Sheba Medical Center Research Articles

The Occurrence of Thrombosis during Intensive Chemotherapy Treatment for Acute Myeloid Leukemia Patients Does Not Impact on Long-Term Survival

Introduction A thrombotic event is seen in 10% of newly diagnosed acute myeloid leukemia (AML) patients and has been shown to be associated with disseminated intravascular coagulation (Libourel et al. Blood. 2016). As of yet, the association of developing thrombosis during intensive chemotherapy with AML risk models such as the Medical Research Council (MRC) cytogenetics-based assessment and the European LeukemiaNet (ELN) 2017 molecular based risk model has not been rigorously evaluated. In addition, there is a paucity of data pertaining to the long-term prognostic impact of thrombosis in AML patients. Aiming to investigate these prognostic facets of thrombosis in AML, we performed an analysis of patients with AML diagnosed with thrombosis during treatment with intensive chemotherapy. Methods For this analysis, we collected data on baseline clinical, laboratory, cytogenetic and molecular characteristics of patients with newly diagnosed AML who were treated with intensive chemotherapy and were diagnosed with venous thrombosis. These data were compared with intensively treated patients who did not experience thrombosis to assess for clinical parameters associated with a higher likelihood of developing thrombosis, and to determine whether overall survival was affected by thrombosis. Results The analyzed cohort consisted of 335 newly diagnosed AML patients diagnosed and treated between 2007 through 2021 at the Sheba Medical Center. Median patient age at diagnosis was 55 years. At the time of data analysis 162 patients were alive (48%). Two hundred and eighty-three patients were classified as de novo AML (85%) and the remainder were categorized as secondary disease (15%). Ninety patients harbored the FLT3-ITD mutation (28%) and 117 patients harbored NPM1 mutations (39%). Of evaluable patients, 7 were found to have biallelic CEBPA mutations (8%). In terms of MRC cytogenetic risk, 35 patients (11%) were classified as favorable risk, 219 (66%) patients as intermediate risk, 58 patients (17%) as adverse risk and 21 patients had technically insufficient cytogenetic studies. Using the ELN 2017 risk stratification model, 132 patients (40%) had favorable risk disease, 122 patients (36%) intermediate risk, and 80 patients (24%) adverse risk disease. Venous thrombosis was seen in 33 patients (9.9%) with 28 patients diagnosed with central catheter related thrombosis and 5 patients with lower extremity deep vein thrombosis. In 23 patients (70%) thrombosis occurred during the initial induction chemotherapy phase, in 5 patients (15%) during the first consolidation treatment phase, in 3 patients (9%) during the second consolidation treatment phase, and in 2 patients (6%) during admission for salvage chemotherapy. Following diagnosis of thrombosis, the central catheter was taken out in 9 patients (28%), and 3 patients (8.8%) experienced a recurrence of thrombosis. At the time of thrombosis diagnosis, 14 patients (42%) were found to have a concurrent blood stream bacterial infection. Nineteen patients (58%) were started on anticoagulation following the diagnosis of thrombosis. In univariate analysis, patient age, initial levels of white blood cells, hemoglobin, platelets, creatinine, uric acid, lactate dehydrogenase, INR, albumin, and liver function tests were not significantly different between patients who developed thrombosis and those who did not. Disease type (de novo versus secondary), FLT3-ITD and NPM1 mutational status, achievement of remission, and ELN 2017 risk category also not did not differ to a significant degree between groups. However, MRC intermediate risk group patients were significantly more likely to experience thrombosis compared to favorable risk and adverse risk patients (12.8% versus 5.7% and 1.7%, respectively; p=0.049). Overall survival was not significantly impacted by the diagnosis of thrombosis with an estimated median overall survival of 3.7 years seen in patients without thrombosis compared with 2.2 years in patients with thrombosis (p=0.47). Leukemia-free survival was also comparable between groups (2.4 years versus 1 year; p=0.15). Conclusion Venous thrombosis is seen mostly during the initial induction phase of AML patients receiving intensive therapy with a tight association with the MRC intermediate risk category, however long-term survival and leukemia related outcomes are not significantly impacted by the diagnosis of thrombosis.

