Publications by authors named "Tzippy Shochat"

85 Publications

Report from a large and comprehensive single-center Women's Health Cardiology Clinic.

Womens Health (Lond) 2021 Jan-Dec;17:17455065211013767

Department of Cardiology, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel.

Objective: This article describes the women population and work at a unique Women's Health Cardiology Clinic in order to raise cardiovascular disease awareness with an emphasis on women-specific risk factors, and thus to improve women's clinical outcomes. This expectantly will aid in opening similar centers allowing more women to get superior care.

Methods: Electronic medical records of women referred to the Women's Health Cardiology Clinic were analyzed. The statistical analysis is descriptive in nature. Women's Health Cardiology Clinic personnel work as a multidisciplinary team, and patients receive specialized diagnostic tests and treatments. Referrals are by physicians according to traditional and women's specific risk factors for cardiovascular disease.

Results: 985 women visited the Women's Health Cardiology Clinic, accumulating 2062 visits. Median age was 57.5 years. The majority of the women were menopausal (575 women, 58%), 62 pregnant with complications and 25 oncology patients. At least, 30% of women had diabetes/hypertension/or dyslipidemia. 72 women had a history of either cerebrovascular event or acute coronary syndrome, and 139 women had evidence of atherosclerosis. Overall, 388 women underwent endothelial function test, 40% of these women had a score indicating endothelial dysfunction. 277 women underwent a psychological intervention.

Conclusion: Described here are the experiences from a multidisciplinary Women's Health Cardiology Clinic using a gender-specific cardiovascular care approach for women geared toward improved health and wellbeing. It is of utmost importance that this report will raise women-specific cardiovascular disease risk factors awareness in order to promote women's cardiovascular and overall health.
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http://dx.doi.org/10.1177/17455065211013767DOI Listing
April 2021

Fluid Responsiveness Predictability in Immediate Postoperative Pediatric Cardiac Surgery. Is the Old Slandered Central Venous Pressure Back Again?

Shock 2021 Apr 20. Epub 2021 Apr 20.

Pediatric Cardiac Intensive Care Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel, 4920235 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, 6997801.

Objective: Acute low cardiac output (CO) is a frequent scenario in pediatric cardiac intensive care units (PCICU). While fluid responsiveness has been studied extensively, literature is scarce for the immediate postoperative congenital heart surgery population admitted to PCICUs. This study analyzed the utility of hemodynamic, bedside ultrasound and Doppler parameters for prediction of fluid responsiveness in infants and neonates in the immediate postoperative cardiac surgery period.

Design: A prospective observational study.

Setting: University affiliated, tertiary care hospital, PCICU.

Participants: Immediate postoperative pediatric patients displaying a presumed hypovolemic low CO state were included. A clinical, arterial derived, hemodynamic, sonographic, Doppler-based, and echocardiographic parameter assessment was performed, followed by a fluid bolus therapy.

Interventions: 15-20cc/kg Crystalloid fluid bolus.

Main Outcome Measures: Fluid responsiveness was defined as an increase in cardiac index > 10% by echocardiography.

Results: Of 52 patients, 34 (65%) were fluid responsive. Arterial systolic pressure variation (SPV), continuous-Doppler preload parameters, and inferior vena-cava distensibility index (IVCDI) by bedside ultrasound all failed to predict fluid responsiveness. Dynamic central venous pressure (CVP) change yielded a significant but modest fluid responsiveness predictability of AUC 0.654 (p = 0.0375).

Conclusions: In a distinct population of mechanically ventilated, young, pediatric cardiac patients in the immediate postoperative period, SPV, USCOM preload parameters, as well as IVC-based parameters by bedside ultrasound failed to predict fluid responsiveness. Dynamic CVP change over several hours was the only parameter that yielded significant but modest fluid responsiveness predictability.
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http://dx.doi.org/10.1097/SHK.0000000000001786DOI Listing
April 2021

Consecutive ovarian stimulation is beneficial in patients with a poor response to high-dose follicle-stimulating hormone.

Gynecol Endocrinol 2021 Apr 9:1-5. Epub 2021 Apr 9.

Infertility and IVF Unit, Helen Schneider Hospital for Women, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Isrel.

Objective: To investigate if an immediate additional IVF-ET cycle bear an advantage to patients with poor ovarian response in comparison to a cycle performed at some delay.

Methods: A cohort study including 632 patients who underwent a fresh IVF-ET cycle with high-dose (≥300 IU/d) FSH stimulation that yielded ≤4 oocytes and did not achieve a clinical pregnancy. All underwent a second stimulation and oocyte pick-up (OPU), either consecutively or separately within 180 days (nonconsecutive OPU). The oocyte yield, number of embryos available for transfer, pregnancy live birth rates of the second OPU were compared between patients who had consecutive and nonconsecutive cycles.

Results: Consecutive OPU was associated with more mature follicles in the second cycle compared to nonconsecutive OPU ( = .03) in addition to higher peak estradiol level ( < .0001), and more aspirated oocytes ( = .03) and available embryos ( = .023). There was no between-group difference in ongoing pregnancy and live birth rates. In a multivariate analysis of variance controlling for potential confounders, the difference in the number of aspirated oocytes and available embryos was associated significantly only with consecutive performance of the second cycle.

Conclusion: Immediate sequential stimulation (without an intervening menstrual cycle) in poor responders is advantageous over delayed stimulation in terms of number of aspirated oocytes and available embryos. The administration of high-dose FSH in the first cycle may benefit follicular recruitment also in the subsequent cycle. Although the effect is modest, given that each additional oocyte aspirated contributes to the outcome, it might be of significance especially in younger patients.
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http://dx.doi.org/10.1080/09513590.2021.1908991DOI Listing
April 2021

BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors.

Front Oncol 2021 10;11:603223. Epub 2021 Mar 10.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objectives: Little is known regarding the outcomes of systemic treatments in BAP1-altered malignant pleural mesothelioma (MPM).

Materials And Methods: Forty five patients with MPM [group A: eight MPM patients with BAP1 inactivating mutation/copy number loss (FoundationOne CDx/TEMPUSxT), selected from the electronic databases of four Israeli cancer centers (ICC); group B: 37 consecutive (years 2016-2018) MPM patients selected from the electronic databases of two ICC-of those six patients without a BAP1 alteration (group B1) and 31 patients not tested for BAP1 (group B2)] were analyzed for ORR, PFS (mRECIST), and OS with 1-line platinum/pemetrexed+/-antiangiogenic drug (CT, n-28), immune check-point inhibitors (ICPi, n-16) and poly (ADP-ribose) polymerase inhibitors (PARPi, n-4). OS since diagnosis (OSDx) was assessed.

Results: There were no differences in ORR or mPFS with CT between the groups: ORR-50% . 47% . 50% . 47% (p>0.9), mPFS-9.1mo (95% CI, 1.2-16.1) . 9.2mo (95% CI, 2.9-13.3) . 7.2mo (95% CI, 2.3-NR) . 10.9mo (95% CI, 2.9-20.3) (p>0.8) in groups A, B, B1, and B2, respectively. There were no differences in ORR or mPFS with ICPi between the groups: ORR-0% . 27% . 33% . 25% (p>0.2), mPFS-2.5mo (95% CI, 1.4-3.7) . 3.0mo (95% CI, 1.3-10.5) . 2.0mo (95% CI, 1.9-NR) . 4.5mo (95% CI, 0.3-10.5) (p>0.3) in groups A, B, B1, and B2, respectively. In group A, no responses were seen with PARPi; mPFS with PARPi was 1.8mo (95% CI, 1.8-NR). OSDx was 98.3mo (95% CI, 9.7-98.3) . 19.4mo (95% CI, 9.7-47.3) . 18.8mo (95% CI, 8.5-NR) . 19.5mo (95% CI, 8.3-82.2) in groups A, B, B1, and B2, respectively (p>0.3).

