frontotemporal) (P < 0.01).

Conclusions: Future use of the ontology infrastructure for expanding characterization for multicenter studies as well as future studies of the disease are needed. Identifying subgroups and adapting them to known clinical variants will enable identification of risk factors, improve prediction of disease progression, and facilitate adaptation of more accurate therapy. Early identification and frequent follow-up may have a significant impact on the prognosis of the atypical variants.

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: When a woman with an endometrioma presents with acute abdominal pain, it is unclear whether ovarian torsion should be suspected.

Objectives: To compare patient characteristics, imaging results, and surgical management of endometriomas in elective versus emergent surgeries.

Methods: This retrospective cohort study included women treated at our institution during the period 1990–2015 who presented with histologically verified endometrioma and who underwent either planned surgery or emergent surgery due to suspected adnexal torsion.

Results: Of 225 surgeries performed, 174 were elective and 51 emergent. Patients in the emergent group were significantly younger (33.9 ± 11.1 vs. 39.01 ± 10.9 years, P = 0.004). Abdominal pain was the main complaint of all the emergent surgery patients and the leading complaint in 21% of the elective surgery patients (P < 0.001), with right-sided predominance in both groups. Sonographic parameters were similar in both groups. Bilateral ovarian cysts were noted in 11.7% and 11.0% of emergent and elective patients, respectively (P = 0.87). Laboratory evaluation was notable for a higher white blood cell count and CA125 levels among emergent patients. All patients in the emergent group and 93% of patients in the elective group were managed laparoscopically. No cases of torsion were noted. The rate of intra-pelvic adhesions was similar in both groups (56.8% vs. 66.6%, P = 0.19).

Conclusions: Endometrioma may present with acute abdominal pain. However, adnexal torsion in these patients is rare. These cases can be managed using a minimally invasive approach, assuming an optimal surgical setting.

Background: Multidisciplinary biopsychosocial rehabilitation for patients presenting with rheumatic diseases has been shown to produce better results in a warm climate. Dead Sea Climatotherapy (DSC) has been successfully used for decades to treat many patients with rheumatic diseases.

Objectives: To evaluate the short-term improvement of Norwegian patients who presented with chronic pain following a multidisciplinary biopsychosocial approach to treatment combined with DSC. Both objective and subjective clinical parameters were evaluated.

Methods: This retrospective study included a statistical analysis of 938 patients presenting with rheumatoid arthritis and ankylosing spondylitis (n=105), osteoarthritis (n=342), fibromyalgia (n=374), and other orthopedic conditions (n=117). Clinical assessments were conducted before and after a 3 week treatment program at the Dead Sea.

Results: Six parameters improved significantly in the rheumatoid arthritis and ankylosing spondylitis group as well as in the osteoarthritis group. Five parameters in the fibromyalgia group improved, while two improved in the orthopedic conditions group. Overall, major significant changes occurred in the pain self-assessment, joint motility, and daily activities scores.

Conclusions: A 3-week multidisciplinary biopsychosocial program combined with DSC induced positive changes in the clinical parameters of Norwegian patients presenting with chronic musculoskeletal pain.