Abstract A063: PARPi and ATRi (AZD6738) in BRCA associated PDAC patient derived xenograft model

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease, with the majority of patients diagnosed at an advanced stage. Comprehensive genomic analysis identified the homologous recombination deficiency (HRD) subgroup which is predominantly enriched in patients harboring germline BRCA1/2 mutations (glBRCA) and presents ~7% and up to 15% in selected high-risk populations. Tumors with HRD are susceptible to DNA-damaging agents and PARP inhibition. However, not all patients demonstrate a similar response, and a spectrum is observed. We analyzed the clinical outcome of ninety-one glBRCA PDAC patients treated at Sheba Medical Center. We identify three main subgroups of response spanning from ~25% patients refractory to first line platinum agents and ~9% patients with durable long-term response with no evidence of disease for over three years. The majority of the patients display a prolonged response to platinum and PARPi maintenance (>24 months) followed by acquired resistance. ATR, a central mediator in DDR, is activated by multiple DNA damage events. Activated ATR induces cell-cycle arrest and facilitates DNA repair. Inhibition of ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA-damaging agents. Therefore, we propose combinational therapy of PARPi with ATRi. This combination treatment is expected to enhance response to PARPi in BRCA-mutated PDAC patients naïve to treatment and might extend efficacy. We generated unique patient derived xenograft (PDX) models (n=25) at distinct clinical scenarios - from naïve to treatment tissue and at clinical resistance. In-vivo efficacy to platinum agents and PARPi demonstrates that these models recapitulate the specific clinical spectrum of response. However, accumulating resistance emerges and additional therapies need to be investigated. Furthermore, we have generated an in-vivo resistant paired models from an initially platinum sensitive BRCA-PDXs, mimicking the patient clinical scenario from sensitivity to resistance. PARP and ATR combined inhibition was assessed in a PDX model generated from a glBRCAmut PDAC patient, naïve to platinum/PARPi treatment. PDX were randomized to the following groups: 1. vehicle control; 2. PARPi olaparib AZD2281 (100 mg/kg, 5 days a week IP); 3. ATRi AZD6738 (25 mg/kg, 5 days a week; PO); 4. ATRi + PARPi combination. PARPi treatment attenuated tumor growth for 42 days followed by re-growth. A significant difference in tumor growth was obtained with the combined PARPi and ATRi treatment (p<0.05). Experiment is ongoing currently on day 84 and we intend to proceed while tolerated or until resistance will develop. Our preliminary in-vivo results suggest that the combinatorial treatment of PARPi and ATRi may delay resistance to single agent PARPi. This extensive preclinical and clinical collection of BRCA associated PDAC, enables further understanding and investigation of this unique subtype in aim to develop alternative treatments to overcome resistance. Citation Format: Talia Golan, Dikla Atias, Chani Stossel, Maria Raitses Gurevich, Yulia Gurmon Glick, Sharon Halparin, Elina Haimov Talmoud, Nora Amison, Tamar Beller, Raanan Berger. PARPi and ATRi (AZD6738) in BRCA associated PDAC patient derived xenograft model [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A063.

Defining Current Patterns of Blood Product Use during Intensive Induction Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia Patients

Introduction Blood product transfusion continues to retain a critical role in the supportive care of patients with acute myeloid leukemia (AML) particularly during the initial phase of intensive induction chemotherapy. Whereas previous studies have shown increased transfusion dependency to portend inferior outcome, clinical and disease features predictive of an increased transfusion burden and the overall prognostic impact of transfusion support in this setting have not been determined as of yet. Herein, we evaluated the various blood product components administered during induction aiming to delineate current transfusion practices in AML patients. Methods We reviewed the medical records of 180 consecutive adult patients with newly diagnosed AML, who were treated with intensive chemotherapy from December 2014 through January 2022 at the Sheba Medical Center. Clinical data extraction and exploration were done with the MDClone big data platform. All patients assessed in the study received standard anthracycline and cytarabine-based intensive induction chemotherapy or CPX-351. Patients received irradiated and leukodepleted blood products. Alloimmunization was defined according to the National Heart, Lung, and Blood Institute working group criteria. Results The analysis comprised 180 patients with a median age of 57 years (range 19-77) with 80% designated as de novo AML and the remainder as secondary AML. Fifty-four patients (31%) were FLT3-ITD mutated and 73 patients (42%) harbored NPM1. Favorable risk and intermediate risk ELN 2017 patients accounted for 43% and 34% of patients, respectively. The median number of red blood cell (RBC) and platelet units given during induction were 9 units and 7, respectively. Seventeen patients (9%) received cryoprecipitate and fresh frozen plasma (FFP) was given to 12 patients (7%). Lower initial hemoglobin and platelet levels were predictive of increased use of RBC (p<0.0001) and platelet transfusions (p<0.0001). Use of FFP was significantly associated with induction related mortality (42% versus 5%; p<0.0001) and with FLT3-ITD status (72% versus 28%; p=0.004). Transfusion associated alloimmunization was seen in 7 patients (4%) with patients with lower mean initial platelet counts being more likely to experience alloimmunization (38 X 109/l versus 83 X 109/l; p=0.01). Alloimmunized patients had significantly higher RBC transfusion (14 units versus 9.5 units; p=0.012) and prestorage leukodepleted filtered RBC (6.1 units versus 1.6 units; p<0.0001) requirements during induction compared with non-alloimmunized patients. Blood group AB experienced improved mean overall survival compared to blood group O patients (4.1 years versus 2.8 years; p=0.025). In multivariate analysis, increased number of FFP [hazard ratio (HR), 4.23; 95% confidence interval (CI), 2.1-8.6; p<0.001) and RBC units (HR, 1.8; 95% CI, 1.2-2.8; p=0.008) given was associated with inferior survival. Conclusion In this analysis we comprehensively mapped the transfusion trajectory of AML patients during induction therapy and identified clinically meaningful associations impacting the need for the various blood components as well as overall survival. Transfusion needs during induction crucially impact the clinical trajectory of AML patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Failure to Detect Leishmania in the Blood of Patients with Old-World Cutaneous Leishmaniasis: Implications for Blood Donation.