Conclusions: BAP1-altered MPM, as compared to non-selected MPM, is characterized by similar efficacy of CT and ICPi. Numerically longer OS in BAP1-altered MPM may reflect favorable tumor biology. No responses were observed with PARPi.
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http://dx.doi.org/10.3389/fonc.2021.603223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987904PMC
March 2021

Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study.

Breast Cancer Res Treat 2021 Mar 27. Epub 2021 Mar 27.

Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, 39 Jabotinsky St., Petach Tikva, 4941492, Israel.

Background: The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial.

Patients And Methods: The databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013-2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile.

Results: The study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36-0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4-1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5-1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2-0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2-0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39-1.23)] or the subgroups.

Conclusions: Patients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.
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http://dx.doi.org/10.1007/s10549-021-06198-4DOI Listing
March 2021

Markers of Chronic Inflammation in Overweight and Obese Individuals and the Role of Gender: A Cross-Sectional Study of a Large Cohort.

J Inflamm Res 2021 25;14:567-573. Epub 2021 Feb 25.

Department of Medicine F - Recanati, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.

Objective: During the last decade, obesity has become an epidemic. As obesity is now considered a state of low-grade inflammation, the purpose of this study was to assess the prevalence of four common elements of inflammation, in individuals with increased BMI. These findings were compared to those of subjects with normal BMI. The effect of gender was also noted.

Methods: Data were collected from medical records of individuals examined at a screening center in Israel between the years 2000-2014. Cross-sectional analysis was carried out on 7526 men and 3219 women. White blood cell count (WBC); platelet (PLT) count; erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were assessed in four BMI categories: normal, overweight, obese and morbidly obese.

Results: Mean (SD) age of the study sample was 47.5 (9.7) and 46.7 (9.8) years for men and women, respectively. The prevalence of each inflammatory marker increased significantly when comparing abnormal to normal BMI (p<0.0001). The odds ratio (OR) of the prevalence of increased inflammatory markers was compared between subjects with overweight, obese and morbid obesity and subjects with normal BMI. This study showed that the higher the BMI, the higher the OR. For those in the morbid obesity group, the OR for the different inflammatory markers adjusting for age, diabetes mellitus hypertension and kidney function were as follows: WBC levels, 5.1 (2.9-8.7) and 4.7 (2.4-9.1) for men and women, respectively; PLT levels, 1.7 (0.3-8.5) and 2.0 (0.6-7.2) for men and women, respectively; ESR levels, 4.2 (3.2-5.4) and 4.6 (3.2-6.6) for men and women, respectively, and CRP levels, 13.4 (10.0-18.2) and 19.2 (12.9-28.6) for men and women, respectively.

Conclusion: Inflammatory markers are significantly higher in subjects with abnormal compared to normal BMI. This difference was found to be greater in women than in men.
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http://dx.doi.org/10.2147/JIR.S294368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920597PMC
February 2021

Abnormal liver tests in patients with SARS-CoV-2 or influenza - prognostic similarities and temporal disparities.

JHEP Rep 2021 Jun 24;3(3):100258. Epub 2021 Feb 24.

Department of Medicine D, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel.

Background & Aims: Abnormal liver tests are common in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but a possible direct role of the virus in liver injury and its association with short-term outcomes are controversial. Therefore, we aimed to compare the pattern of abnormal liver tests in patients with SARS-CoV-2 with those of patients infected with influenza, a non-hepatotropic respiratory virus, and their association with worse outcomes during hospitalisation.

Methods: We performed a retrospective cohort study of 1,737 hospitalised patients (865 with influenza and 872 with SARS-CoV-2) in a tertiary medical centre. We defined abnormal liver tests as alanine transaminase or aspartate transaminase ≥40 IU/ml at any time-point during hospitalisation.

Results: Abnormal liver tests were mild to moderate in most patients regardless of infection type, but the majority of patients with influenza had a transaminase peak earlier during hospitalisation compared with patients with SARS-CoV-2. Abnormal liver tests correlated with markers of severe disease in either influenza or SARS-CoV-2 infections, and were associated with death, occurring mainly in patients with severe liver test abnormalities (>200 IU/L) (38.7% and 60% of patients with influenza or SARS-CoV-2, respectively). In multivariate analysis, controlling for age, sex, lymphopaenia, and C-reactive protein, liver test abnormalities remained significantly associated with death for influenza (odds ratio 4.344; 95% CI 2.218-8.508) and SARS-CoV-2 (odds ratio 3.898; 95% CI 2.203-6.896). These results were confirmed upon propensity score matching.

Conclusions: Abnormal liver tests during hospitalisation with SARS-CoV-2 or influenza infections are common, may differ in their time course, and reflect disease severity. They are associated with worse outcomes, mainly in patients with severe liver test abnormalities, regardless of infection type.

Lay Summary: Coronavirus disease 2019 (COVID-19) is a serious global health pandemic, the causative agent of which is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Abnormal liver tests are common among SARS-CoV-2 infected patients and are often associated with worse outcomes. Herein, we compare the pattern of abnormal liver tests and their association with disease severity between 2 major non-hepatotropic respiratory viruses: SARS-CoV-2 and influenza. We show that abnormal liver tests are common in both infections, may slightly differ in their kinetics, and are associated with worse outcomes, especially in patients with severe liver test abnormalities. These results strongly suggest that abnormal liver tests in SARS-CoV-2 patients reflect disease severity, rather than a virus-mediated direct liver injury, and should be closely followed in admitted patients.
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http://dx.doi.org/10.1016/j.jhepr.2021.100258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902222PMC
June 2021

Venous thromboembolism incidence and risk assessment in lung cancer patients treated with immune checkpoint inhibitors.

J Thromb Haemost 2021 May 16;19(5):1250-1258. Epub 2021 Mar 16.

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: There are scarce data on venous thromboembolism (VTE) rates among non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors (ICI). The Khorana Score (KS), used to guide thromboprophylaxis in cancer patients, was validated in patients receiving chemotherapy.

Objective: To assess VTE rates and KS performance among NSCLC patients treated with ICI or chemotherapy.

Methods: We performed a retrospective cohort study of NSCLC patients starting either ICI or platinum-based chemotherapy. The 6-month cumulative incidence of VTE in the ICI and chemotherapy cohorts and hazard ratios (HR) with 95% confidence intervals (CI) were calculated, using death as a competing risk. Subgroup analysis of low (0-1) and high (≥2) KS risk groups was performed.

Results: The study included 345 NSCLC patients receiving single agent ICI (n = 176) or chemotherapy (n = 169). The 6-month cumulative incidence of VTE was 7.1% in the chemotherapy cohort and 4.5% in the ICI cohort (HR for chemotherapy = 1.6, 95% CI 0.66-3.9). Among chemotherapy treated patients, the high-risk KS group had a trend toward a higher VTE incidence, compared with patients with a low-risk KS (HR 3.04, 95% CI 0.82-11.22). Among ICI-treated patients, the high-risk KS group had a trend toward a lower VTE incidence compared with the low-risk group (HR 0.17, 95% CI 0.02-1.36).

