Israel Medical Association Journal

Background: Klotho is a transmembrane protein that can be shed and can act as a circulating hormone in three forms: soluble klotho (KL1 + KL2), KL1, and KL2. Klotho was discovered as a gene implicated in aging through inhibition of the IGF-I pathway. Our laboratory discovered the role of klotho as a tumor suppressor in breast cancer and other malignancies. Furthermore, we showed that the KL1 domain mediates this activity. Altered cancer cell metabolism is a hallmark of cancer and our lab demonstrated various effects of klotho on breast cancer cell metabolism. Thus, klotho inhibited glycolysis and activated adenosine monophosphate activating kinase (AMPK), an energy sensor pathway. Moreover, inhibition of AMPK reduced the tumor suppressor activity of klotho.

Objectives: To assess the effect of KL1 on breast tumor cells metabolism, as KL1 possesses the tumor suppressor activity of klotho.

Methods: We used MCF-7 breast cancer cells treated with soluble or over-expressed KL1 and klotho. Glycolysis was assessed by measuring mRNA levels of key glycolytic enzymes using reverse transcription polymerase chain reaction and by measuring lactate and glucose levels in media. The AMPK pathway was studied by monitoring AMPK phosphorylation as well as its down-stream target, acetyl-CoA carboxylase, using western blotting. Wound healing assay was used to assess cell migration.

Results: KL1 treatment reduced glycolytic enzymes mRNA levels and the activity of hexokinase, similar to klotho treatment. Furthermore, KL1 reduced glucose uptake and decreased lactate production. KL1 elevated phosphorylated acetyl-CoA carboxylase and phosphorylatedAMPK levels. Inhibition AMPK (using a mutant AMPK activator) stopped KL1 from inhibiting cell migration, suggesting AMPK underlies klotho’s tumor suppressor activity.

Conclusions: Our data indicate KL1 as a regulator of metabolic activity in breast cancer and suggest that metabolic alterations underlie KL1 tumor suppressor activities. Furthermore, as KL1 and klotho share a similar effect on cell metabolism, our results further support the central role KL1 domain plays in klotho’s tumor suppressor activity.

Background: Malignancy is a known risk factor for venous thromboembolism; however, the association with arterial thromboembolic events remains unclear.

Objectives: To examine the association between non-ST-elevation myocardial infarction (NSTEMI) and non-significant coronary artery disease (CAD) and the presence of new or occult malignancy.

Methods: An observational cohort, single-center study was performed 2010–2015. Adult patients with NSTEMI, who underwent coronary angiography and had no significant coronary lesion, were included. Using propensity score matching, we created a 2:1 matched control group of adults with NSTEMI, and significant coronary artery disease. Risk factors for new or occult malignancy were assessed using multivariate backward stepwise logistic regression analysis. The primary outcome was new or occult malignancy, defined as any malignancy diagnosed in the 3 months prior and 6 months following the myocardial infarction (MI).

Results: During the study period, 174 patients who presented with MI with non-obstructive coronary arteries were identified. The matched control group included 348 patients. There was no significant difference in the group demographics, past medical history, or clinical presentation. The incidence of new or occult malignancy in the study group was significantly higher (7/174, 4% vs. 3/348, 0.9%, P = 0.019). NSTEMI with non-significant CAD was an independent risk factor for occult malignancy (odds ratio [OR] 4.6, 95% confidence interval [95%CI] 1.1–18.7). Other risk factors included active smoking (OR 11.2, 95%CI 2.5–49.1) and age (OR 1.1, 95%CI 1.03–1.17).

Conclusions: NSTEMI with non-significant CAD may be a presenting or early marker of malignancy and warrants further investigation.

Background: Recently, studies have found that non-alcholic fatty liver disease (NAFLD) is associated with bacterial infections. Attempts to identify risk factors for recurrent urinary tract infections (rUTIs) are still underway.

Objectives: To examine a possible association between NAFLD and rUTIs among premenopausal women.

Methods: In a case-control study, 1009 hospitalized premenopausal women with a UTI during a period of 3 years were retrospectively studied. A total of 186 subjects with rUTIs and 186 controls without a history of rUTIs were included in this study. Each participant had an abdominal ultrasonogram as part of the inclusion criteria. The two groups were compared in terms of risk factors for rUTIs, such as maternal history of rUTIs, use of contraceptives, frequency of sexual intercourse, metabolic syndrome, obesity, use of probiotics, serum levels of vitamin D, and NAFLD. An rUTI was defined as three or more episodes of UTI over a period of 1 year. NAFLD was diagnosed based on abdominal ultrasonography examination.