Cutaneous leishmaniasis (CL) is endemic in Israel, caused mainly by Leishmania major (L. major) and L. tropica. In addition, returning travelers import another leishmanial species such as L. braziliensis. Although we are dealing with a skin disease, the blood bank in Israel does not accept blood donations from people infected with CL in cases of multiple lesions due to the possibility of transfusion. Our purpose was to investigate the prevalence of Leishmania in the blood of patients with active or previous CL. This pilot study screened patients with active or previous CL for parasites in their blood. All patients were infected in Israel or were returning travelers with leishmaniasis acquired in Latin America. Patients were seen at the Sheba Medical Center. In addition, patients were seen at their homes in L. tropica and L. major endemic regions in Israel. Blood samples were taken from each patient for culture and polymerase chain reaction (PCR). Altogether 62 blood samples were examined (L. tropica = 26, L. major = 33, and L. braziliensis = 3). Twenty-seven patients had an active disease and 35 were recovered. All blood cultures and PCR were negative for parasites except one blood sample that was PCR positive for L. braziliensis. The findings of our study, although a small sample, suggest that people with active or recent CL caused by L. major and L. tropica, do not harbor parasites in their blood. Thus, their exclusion from blood donation should be revisited. Further studies are needed with larger sample size and highly sensitive tests.

BREAst Cancer Personalised NuTrition (BREACPNT): dietary intervention in breast cancer survivors treated with endocrine therapy – a protocol for a randomised clinical trial

IntroductionBreast cancer survivors treated with adjuvant endocrine therapy commonly experience weight gain, which has been associated with low adherence to therapy and worse breast cancer prognosis. We aim to assess...

Management and outcome of patients with non-ST elevation myocardial infarction and intercurrent non-coronary precipitating events.

To evaluate the effect of an intercurrent non-coronary illness on the management and outcome of patients with non-ST-segment elevation myocardial infarction (NSTEMI). Consecutive hospitalized patients with a primary diagnosis of NSTEMI between August 2008 and December 2019 at Sheba Medical Center. All patients' records were reviewed for the presence of a non-coronary precipitating event (NCPE): a major intercurrent acute non-coronary illness or condition, either cardiac or non-cardiac. The primary outcome was all-cause mortality. Cox regression with interaction analysis was applied. Final study population comprised 6491 patients, of whom 2621 (40%) had NCPEs. Patients with NCPEs were older (77 vs. 69 years) and more likely to have comorbidities. The most prevalent event was infection (35%, n = 922). During a median follow-up of 30 months, 2529 patients died. Patients with NCPEs were 43% more likely to die during follow-up in a multivariable model (95% CI: 1.31-1.55). Invasive strategy was associated with a 55% lower mortality among patients without NCPE and only 44% among patients with NCPE (P for interaction < 0.001). Dual antiplatelet therapy (DAPT) was associated with a 20% lower mortality in patients without NCEP and a non-significant mortality difference among patients with NCPE (P for interaction = 0.014). Sub-analysis by the specific NCPE showed the highest mortality risk among patients with infectious precipitant. The lower mortality associated with invasive strategy was not observed in this subgroup. Among NSTEMI patients, the presence of an NCPE is associated with poor survival and modifies the effect of management strategies.