Conclusions: VTE rates were higher among NSCLC patients treated with platinum-based chemotherapy than those treated with ICI alone, though the precision of the relative estimate is low. The KS did not identify high-risk ICI-treated patients, suggesting that an ICI-specific risk model is warranted.
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http://dx.doi.org/10.1111/jth.15272DOI Listing
May 2021

Pembrolizumab as a monotherapy or in combination with platinum-based chemotherapy in advanced non-small cell lung cancer with PD-L1 tumor proportion score (TPS) ≥50%: real-world data.

Oncoimmunology 2021 Jan 28;10(1):1865653. Epub 2021 Jan 28.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Both pembrolizumab (P) and combination of pembrolizumab with platinum-based chemotherapy (PCT) represent standard 1-line options for advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score (TPS) ≥50%. The two strategies have never been compared in a randomized trial. 256 consecutive patients with -wild-type PD-L1 TPS ≥50% aNSCLC receiving P (group P, n = 203) or PCT (group PCT, n = 53) as a 1-line treatment were identified in the electronic databases of 4 Israeli cancer centers. Time-to-treatment discontinuation (TTD) and overall survival (OS) were assessed. Baseline characteristics were well balanced, except for age and ECOG PS differences in favor of group PCT. Median (m)TTD was 4.9 months (mo) (95% CI, 3.1-7.6) 8.0mo (95% CI, 4.7-15.6) (-0.09), mOS was 12.5mo (95% CI, 9.8-16.4) 20.4mo (95% CI, 10.8-NR) (-0.08), with P and PCT, respectively. In the propensity score matching analysis (n = 106; 53 patients in each group matched for age, sex and ECOG PS), mTTD was 7.9mo (95% CI, 2.8-12.7) 8.0mo (95% CI, 4.7-15.6) (-0.41), and mOS was 13.3mo (95% CI, 6.8-20.3) 20.4mo (95% CI, 10.8-NR) (-0.18), with P and PCT, respectively. Among various subgroups of patients examined, only in females (n = 86) mOS differed significantly between treatments (10.2mo (95% CI, 6.8-17.2) with P NR (95% CI, 11.4-NR) with PCT; -0.02). In the real-world setting, no statistically significant differences in long-term outcomes with P PCT were observed; a prospective randomized trial addressing the comparative efficacy of P and PCT in different patient subgroups is highly anticipated.:
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http://dx.doi.org/10.1080/2162402X.2020.1865653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849771PMC
January 2021

Sex Differences in Folate Levels: A Cross Sectional Study of a Large Cohort from Israel.

Isr Med Assoc J 2021 Jan;23(1):17-22

Department of Medicine F, Rabin Medical Center (Beilinson Campus), Petah Tikva, Israel.

Background: Low folate levels are associated with megaloblastic anemia, neural tube defects, and an increased risk of cancer. Data are scarce regarding the sex aspect of this deficiency.

Objectives: To assess sex differences in folate levels in a large cohort of patients and to investigate the effect of low folate levels on homocysteine concentrations.

Methods: Data were collected from medical records of patients examined at a screening center in Israel between 2000 and 2014. Cross sectional analysis was conducted on 9214 males and 4336 females.

Results: The average age was 48.4 ± 9.5 years for males and 47.6 ± 9.4 years for females. Average folate levels were 19.2 ± 8.6 and 22.4 ±10.3 nmol/L in males and females, respectively (P < 0.001). The prevalence of folate levels below 12.2 nmol/L was 19.5% in males compared to 11.6% in females (P < 0.001). In patients with low folate levels and normal B12 levels, homocysteine levels above 15 μmol/L were found in 32.4% of males and 11.4% of females (P < 0.001). Males had a significantly higher odds ratio (OR) of having folate levels below 12.2 nmol/L: OR 1.84 (95% confidence interval [95%CI] 1.66-2.05) in a non-adjusted model, and OR 2.02 (95%CI 1.82-2.27) adjusted for age, smoking status, body mass index, kidney function, albumin, and triglycerides levels.

Conclusions: Folate levels are lower in males compared to females, which may contribute to the higher homocysteine levels found in males and thus to their increased risk of developing atherosclerosis and coronary artery disease.
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January 2021

Timing to imaging and surgery after neoadjuvant therapy for breast cancer.

Clin Imaging 2021 Mar 5;71:24-28. Epub 2020 Nov 5.

Oncology Department, Rabin Medical Center, Beilinson, Petah Tikva affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Neoadjuvant therapy (NAT) is increasingly used in breast cancer (BC), yet, the recommended time interval between NAT completion, preoperative imaging assessment, and breast surgery is not clearly defined. This single-center retrospective study investigated tumor growth between NAT completion and surgery. The analysis included 106 BC patients who received NAT (69% chemotherapy alone, 31% chemotherapy plus anti-HER2 therapy), had post-NAT breast MRI, and definitive surgery between 2012 and 2019. The median time interval between end-of-treatment and surgery was 6 weeks; 90% had surgery within 8 weeks of NAT completion, and 10% had surgery 8-12 weeks after NAT completion. No significant correlation was found between any of the time intervals (i.e., NAT completion-to-surgery, NAT completion-to-MRI, post-NAT MRI to surgery) and the tumor size as captured in the pathology report. The only parameter that was significantly correlated with pathological tumor size was tumor size as measured on the post NAT MRI (P < .0001). The difference in tumor size between post NAT MRI and surgical pathology did not correlate with the time interval between end-of-treatment and surgery. The ratio between residual tumor size on post-NAT MRI and the time interval from the end-of-treatment to surgery, significantly correlated with the tumor size on surgical pathology (P < .0001) suggesting that NAT has a beneficial effect weeks after end-of-treatment. In conclusion, our results suggest that for patients undergoing neoadjuvant chemotherapy, surgery within 4-8 weeks of completing NAT is reasonable, and is unlikely to result in a clinically significant change in residual tumor size.
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http://dx.doi.org/10.1016/j.clinimag.2020.10.043DOI Listing
March 2021

Denosumab-associated hypocalcemia: Does gender play a role?

Maturitas 2020 Dec 4;142:17-23. Epub 2020 Jul 4.

Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center - Beilinson Hospital, Petach Tikva 4941492, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997802, Israel. Electronic address:

Objective: It is well recognized that the presentation, treatment, and outcomes of various diseases may differ between men and women. We recently reported a 7.4% rate of denosumab-associated hypocalcemia in community-dwelling osteoporotic patients. This study sought to investigate the role of gender in this complication.

Study Design: Retrospective community-dwelling cohort.

Method: The databases of a large health maintenance organization were searched for adult patients treated with denosumab for osteoporosis in 2010-2018. Rates and predictors of denosumab-associated hypocalcemia (serum calcium ≤8.5 mg/mL) were analyzed by gender.

Results: The cohort included 1871 women and 134 men. Compared with the women, the men were characterized by older median age (81 vs. 77 years, p = 0.005), higher likelihood to receive denosumab as a first-line treatment (22% vs. 6%, p < 0.001), less treatment with calcium supplements (42% vs. 53%, p = 0.012), and lower median eGFR level (66.1 vs. 79.8 mL/min/1.73m, p < 0.001). Denosumab-associated hypocalcemia developed in 133 women (7.1%) and 16 men (11.9%) (p = 0.04); the drug was discontinued in 75% and 61%, respectively. The strongest predictors of hypocalcemia in women were levels of pretreatment albumin-adjusted serum calcium (OR 0.08, 95% CI (0.04, 0.14)) and creatinine (OR 2.43, 95% CI (1.45, 4.05)). There were no predictors in men. On propensity matching of 126 men and 126 women, gender was not a predictor of hypocalcemia.