Results: Mean age of the 372 participants was 39.7 ± 5 years. NAFLD was diagnosed in 81/186 subjects (43.5%) with rUTIs vs. 40/186 controls (21.5%), P = 0.05. Women with rUTIs were more often obese and presented with lower serum levels of vitamin D than controls. Multivariate analysis showed that NAFLD (odds ratio = 1.6, 95% confidence interval 1.3–2.0, P = 0.04) were associated with rUTIs in premenopausal women.

Conclusions: NAFLD was associated with rUTI in premenopausal women, independent of metabolic syndrome. Further studies are needed to confirm this association.

Background: The sentinel lymph node (SLN) biopsy procedure is a well-known method for identifying solid tumors such as breast cancer, vulvar cancer, and melanoma. In endometrial and cervical cancer, SLN has recently gained acceptance.

Objectives: To evaluate the detection rate of SLN with an indocyanine green and near-infrared fluorescent imaging (ICG/NIR) integrated laparoscopic system in clinically uterine-confined endometrial or cervical cancer.

Methods: Patients with clinically early-stage endometrial or cervical cancer were included in this retrospective study. ICG was injected into the uterine cervix and an ICG/NIR integrated laparoscopic system was used during the surgeries. The National Comprehensive Cancer Network (NCCN) protocol was followed. SLN and/or suspicious lymph nodes were resected. Side-specific lymphadenectomy was performed when mapping was unsuccessful. Systematic lymphadenectomy was completed in patients with high-grade histology or deep myometrial invasion. Enhanced pathology using ultra-staging and immunohistochemistry were performed in all cases.

Results: We analyzed 46 eligible patients: 39 endometrial and 7 cervical cancers. Of these, 44 had at least one SLN (93.6%). In 41 patients (89%) we detected bilateral SLN, in 3 (7%) only unilateral, and in 2 (4%) none were detected. Seven patients presented with lymph node metastasis. All were detected by NCCN/SLN protocol. Of these cases, two were detected with only pathological ultra-staging.

Conclusions: SLN mapping in endometrial and cervical cancer can easily be performed with a high detection rate by integrating ICG/NIR into a conventional laparoscopic system. Precision medicine in patients evaluated by SLN biopsy changes the way patients with endometrial or cervical cancer are managed.

Background: The main acquired resistance mechanism to first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant non-small cell lung cancer (NSCLC) is the propagation of T790M clones, which can be detected in circulating tumor DNA (ctDNA).

Objectives: To analyze osimertinib outcomes according to T790M testing method.

Methods: The study comprised 33 consecutive patients with advanced EGFR mutant NSCLC who were diagnosed with a T790M mutation after progression on first- or second-generation EGFR TKIs and treated with osimertinib. The patients were divided into groups A (diagnosed by tumor testing) and B (by ctDNA testing). Osimertinib outcomes were compared between the groups.

Results: Objective response rate with osimertinib comprised 54% and 62% in groups A and B, respectively (P = 0.58). Median progression-free survival (PFS) with osimertinib was 8.9 months (95% confidence interval [95%CI] 1.8–17.5) and 9.1 months (95%Cl 5.3–12.6) in groups A and B, respectively (log-rank test 0.12, P = 0.73). Median overall survival (OS) was 13.8 months (95%CI 4.9–25.5) and 13.8 months (95%Cl 7.7–27.7) in groups A and B, respectively (log-rank test 0.09, P = 0.75). T790M testing technique did not affect PFS (hazard ratio [HR] 1.16, 95%CI 0.50–2.69, P = 0.73) or OS (HR = 1.16, 95%CI 0.45–3.01, P = 0.76). The proportion of patients diagnosed by ctDNA grew from 56% in 2015 to 67% in 2016–2017.

Conclusions: Our study provides a ctDNA validation for the purpose of T790M testing in EGFR mutant NSCLC.

Background: Hysterectomy is common in the management of symptomatic uterine prolapse. Vaginal wall repair is often necessary, for which vaginal mesh remains a popular option.

Objectives: To evaluate the risk of mesh erosion following mesh-augmented vaginal prolapse repair, with or without concomitant vaginal hysterectomy.

Methods: This retrospective cohort comprised 70 women who underwent vaginal mesh-augmented pelvic organ prolapse repair from 2007 to 2010. Of the participants, 36 (51.4%) had a vaginal hysterectomy concomitant to the anterior and/or posterior vaginal mesh repair (hysterectomy group) and 34 (48.6%) underwent mesh repair without vaginal hysterectomy (no hysterectomy group).