Trans-catheter edge-to-edge mitral valve repair in patients with acute decompensated heart failure due to severe mitral regurgitation – a single centre experience

Abstract Introduction Recent series have demonstrated the benefit of trans-catheter edge-to-edge mitral valve repair (TEER) in acutely ill hospitalised patients with severe mitral regurgitation (MR) and intractable heart failure despite intensive intravenous therapy. We describe our cumulative experience with such patients at the Sheba Medical Centre over a 10 year period. Purpose The purpose of this study was to evaluate the safety and efficacy of TEER in hospitalized patients with acute decompensated heart failure and severe MR that was deemed to play a major role in the patients' deterioration. Methods We included 30 hospitalised patients with intractable heart failure and MR ≥3+ (20 males; mean age 74.2±10.6 years; 10 had cardiogenic shock). MR was primary in 4, secondary in 24 and mixed in 2 patients. Acute results were assessed by echocardiography prior to discharge and safety was evaluated clinically, according to the occurrence of procedure-related adverse events. Mortality data were drawn from the national death registry. Results TEER devices were successfully implanted in 28 patients. Early (POD 1) procedure-failure was noted in one patient due to recurrence of flail. There was no peri-procedural mortality. Two patients were hemodynamically unstable during the procedure. One patient had peri-procedural access site bleeding necessitating blood transfusion. Following intervention, 16 patients required ICU care (mean stay 4.8±2.5 days), shock was recorded in 7 patients, 16 required hemodynamic support, and 8 required invasive ventilation. At 30 days 7 patients had died and an additional 4 died 1 to 6 months following intervention. However, mortality in the remaining patients was low with only 3 additional deaths up to 4 years after the procedure (80% of patients alive at 6 months). MR reduction was achieved in 24 patients (to ≤mild in 10 and to moderate in 11). At 12 months follow up MR severity was mild in 3 (37.5%) and moderate in 5 (62.5%) patients. Only 1 patient reported HF rehospitalisation during the year following the procedure. Conclusion TEER for hospitalised patients with severe MR and intractable heart failure is safe, associated with high early mortality, and good long-term outcome for patients alive 6 months after the procedure. More research is needed to better characterise patients likely to benefit from TEER in this clinical scenario. Funding Acknowledgement Type of funding sources: None.

Outcome of subsequent pregnancies post uterine rupture in previous delivery: A case series, a review, and recommendations for appropriate management.

To provide clinicians with concrete solutions on the best management of and counseling for patients in a subsequent pregnancy following uterine rupture. A retrospective analysis of patients treated between 2005 and 2020 at Sheba Medical Center was conducted. All patients who had undergone a complete uterine rupture and subsequently had a full-term pregnancy were included. A literature review was conducted using Pubmed database and including previously published literature reviews. Fifteen patients with subsequent pregnancies following uterine rupture were included in our cohort. Mean interval between rupture and subsequent pregnancy was 3.8 years (range 2.2-6.9 years). One patient had repeat uterine rupture of less than 2cm at 36+5 weeksof pregnancy. A total of 17 studies were selected in this literature review, including a total of 774 pregnancies in 635 patients. The risk of repeated uterine rupture was 8.0% (62/774), ranging from 0% to 37.5%. Overall, the risk of maternal death was of 0.6% (4/635), with only four cases reported in three studies. The risk of recurrence after uterine rupture is significant but should not prevent patients from conceiving.

Changing spectrum of hair and scalp disorders over the last decade in a tertiary medical centre.