Conclusion: Denosumab-treated men were significantly older than treated women and had a lower eGFR and more advanced osteoporosis. These findings suggest that selection bias rather than male genderper se underlies the higher rate of denosumab-associated hypocalcemia in men.
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http://dx.doi.org/10.1016/j.maturitas.2020.07.003DOI Listing
December 2020

Dose-dependent association of proton pump inhibitors use with gastric intestinal metaplasia among Helicobacter pylori-positive patients.

United European Gastroenterol J 2021 Apr 18;9(3):343-353. Epub 2021 Mar 18.

Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel.

Background: Gastric intestinal metaplasia is a pre-cancerous condition associated with multiple factors.

Objective: We evaluated whether cumulative proton pump inhibitor dose is associated with the diagnosis of gastric intestinal metaplasia while controlling for multiple variables.

Methods: We retrospectively identified patients who underwent upper endoscopy with gastric biopsy between 2005 and 2014. Covariate data retrieved included age, sex, ethnicity, smoking status, Helicobacter pylori status (based on clarithromycin-amoxicillin-proton pump inhibitor issued), cumulative proton pump inhibitor issued within 10 years (quartiles [PPI-Q ] of daily drug dose), anti-parietal cell antibodies, body mass index and comorbidity index.

Results: Of the 14,147 included patients (median age 63.4 years; women 54.4%; Helicobacter pylori-positive 29.0%), 1244 (8.8%) had gastric intestinal metaplasia. Increasing age, Helicobacter pylori infection, smoking, anti-parietal cell antibodies and proton pump inhibitor use were all associated with the diagnosis of gastric intestinal metaplasia. Upper quartiles of cumulative proton pump inhibitor doses (PPI-Q and PPI-Q vs. PPI-Q ) were associated with the diagnosis of gastric intestinal metaplasia: adjusted odds ratios 1.32 (95% confidence interval [CI] 1.111.57) and 1.27 (95% CI 1.07-1.52), respectively, for the whole cohort (P 0.007, P 0.013), 1.69 (95% CI 1.23-2.33) and 1.40 (95% CI 1.04-1.89), respectively, for Helicobacter pylori-positive patients (P 0.004, P 0.005) and 1.21 (95% CI 0.98-1.49) and 1.20 (95% CI 0.96-1.49), respectively, for Helicobacter pylori-negative patients (P 0.288, P 0.018). Upper quartiles of proton pump inhibitor dose were associated with a 5-10-fold increased risk of low-grade dysplasia.

Conclusions: Among Helicobacter pylori-positive patients, proton pump inhibitor use appears to be associated with a dose-dependent increased likelihood of gastric intestinal metaplasia.
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http://dx.doi.org/10.1177/2050640620951403DOI Listing
April 2021

Features and long-term outcomes of patients hospitalized for diabetic ketoacidosis.

Diabetes Metab Res Rev 2020 Sep 17:e3408. Epub 2020 Sep 17.

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Diabetic ketoacidosis (DKA) is an acute metabolic complication characterized by hyperglycaemia, ketones in blood or urine, and acidosis.

Objective: The aim of this study was to characterize features of patients hospitalized for DKA, to identify triggers for DKA and to evaluate the long-term effects of DKA on glycaemic control, complications of diabetes, re-hospitalizations, and mortality.

Methods: Historical prospectively collected data of patients hospitalized to medical wards for DKA between 2011 and 2017. Data regarding comorbidities, mortality, triggers, and re-hospitalizations for DKA were also collected.

Results: The cohort consisted of 160 patients (mean age 38 ± 18 years, 43% male). One fifth of the patients (34 patients, 21%) were newly diagnosed with diabetes, and DKA was their first presentation of the disease. Among the 126 patients with pre-existing diabetes, the common identified triggers for DKA were poor compliance to treatment (22%) and infectious diseases (18%). During over 7 years of follow-up, mortality rate was 9% (15 patients), and re-hospitalization for DKA rate was 31% (50 patients). Risk factors for re-hospitalization for DKA included young age (OR = 1.02, 95% CI, 1.00-1.04), pre-existing diabetes compared to DKA as the first presentation (OR = 5.4, 95% CI, 1.7-18), and poorer glycaemic control before initial hospitalization (10.5 ± 2.5% vs. 9.4 ± 2.2%; OR = 0.8, 95% CI [0.68-0.96]) and after discharge (10.3 ± 2.4% vs. 9.0 ± 1.9%; OR = 0.73, 95% CI [0.61-0.87]). Laboratory tests during the initial hospitalization, smoking, alcohol, or comorbidities did not increase the risk for re-hospitalization for DKA.

Conclusions: The risk for readmission for DKA is higher for young patients with long duration of diabetes, poor compliance of insulin treatment and poorly controlled diabetes.
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http://dx.doi.org/10.1002/dmrr.3408DOI Listing
September 2020

Alternative nivolumab duration and scheduling in advanced nonsmall cell lung cancer: A real-world evidence.

Int J Cancer 2021 Mar 16;148(5):1183-1191. Epub 2020 Sep 16.

Thoracic Oncology Service, Institute of Oncology, Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel.

In advanced nonsmall cell lung cancer (aNSCLC), stopping nivolumab after 12 months negatively affects outcomes. We performed a world data-based analysis assessing the value of nivolumab continuation and optimal dosing beyond 24 months. Out of 697 consecutive patients with aNSCLC in whom nivolumab was initiated between 2015 and 2018, 45 patients receiving nivolumab for ≥24 months were selected. These were divided into Groups A: nivolumab administered at a dose 3 mg/kg q2 weeks/240 mg q2 weeks/480 mg q4 weeks, n = 25; B: nivolumab re-scheduled to a nonstandard dose 3 mg/kg q3 weeks-q8 weeks, n = 13; C: nivolumab stopped after 24 months, n = 7; (in Groups B and C-for reasons other than progressive disease or intolerable toxicity). Progression-free survival (PFS) (Revised Response Evaluation Criteria in Solid Tumors, version 1.1) and safety (Common Terminology Criteria for Adverse Events, version 4.03) were assessed. With median follow-up of 35.6 months (interquartile range 28.4-41.8), 4%, 31%, 29% and 30% of patients progressed in Groups A, B, C and B+C, respectively. PFS at 36 months since nivolumab initiation comprised 100%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. PFS at 40 months since nivolumab initiation comprised 83%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. Allocation to Group A vs Group B, C and B+C was associated with hazard ratio for PFS-0.20 (95% confidence interval [CI], 0.02-1.77, P-.15), 0.20 (95% CI, 0.02-2.25, P-.19) and 0.20 (95% CI, 0.02-1.66, P-.14), respectively. No differences in newly occurring or worsening adverse events between the groups were observed. A trend for worse PFS was observed with alternative nivolumab scheduling or quitting 24 months after initiation. Continuing nivolumab at a standard dose until disease progression or intolerable toxicity remains the standard treatment option.
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http://dx.doi.org/10.1002/ijc.33281DOI Listing
March 2021

Lower tumor volume is associated with increased benefit from immune checkpoint inhibitors in patients with advanced non-small-cell lung cancer.