Results: There were no inter-group differences in age, parity, menopausal state, hormonal use, or presenting symptoms. Previous prolapse repair surgery was much more common in the no hysterectomy group (29.4% vs. 5.5%, P = 0.01). Eleven patients (32.3%) in the no hysterectomy group had previously undergone hysterectomy. Anterior mesh repair was performed in 77.7% and 67.6% of hysterectomy and no hysterectomy patients, respectively. Posterior mesh repair was performed in 27.7% and 44.1%, respectively. One patient in the hysterectomy group underwent immediate removal of mesh due to infection. Surgically treated mesh erosion (limited local excision) occurred in three patients (8.3%) in the hysterectomy group (3, 16, and 18 months following surgery) and in two patients (5.8%) in the no hysterectomy group at 6 months following surgery (P = 0.67).

Conclusions: Vaginal mesh-augmentation concomitant with vaginal hysterectomy for pelvic organ prolapse repair does not carry an increased risk of erosion.

Background: Cannabinoid hyperemesis syndrome (CHS) is under-recognized by clinicians. It is characterized by nausea, severe abdominal pain, and cyclical vomiting in the context of chronic cannabis use. Oral benzodiazepine is a proposed treatment for CHS. It decreases activation of Cannabinoid Type 1 Receptor (CB1) in the frontal cortex, has a sedative and hypnotic effect and reduces the anticipation of nausea and vomiting. These effects on the central nervous system (CNS) might explain its beneficial antiemetic effect for this syndrome.

Objectives: To increase the index of suspicion for CHS, a unique syndrome that requires a unique treatment with benzodiazepines and not antiemetics.

Methods: We describe a series of four patients with documented cannabis use, who were admitted to an internal medicine department of Meir Medical Center due to symptoms consistent with abdominal pain, nausea, and vomiting. They were initially treated with conventional antiemetics and proton pump inhibitors without response. Intensive investigations were conducted to exclude common and sometimes urgent gastrointestinal or CNS syndromes.

Results: After excluding urgent gastrointestinal and CNS origins for the vomiting, we suspected CHS. All four patients experienced similar symptoms and failure of conventional treatment with antiemetics and proton pump inhibitors. They experienced relief after administration of benzodiazepines.

Conclusions: A high index of suspicion for CHS allows for rapid, appropriate treatment with benzodiazepines, which in turn may lead to cessation of the debilitating symptoms caused by this syndrome.

Background: Israel's population is diverse, with people of different religions, many of whom seek spiritual guidance during ethical dilemmas. It is paramount for healthcare providers to be familiar with different religious approaches.

Objectives: To describe the attitudes of the three major monotheistic religions when encountering four complex neonatal situations.

Methods: A questionnaire related to four simulated cases was presented to each participant: a non-viable extremely premature infant (case 1), a severely asphyxiated term infant with extensive brain damage (case 2), a small preterm infant with severe brain hemorrhage and likely extensive brain damage (case 3), and a term infant with trisomy 21 syndrome and a severe cardiac malformation (case 4).

Results: Major differences among the three religious opinions were found in the definition of viability and in the approach towards quality of life.

Conclusions: Neonatologists must be sensitive to culture and religion when dealing with major ethical issues in the neonatal intensive care unit.

Background: Congenital factor VII deficiency is a rare recessive autosomal bleeding disorder with a wide spectrum of clinical manifestations.

Objectives: To compare the clinical and laboratory findings in Jewish and Bedouin patients with factor VII deficiency.

Methods: The clinical and laboratory findings of patients with factor VII deficiency treated at Soroka Medical Center, a tertiary hospital in Israel, from 2005 to 2015 were analyzed regarding blood factor levels, illness severity, treatment administration, and disease outcome.

Results: Seventy-eight patients were enrolled (1:13,000 of the population in southern Israel) of whom 26 were diagnosed with severe factor VII deficiency (1:40,000). Sixty (76.9%) patients were Jewish and 18 (23.1%) were Bedouin. In univariable analysis, Bedouin patients exhibited a more severe illness, with significantly higher complication and fatality rates, and required more preventive treatment than the Jewish patients.

Conclusions: The prevalence of congenital factor VII deficiency (including severe deficiency) in the Jewish and Bedouin populations of southern Israel is higher than previously reported. The clinical spectrum of the disease was found to be more severe in the Bedouin population.