Asia Pac J Clin Oncol 2021 Apr 6;17(2):e125-e131. Epub 2020 Aug 6.

Thoracic Cancer Unit, Davidoff Cancer Institute, Rabin Medical Center, Petah Tikva, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Aim: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment for advanced non-small-cell lung cancer (NSCLC), yet many patients do not benefit from Programmed cell death protein 1 (PD-1) axis inhibitors, emphasizing the need for additional markers for better patient selection. Our aim was to evaluate the association between tumor volume and response to ICI.

Methods: This retrospective ethically-approved study included all consecutive patients with advanced NSCLC who were evaluated with a fluorodeoxyglucose-positron emission tomography scan, prior to the first administration of a single-agent ICI between 1/2016 and 6/2017. Tumor burden was calculated based on total body metabolic tumor volume and sum of all measurable lesions (SOML).

Results: Median SOML was 88 mm, and was inversely and significantly associated with progression-free survival (PFS) (hazard ratio [HR] 2, CI 1.28-3.37, P = .003) and overall survival (OS) (HR 2.36, CI 1.13-4.94, P = .02). SOML≤80 mm had a significantly longer PFS compared to patients with a SOML≥80 mm (median PFS 9.7 vs 3.7 months, respectively, HR for progression 2.26, CI 1.1-4.5, P = .02). Patients with a SOML≤80 also had longer median OS compared to patients with SOML≥80 (median OS 12 vs 9.8 months, respectively, HR for death 3.1, CI 1.2-8, P = .018).

Conclusions: Low tumor burden was associated with higher response rates (RR), and better PFS and OS in advanced NSCLC patients treated with ICI. These results may improve the selection of patients for treatment with single-agent ICI, as opposed to the combination with chemotherapy, which might be more appropriate for patients with high tumor burden. Prospective analysis is warranted.
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http://dx.doi.org/10.1111/ajco.13360DOI Listing
April 2021

The entire range of trigger-day endometrial thickness in fresh IVF cycles is independently correlated with live birth rate.

Reprod Biomed Online 2020 Aug 12;41(2):239-247. Epub 2020 May 12.

Infertility and IVF Unit, Helen Schneider Hospital for Women, Rabin Medical Center - Beilinson Hospital, Petach Tikva 4941492; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Electronic address:

Research Question: What is the association of the entire range of trigger-day endometrial thickness (EMT) with live birth rate (LBR) after IVF and fresh embryo transfer? Although EMT is amenable to convenient non-invasive routine measurement, studies of the association between pre-trigger EMT and assisted reproductive technology outcome have yielded equivocal results.

Design: A cohort of IVF fresh day-3 embryo transfers in patients aged 42 years and younger in a single centre between 2009 and 2017. The LBR was calculated for all trigger-day EMT values, stratified into five groups overall and within subgroups of patient age and ovarian response. Univariate analysis and multivariate logistic regression models were used to compare the LBRs at different EMT measurements adjusting for various independent variables.

Results: A total of 5133 cycles were included. The LBRs were as follows: 11.22% (35/312) in cycles with EMT 6 mm or less, 17.98% (380/2114) in cycles with EMT 7-9 mm, 23.44% (476/2031) in cycles with EMT 10-12 mm, 25.62% (144/562) in cycles with EMT 13-15 mm and 34.21% (39/114) in cycles with EMT 16 mm or more (P < 0.001). Similar findings were observed by patient age and ovarian response. The observation was confirmed by multivariate logistic regression analysis in which the EMT was found to be a significant independent predictor of LBR even after controlling for various confounders (OR 0.935, 95% CI 0.908 to 0.962; P < 0.001).

Conclusions: Pre-trigger EMT is in significant independent correlation with LBR, even after adjusting for age and ovarian response. Maximal endometrial proliferation is beneficial, and fresh embryo transfer can be carried out at high EMT values without endangering the outcome of the cycle.
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http://dx.doi.org/10.1016/j.rbmo.2020.04.008DOI Listing
August 2020

Risk Factors and Outcome of Polymicrobial Bacteremia: A Retrospective Cohort Study.

Isr Med Assoc J 2020 May;22(5):279-284

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Recent data regarding polymicrobial bacteremia (PMB) are lacking.

Objectives: To characterize risk factors as well as clinical, microbiological, and prognostic patterns of patients with PMB in a modern hospital setting.

Methods: A single center retrospective study including all patients diagnosed with PMB during 2013 was conducted. PMB was defined as two or more organisms cultured from the blood of the same patient within 72 hours. Patients with monomicrobial infections served as controls.

Results: There were 135 episodes (2% of all bacteremia episodes) of true PMB among 123 patients during the study period. Recent invasive procedures (odds ratio [OR] 3.59, 95% confidence interval [95%CI] 1.41-9.12, P = 0.006) and foreign bodies (OR 1.88, 95%CI 1.06-3.33, P = 0.04) were risk factors for PMB when compared with 79 patients with monomicrobial bacteremia. Central-line-associated infections were the most common infection source among patients with PMB (n=34, 28%). Enterobacteriaceae were the most commonly implicated pathogen (n=95, 77%). Non-fermenting Gram-negative bacilli were significantly more common than previously reported (n=55, 45%). Although crude 30-day mortality was higher (48% vs. 33%) in PMB patients, adjusted mortality was comparable in the two groups.

Conclusions: PMB rate in our cohort was considerably lower than in previous reports. Central-line-associated infections were more common than classic PMB sources. Mortality remained high. Strategies for early identification and better care for these patients should be pursued.
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May 2020

The concordance of treatment decision guided by OncotypeDX and the PREDICT tool in real-world early-stage breast cancer.

Cancer Med 2020 07 6;9(13):4603-4612. Epub 2020 May 6.

Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Petach-Tikva, Israel.

Background: Decision-making regarding adjuvant chemotherapy for early-stage breast cancer can be guided by genomic assays such as OncotypeDX. The concordance of expected clinical decisions guided by OncotypeDX and prognostication online tools such as PREDICT is unknown.

Methods: We performed a retrospective single-center cohort study comprising all women with estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative, node negative disease, whose tumors were sent for OncotypeDX analysis. Expected decision on adjuvant chemotherapy was evaluated using OncotypeDX and using PREDICT. The concordance between these two tools was calculated. The impact on concordance of prespecified features was assessed, including age, tumor size, intensity of ER and progesterone receptor (PR), grade, Ki67 and perineural and lymphovascular invasion.

Results: A total of 445 women were included. Overall concordance was 75% (K = 0.284). The concordance was significantly higher for grade 1 disease compared to grade 2-3 (93% vs 72%, P < .001), tumor ≤ 1 cm compared to >1 cm (85% vs 72%, P = .009), PR positive compared to PR negative (78% vs 58%, P < .001) and ki67 < 10% compared to ≥10% (92% vs 63%, P < .001). The intensity of ER and the presence of perineural or lymphovascular invasion had no significant impact on concordance.

Conclusions: Compared to PREDICT, using OncotypeDx in node negative, ER positive disease is expected to change the clinical decision in a quarter of patients. The concordance between OncotypeDx and PREDICT is influenced by pathological features. In patients with very low risk, treatment decisions may be made based solely on clinical risk assessment.
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http://dx.doi.org/10.1002/cam4.3088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333833PMC
July 2020

Efficacy of immune check-point inhibitors (ICPi) in large cell neuroendocrine tumors of lung (LCNEC).

Lung Cancer 2020 05 12;143:40-46. Epub 2020 Mar 12.

Thoracic Cancer Service, Davidoff Cancer Center, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel. Electronic address:

Objectives: Little is known regarding the ICPi efficacy in LCNEC. We explored the efficacy and safety of ICPi in LCNEC and assessed its impact on OS.

Materials And Methods: Thirty-seven consecutive patients with advanced LCNEC were selected from the Davidoff Cancer Center database. These were divided into groups A1 (patients treated with ICPi, n-23) and A2 (patients not treated with ICPi, n-14). Additionally, group A1* was introduced (patients treated with ICPi as a monotherapy, n-21). Another cohort of advanced non-LCNEC lung cancer patients treated with nivolumab at five Israeli cancer centers was chosen as a comparator (group B, n-270). ORR, PFS with ICPi in group A1* were assessed (RECIST 1.1), OS with ICPi was compared between groups A1* and B. OS since advanced disease diagnosis (OSDx) was compared between groups A1 and A2.

Results: In group A1*, ORR and median PFS with ICPi were 33 %, and 4.2 months (95 % CI, 2.4-8.1), respectively. With median follow-up since start of ICPi of 6.2 months [IQR 2.2-12.1] and 4.9 months [IQR 2.3-8.9] in groups A1* and B, respectively, 52 % and 64 % of patients died in groups A1* and B, respectively. Median OS with ICPi comprised 11.8 months (95 % CI, 3.7-NR) and 6.9 months (95 % CI, 5.5-8.1) in groups A1* and B, respectively (p-0.23). Median OSDx was 14.5 months (95 % CI, 10.1-38.9) and 10.3 months (95 % CI, 2.6-NR), in groups A1 and A2, respectively (p-0.54).

Conclusion: In advanced LCNEC, ICPi outcomes are comparable to the outcomes observed in advanced NSCLC. Future research is needed to clarify the impact of ICPi on OS, and to correlate its benefit with tumor mutational landscape.
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http://dx.doi.org/10.1016/j.lungcan.2020.03.008DOI Listing
May 2020

CPAP (Continuous Positive Airway Pressure) is an effective and stable solution for heart sparing radiotherapy of left sided breast cancer.

Radiat Oncol 2020 Mar 6;15(1):59. Epub 2020 Mar 6.

Department of Radiotherapy, Davidoff Center Rabin Medical Center and Sackler Faculty of Medicine Tel Aviv University, 49 Jabotinksi St, 49100, Petach Tikvah, Israel.

Purpose: Limiting the heart dose in left sided breast cancer radiotherapy is critical. We sought to study the effect of using CPAP (continuous positive airway pressure) as an aid in reducing heart dose in breast cancer radiotherapy.

Methods: Patients with left sided breast cancer receiving adjuvant radiotherapy were enrolled on a prospective IRB (institutional review board) approved clinical trial utilizing CPAP during radiotherapy. Each patient was simulated and planned with and without CPAP and the best dosimetric results determined the patient's treatment. Data on the differences in lung and heart volume and position as well as boost cavity position with and without CPAP were analyzed.

Results: Twenty-four women from 10/16 to 10/18 were enrolled. Seven patients were not treated on study; only two of these were due to treatment issues. Median age was 54 years. 70% had breast only radiation and 30% were treated to breast\CW (chest wall) and regional nodes. The median lung volume with CPAP was 60% larger than without CPAP. (1637 vs. 996 cc) p < 0.001. The median heart volume decreased 12% with CPAP. (338 vs. 382 cc) In regards to the DVH, CPAP decreased mean heart dose from 3.02 to 1.6Gy (p = .0075) and V20 of the lungs from 17.1 to 13.8 with CPAP but this was not significant.

Conclusion: CPAP assisted radiotherapy was tolerable and produced superior treatment plans in left sided breast cancer. This method is worthy of further investigation as a method to normal tissue sparing treatment of left sided breast cancer patients.
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http://dx.doi.org/10.1186/s13014-020-01505-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060550PMC
March 2020

Complications of the third stage of labor are more prevalent in IVF pregnancies.

J Matern Fetal Neonatal Med 2020 Feb 23:1-5. Epub 2020 Feb 23.

IVF Unit, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel.

Pregnancies conceived by fertilization (IVF) are associated with a higher prevalence of perinatal complications than pregnancies conceived spontaneously, even after correction of confounding factors. Little is known about the prevalence of complications of the third stage of labor in IVF pregnancies. To compare the prevalence and types of complications of the third stage of labor following vaginal delivery of singleton infants born to matched groups of women who conceived through IVF or spontaneously. A retrospective case-control study design was used. The electronic delivery files of a tertiary medical center were reviewed for all women with a singleton IVF pregnancy who gave birth by vaginal delivery from August 2011 to March 2014. The women were matched 1:2 for age, gravidity, parity, and week of delivery to women with a singleton spontaneously conceived pregnancy who gave birth by vaginal delivery during the same period at the same hospital. The impact of mode of conception on the length and complications of the third stage of labor was evaluated. The study group consisted of 242 women with IVF pregnancies (cases), and 484 matched controls with spontaneously conceived pregnancies (controls). The length of the third stage was similar in the cases and controls (14.23 ± 8.89 and 13.69 ± 9.19 min, respectively). IVF pregnancy was associated with a significantly higher rate of postpartum hemorrhage (PPH) (5.79 versus 1.45%,  = .001), manual removal of retained placenta (11.98 versus 7.02%,  = .025), and blood transfusion (2.07 versus 0.41%,  = .032). On multivariate analysis, pregnancy conceived by IVF was an independent risk factor for an adverse outcome of the third stage of labor (OR 2.86, 95% CI 1.53-5.33). After correction for confounders, IVF conception proved to be a significant independent risk factor for PPH, manual removal of the placenta, and blood transfusion in the third stage of labor. Therefore, the management of women who give birth vaginally following IVF pregnancy should be designed to anticipate complications in the third stage even in the absence of other risk factors.
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http://dx.doi.org/10.1080/14767058.2020.1730797DOI Listing
February 2020

Stereotactic Radiosurgery for Brain Metastases in Small Cell Lung Cancer: The Davidoff Cancer Center Experience.

Isr Med Assoc J 2020 Jan;22(1):22-26

Davidoff Cancer Center.

Background: Prophylactic cranial irradiation (PCI) exclusion in favor of brain magnetic resonance imaging (MRI) staging and surveillance in the management of small cell lung cancer (SCLC) is controversial yet accepted by some centers. The use of MRI suggests performing stereotactic radiosurgery (SRS) treatment for limited brain metastases. Data regarding SRS efficacy in this setting is limited.

Objectives: To assess intracranial objective response rate (iORR), progression-free survival (iPFS), intracranial failure patterns, overall survival (OS) and time-to-whole-brain radiation therapy (WBRT)/death, whichever occurred first (TTWD) with SRS in SCLC.

Methods: The study comprised 10 consecutive SCLC patients with brain metastases treated with SRS and followed-up at Davidoff Cancer center between Aug 2012 and March 2019. Brain MRI images were reviewed by a neuro-radiology specialist.