Background: Access-site bleeding is a common complication of transfemoral transcatheter aortic valve implantation (TAVI). Percutaneous stent-graft implantation within the femoral artery may achieve hemostasis and avert the need for more invasive surgical vascular repair; however, failure to advance a guidewire antegradely via the injured vessel may preclude stent delivery. While retrograde stent-graft delivery from the distal vasculature may potentially enable percutaneous control of bleeding, this approach has not been reported.

Objectives: To assess the feasibility of a retrograde approach for stent-graft implantation in the treatment of access-site bleeding following transfemoral TAVI.

Methods: A prospective TAVI registry was analyzed. Of 349 patients who underwent TAVI, transfemoral access was used in 332 (95%). Access-site injury requiring stent-graft implantation occurred in 56 (17%). In four patients (7%), antegrade wiring across the site of vascular injury was not possible and a retrograde approach for stent delivery was used.

Results: Distal vascular access was achieved via the superficial femoral or profunda artery. Retrograde advancement of a polymer-coated 0.035” wire to the abdominal aorta, followed by stent-graft delivery to the common femoral artery, achieved hemostasis in all cases. During a median (interquartile range) follow-up period of 198 (618) days (range 46–2455) there were no deaths and no patient required additional vascular interventions.

Conclusions: A retrograde approach for stent-graft delivery is feasible and allows percutaneous treatment of a common femoral artery injury following TAVI in patients who are not suitable for the conventional antegrade approach.

Background: Pulmonary rehabilitation has shown significant benefit for patients with chronic obstructive pulmonary disease (COPD). The effect on non-COPD pulmonary patients is less well established.

Objectives: To determine whether pulmonary rehabilitation is also beneficial for non-COPD pulmonary patients.

Methods: Clinical and demographic data on non-COPD pulmonary patients who participated in our institutional pulmonary rehabilitation program between January 2009 and December 2016 were collected. Participants engaged in a 60-minute, twice-weekly, ambulatory hospital-based program lasting 12 to 24 sessions. Sessions included both endurance and muscle training as well as healthy lifestyle educational activities. The six-minute walk test (6MWT) and the St. George's Respiratory Questionnaire (SGRQ) were conducted before and after the rehabilitation program.

Result: We recruited 214 non-COPD patients, of whom 153 completed at least 12 sessions. Of these, 59 presented with interstitial lung disease (ILD), 18 with non-ILD restrictive lung defects, 25 with asthma, 30 with lung cancer, and 21 with other conditions (e.g., pulmonary hypertension, bronchiectasis) The groups demonstrated significant improvement in 6MWT and in SGRQ scores. Non-COPD patients gained a 61.9 meter (19%) improvement in the 6MWT (P < 0.0001) and 8.3 point reduction in their SGRQ score (P < 0.0001).

Conclusions: Pulmonary rehabilitation is effective in non-COPD pulmonary patients. As such, it should be an integral part of the treatment armament provided to the vast majority of those suffering from chronic respiratory disease.

Background: The prevalence of Helicobacter pylori varies geographically by age, race, and socioeconomic status (SES). However, the impact of ethnicity on endoscopic outcomes in infected individuals is not well known.

Objectives: To assess the impact of ethnicity among Israelis with biopsy-proven H. pylori infection.

Methods: A retrospective study, including patients who underwent gastroscopy and were diagnosed histologically with H. pylori infection, was conducted. Information on demographics, SES, medications, and co-morbidities were extracted from medical records. Univariate (Student's t-test, chi-square test) and multivariate (multinomial and logistic) regression analysis were conducted to examine the predictors of the clinical outcome.

Results: The study included 100 Israeli Jews and 100 Israeli Arabs diagnosed with biopsy-proven H. pylori infection. At univariate analysis, the number of households was higher among Arabs (P < 0.001), whose family income and parental education were lower than among Jews (P < 0.001 for both variables). The response to amoxicillin and clarithromycin differed between the two groups, being higher among Jews (P < 0.001).In clinical outcomes (gastritis severity, gastric and duodenal ulcer, intestinal metaplasia, atrophic gastritis, and MALT), no statistically significant differences could be detected between Jews and Arabs. Concerning intestinal metaplasia, lack of consumption of nonsteroidal anti-inflammatory drugs resulted a statistically significant protective factor (odds ratio 0.128, 95% confidence interval 0.024–0.685, P = 0.016).

Conclusions: Although in the literature ethnicity seems to be a risk factor for H. pylori colonization, no statistical significance was detected in various endoscopic and histological findings related to H. Pylori infection between Israeli Arabs and Jews.