Results: iORR was 57% as assessed by response assessment in neuro-oncology brain metastases. Intracranial progression developed in 8 patients. Median iPFS was 4.0 months (95% confidence interval [95%CI] 1.7-7.2). In-site, off-site and combined pattern of intracranial failure was seen in 0, 5, and 3 patients, respectively; median number of new brain lesions following SRS was 4 (range, 1-12). SRS was performed 10 additional times in 6 patients (median number of lesions irradiated per round was 1, range 1-5). WBRT was administered in 3 patients. Median TTWD was 20.9 months (95% CI, 1.9-26.8). Median OS since SRS administration was 23.2 months (95% CI, 4.2-not reached).

Conclusions: MRI surveillance with multiple rounds of SRS may serve a reasonable alternative to PCI or therapeutic WBRT in SCLC.
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January 2020

Comparative Effect of Proton-Pump Inhibitors on the Success of Triple and Quadruple Therapy for Helicobacter pylori Infection.

Dig Dis 2020 7;38(5):408-414. Epub 2020 Jan 7.

The Ministry of Health, Jerusalem, Israel.

Introduction: Suppression of gastric acid secretion with proton-pump inhibitors (PPI) is an integral part of the treatment of Helicobacter pylori infection. Esomeprazole has been shown to be superior to other PPIs when used in the context of triple therapy; however, comparative data for PPI efficacy in quadruple therapy are lacking. Current guidelines recommend H. pylori eradication with quadruple therapy in areas with high clarithromycin resistance.

Objective: To determine whether esomeprazole is more effective than other PPIs in the context of quadruple therapy for H. pylori eradication.

Methods: We retrospectively identified 25- to 60-year-old subjects with a positive 13C-urea breath test and no prior laboratory or endoscopic test for H. pylori infection. Pharmacy dispensation data were retrieved.

Results: A total of 7,896 subjects including 2,856 (36.2%) males, aged 40.4 ± 10.6 years, were identified. Of those, 78.1% received omeprazole, 20.1% received lansoprazole, 1.5% received esomeprazole, and 0.34% received pantoprazole together with antibiotics for H. pylori eradication. Esomeprazole was associated with a greater proportion of successful eradication (85.0 vs. 77.5%, esomeprazole vs. omeprazole, OR 1.64; 95% CI 0.99-2.72; p = 0.05). A nonsignificant trend favored esomeprazole over omeprazole among subjects receiving quadruple therapy (90.0 vs. 82.0%, respectively, OR 1.98; 95% CI 0.68-5.72; p = 0.16). Independent predictors of treatment success included older age and quadruple therapy.

Conclusion: Esomeprazole is more beneficial than other PPIs for H. pylori eradication. Studies with larger subgroups are necessary to confirm our findings among subjects receiving quadruple therapy.
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http://dx.doi.org/10.1159/000504909DOI Listing
October 2020

Post-Liver Transplantation Anemia and Its Correlation with Mortality and Graft Failure.

Dig Dis Sci 2020 10 3;65(10):3040-3051. Epub 2020 Jan 3.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: In adults, post-liver transplantation anemia (PLTA) is common, but its characteristics and long-term influence on major outcomes have yet to be elucidated.

Aim: We aimed to assess prevalence, characteristics, predictors, and outcomes of PLTA at 6 months (early PLTA) and at 2 years (late PLTA).

Methods: A single-center retrospective cohort study using prospectively collected data from liver transplantations in adults during January 2007-December 2015. PLTA impact on various long-term outcomes was assessed, including mortality, composites of mortality or graft failure, cardiovascular outcomes, and malignancy occurrences.

Results: Hundred and fifty liver transplanted individuals were included. There was a 79% prevalence of anemia pre-transplantation, whereas early and late PLTA were evident in 58% and 40% of patients, respectively. Pre-transplantation anemia was associated with development of early PLTA which was associated with late PLTA. In a multivariate analysis, early PLTA was significantly associated with mortality or graft failure at a follow-up of 3 years (odds ratio 3.838, 95% CI 1.114-13.226). Late PLTA was not significantly associated with worse long-term outcomes.

Conclusions: Early and late PLTA are prevalent among liver transplanted patients. Early PLTA is associated with long-term mortality or graft failure.
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http://dx.doi.org/10.1007/s10620-019-06021-7DOI Listing
October 2020

Alveolar Dead-Space Fraction and Arterial Saturation Predict Postoperative Course in Fontan Patients.

Pediatr Crit Care Med 2020 04;21(4):e200-e206

Pediatric Cardiac Intensive Care Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.

Objectives: Fontan surgery, the final surgical stage in single ventricle palliation, redirects systemic venous blood into the pulmonary circulation for gas exchange. A decrease in pulmonary blood flow can lead to major complications and grave outcomes. Alveolar dead-space fraction represents the portion of inhaled air that does not participate in gas exchange and hence quantifies ventilation-perfusion abnormalities in the lung. Increased alveolar dead-space fraction has been associated with prolonged mechanical ventilation and worse outcome after congenital heart surgery. The association of alveolar dead-space fraction with clinical outcomes in patients undergoing Fontan operation has not been reported.

Interventions: None.

Design, Setting, And Patients: A retrospective charts review of all pediatric patients who underwent Fontan surgery during June 2010-November 2018 in a tertiary-care pediatric hospital. Associations between alveolar dead-space fraction and arterial oxyhemoglobin saturation to a composite outcome (surgical or catheter-based intervention, extracorporeal membrane oxygenation use, prolonged ventilation, prolonged hospital length of stay, or death) were explored. Secondary endpoints were parameters of severity of illness, chest drainage duration, and length of stay.

Measurements And Main Results: Of 128 patients undergoing Fontan operation, 34 met criteria for composite outcome. Alveolar dead-space fraction was significantly higher in the composite (0.33 ± 0.14) versus control (0.25 ± 0.26; p = 0.016) group. Alveolar dead-space fraction greater than or equal to 0.29 indicated a 37% increase in risk to meet composite criteria. Admission arterial oxygen saturation was significantly lower in composite versus control group (93.4% vs 97.1%; p = 0.005). Alveolar dead-space fraction was significantly associated with increased durations of mechanical ventilation, ICU length of stay, duration of thoracic drainage, and parameters of severity of illness.

Conclusions: Alveolar dead-space fraction and arterial saturation may predict complicated postoperative course in patients undergoing the Fontan operation.
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http://dx.doi.org/10.1097/PCC.0000000000002205DOI Listing
April 2020

Extended Follow-up of an Educational Intervention Encouraging Appropriate Use of Blood Transfusions.

Acta Haematol 2020 21;143(5):446-451. Epub 2019 Nov 21.

Institute of Hematology, Davidoff Center, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.

Introduction: A restrictive transfusion strategy of packed red blood cells (PRBCs) has been associated with at least non-inferior patient outcomes in a variety of clinical settings. In December 2014, we conducted an educational intervention which consisted of an oral presentation and computerized notifications at a single tertiary medical center.

Objective: The aim of this study was to examine the long-term effects of a simple and low-cost educational intervention aimed to promote awareness to transfusion guidelines.

Methods: We retrospectively analyzed all PRBC transfusions ordered between 2014 and 2017. The primary end point was defined as the percentage of PRBC transfused to patients with hemoglobin (Hb) ≥8 g/dL.

Results: Between 2014 and 2017, a total of 27,475 PRBCs were transfused in our medical center. There was a continuous reduction in the percentage of PRBCs transfused at a Hb level ≥8 g/dL between 2014 and 2017, with a matching increase in the PRBC percentage trans-fused at Hb <7 g/dL (OR reduction of 42%, 95% CI 0.54-0.62 and OR increase of 68% [95% CI 1.56-1.81], respec-tively).

Conclusion: A simple educational intervention likely contributed to sustained improvement in the appropriateness of PRBC transfusions.
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http://dx.doi.org/10.1159/000503988DOI Listing
October 2020

Distribution of Extreme Vital Signs and Complete Blood Count Values of Healthy Parturients: A Retrospective Database Analysis and Review of the Literature.

Anesth Analg 2019 12;129(6):1595-1606

Surgical Intensive Care Department, Shaare Zedek Medical Center, Jerusalem, Israel.

Background: The impact of physiological adjustments throughout pregnancy on maternal vital signs and laboratory values has yet to be fully defined. The present study was designed to determine the normal range of these parameters among healthy pregnant women during the peripartum period.

Methods: This is a retrospective analysis of data collected during real-time deliveries in a single medical center. Vital signs and laboratory results from the 24 hours preceding delivery room admission and up to 72 hours postpartum were collected. Only pregnant women at term (37 to 41 weeks' gestation) with a liveborn, singleton gestation, and no chronic disease or obstetric complication that could affect the physiological parameters under study were included. The mean, range, and standard deviations of the extremes of all parameters at 3 distinct time points (prelabor, intrapartum, and postpartum) were calculated. The 2.5 and 97.5 percentiles for each parameter were reported as the normal range.

Results: A total of 32,161 cases fulfilled inclusion criteria. The average gestational age at delivery was 39 weeks ± 8 days, and one-third of the cases were primiparous. During labor and after delivery, the upper limits of normal blood pressure values were 147/94 and 145/94 mm Hg, respectively. The lower limits were 83/43 and 83/42 mm Hg, respectively. Normal heart rates were 60-115 beats/min prelabor, 51-120 beats/min intrapartum, and 50-120 beats/min postpartum. Lowest normal temperatures ranged between 36.0°C and 36.3°C in the 3 study time points, and highest normal temperatures were 37.2°C prelabor and 37.6°C intra- and postpartum. The normal ranges of white blood cell counts were 6.1-16.8 prelabor, 6.5-22.5 intrapartum, and 6.4-23.9 K/µL postpartum. Normal low values of hemoglobin were 9.7, 8.7, and 7.1 g/dL and of platelets were 117, 113, and 105 K/µL, respectively.

Conclusions: Our findings justify the practice of using ≥2 repeated measurements for diagnosing hypertensive disorders of pregnancy. Lower normal blood pressure limits may be below those defining hypotensive shock. Normal heart rates exceed the accepted definitions of both tachy- and bradycardia. Normal temperatures at all times have a more narrow range than previously thought, and the normal range of white blood cell count has outliers exceeding the current definitions of leukocytosis or leukopenia at all times. The normal lower range of hemoglobin was constantly below 10 g/dL, and normal platelet counts were considerably lower than those previously described. The vital signs and complete blood count values thus far considered normal for the peripartum period may require some adjustment. New definitions for hypotension, tachy- and bradycardia, fever, and leukocyte quantitative disorders should be considered.
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http://dx.doi.org/10.1213/ANE.0000000000003866DOI Listing
December 2019

Undisclosed Financial Conflicts of Interest of Authors of Clinical Drug Trials Published in Influential Medical Journals: A Cohort Study.

Mayo Clin Proc 2019 11;94(11):2272-2276

Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; Medicine A, Beilinson Hospital, Rabin Medical Center, Petach Tikva, Israel. Electronic address:

The International Committee of Medical Journal Editors requires authors to disclose all financial conflicts of interest (COI) that can be perceived as influencing the related trials. Undisclosed financial COI may influence the perception of the authors' scientific impartiality and erode the public trust in the reported results. Data regarding completeness of COI disclosure in high-impact-factor general medicine journals are limited. We compared payments disclosed by US-based physicians who were first or last authors of clinical drug trials published between August 2016 and August 2018 in the New England Journal of Medicine, JAMA, and Lancet, to payments reported by industry to the Centers for Medicare & Medicaid Services Open Payments Database. Of 247 included authors, 198 (80%) have not disclosed some or all received payments. The median undisclosed sum was $8409 (US Dollars) (interquartile range [IQR] $123 to $44,890). Most authors (n=170, 69%) have received more than $10,000 per year (median $120,403, IQR $58,905 to $242,014). The median undisclosed sum for these authors was $26,530 (IQR $7462 to $71,562). Median undisclosed sums for authors of papers from studies performed with and without industry funding were $20,899 (IQR $4191 to $59,883) and $149 (IQR $0 to $3276), respectively. In 10 (8%) of 125 industry-funded trials, the first or last author had not disclosed personal payments from the study sponsor (median $9741, IQR $4508 to $101,484). These findings could raise concerns about the authors' equipoise toward the trial results and influence the public perception of the credibility of reported data. Health care professionals, reviewers, and journal editors should demand more transparent reporting of financial COI.
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http://dx.doi.org/10.1016/j.mayocp.2019.08.025DOI Listing
November 2019

Immune-related Neutropenia Following Treatment With Immune Checkpoint Inhibitors.

J Immunother 2020 Feb/Mar;43(2):67-74

Thoracic Cancer Service, Davidoff Cancer Center.

The existing data with regard to immune-related neutropenia (irN), a rare (incidence-1%) immune-related adverse event of immune checkpoint inhibitors, are scarce. Eight patients with irN were identified through internal databases of 3 participating Israeli cancer centers. In addition, 11 original articles focusing on the clinical course of 24 patients with irN were selected during the PubMed search. Descriptive analysis of clinical and pathologic factors related to irN was performed (n=32); the effect of these on the irN outcomes was assessed. An algorithm for irN evaluation and treatment was proposed. The median time-to-onset of irN (n=32) was 60 days (range, 10-465 d). Grade 3-5 irN, febrile neutropenia, and irN-related death occurred in 81%, 50%, and 9% of patients, respectively. In all, 56%, 22%, 62%, and 25% of patients received PO corticosteroids, IV corticosteroids, granulocyte colony-stimulating factor (GCSF), and intravenous immunoglobulins (IVIG), respectively, with an improvement/resolution rate of 84%. Odds ratios for irN improvement/resolution were as follows: 1.40 [95% confidence interval (CI), 0.03-68.72], 0.43 (95% CI, 0.04-4.22), 2.60 (95% CI, 0.07-97.24), 0.36 (95% CI, 0.03-4.38), 4.02 (95% CI, 0.16-99.48), 2.01 (95% CI, 0.32-12.70), 1.08 (95% CI, 0.02-49.89), 0.42 (95% CI, 0.06-2.91), and 2.73 (95% CI, 0.42-17.51) for granulocyte hyperplasia, granulocyte/all lineage hypoplasia, granulocyte maturation blockade, lymphocyte infiltration on bone marrow biopsy, IV corticosteroids, PO corticosteroids, cyclosporine, IVIG, and GCSF, respectively (P>0.05 for all factors). IrN recurrence rate following immune checkpoint inhibitors rechallenge was 80%. IrN is a rare, life-threatening, early-onset immune-related adverse event. Differentiating between the central, peripheral, and modified peripheral types allows a better prognosis definition. Corticosteroids and GCSF represent the main treatment approaches; IVIG and cyclosporine should be used as salvage treatment.
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http://dx.doi.org/10.1097/CJI.0000000000000293DOI Listing
September 2019