Hair- and scalp-related disorders (HSRDs) encompass a wide range of conditions that affect people of all ages. To evaluate the workload and trends in HSRDs at an outpatient dermatological clinic in a tertiary medical centre over a 10-year period. Medical records for HSRD visits to the outpatient dermatology clinic at the Sheba Medical Center, an Israeli tertiary care center, were reviewed between 1 January, 2010 and 31 December, 2020. There were 10,396 HSRD visits with a new-to-follow-up visit ratio of 1:1.9. The annual number of HSRD visits, as well as their proportion out of all dermatological outpatient visits, have increased from 295 (1.24%) in 2010 to 1726 (9.44%) in 2020. The patients' mean age was 35.3 years (women 39.5 years, men 28.8 years), age range 1-87 years. Over the decade, there was a growing predominance of women with an average female-to-male ratio of 2:1. The winter season accounted for 28.7% of annual visits, followed by the autumn (25.6%), summer (24.3%) and spring (21.4%). The most prevalent HSRDs included androgenetic alopecia (30.6%), alopecia areata (19.3%), telogen effluvium (15.4%), non-scarring folliculitis (15.4%), seborrheic dermatitis (14.9%), lichen planopilaris (7.1%) and folliculitis decalvans (6.6%). Androgenetic alopecia demonstrated the highest increase over the decade examined (from 17% to 32%). HSRDs account for a significant percentage of visits at a tertiary dermatology outpatient clinic. The number of HSRD visits has increased annually over the past decade. The recent advancement in diagnosis and treatment may account, at least in part, for the growing burden of HSRDs within dermatological ambulatory care.

Determining the origin of different variants associated with familial mediterranean fever by machine-learning

A growing number of familial Mediterranean fever (FMF) patients in Israel do not have a single country of origin for all four grandparents. We aimed to predict the Mediterranean fever gene (MEFV) variant most likely to be found for an individual FMF patient, by a machine learning approach. This study was conducted at the Sheba Medical Center, a referral center for FMF in Israel. All Jewish referrals included in this study carried an FMF associated variant in MEFV as shown by genetic testing performed between 2001 and 2017. We introduced the term ‘origin score’ to capture the dose and different combinations of the grandparents’ origin. A machine learning approach was used to analyze the data. In a total of 1781 referrals included in this study, the p.Met694Val variant was the most common, and the variants p.Glu148Gln and p.Val726Ala second and third most common, respectively. Of 26 countries of origin analyzed, those that increased the likelihood of a referral to carry specific variants were identified in North Africa for p.Met694Val, Europe for p.Val726Ala, and west Asia for p.Glu148Gln. Fourteen of the studied countries did not show a highly probable variant. Based on our results, it is possible to describe an association between modern day origins of the three most common MEFV variant types and a geographical region. A strong geographic association could arise from positive selection of a specific MEFV variant conferring resistance to endemic infectious agents.

Assessment of Immediate Allergic Reactions After Immunization With the Pfizer BNT162b2 Vaccine Using Intradermal Skin Testing With the COVID-19 Vaccines

BackgroundAllergic reactions to the coronavirus disease 2019 (COVID-19) vaccines have raised concerns, particularly as repeated doses are required. Skin tests with the vaccines excipient were found to be of low value, whereas the utility of skin tests with the whole vaccine is yet to be determined.ObjectiveTo evaluate a panel of skin tests and the outcomes of subsequent doses of immunization among subjects who suffered an immediate allergic reaction to the BioNTech (BNT162b2) COVID-19 vaccine.MethodsBetween March and December 2021, patients who experienced symptoms consistent with immediate allergic reactions to the BNT162b2 vaccine and were referred to the Sheba Medical Center underwent skin testing with polyethylene glyol (PEG)-containing medicines, Pfizer-BNT162b2, and Oxford–AstraZeneca vaccine (AZD1222). Further immunization was performed accordingly and under medical observation.ResultsA total of 51 patients underwent skin testing for suspected allergy to the COVID vaccines, of which 38 of 51 (74.5%) were nonreactive, 7 of 51(13.7%) had no skin sensitization but suffered a clinical reaction during skin testing (mainly cough), and 6 of 51 (11.7%) exhibited immediate skin sensitization. Both skin sensitization and cough during testing were related to a higher use of adrenaline following immunization (P = .08 and P = .024, respectively). Further immunization with the BNT162b2 vaccine was recommended unless sensitization or severe reaction to previous immunization was evident. The latter were referred to be tested/receive the alternative AZD1222 vaccine. Ten patients underwent skin testing with AZD1222: 2 of 10 (20%) demonstrated skin sensitization to both vaccines; thus, 8 of 10 were immunized with the AZD1222, of which 2 of 8 (25%) had allergic reactions.ConclusionsImmediate allergic reactions to COVID-19 vaccines are rare but can be severe and reoccur. Intradermal testing with the whole vaccine may discriminate sensitized subjects, detect cross-sensitization between vaccines, and enable estimation of patients at higher risk.

Rapid Antigen Tests For Safe School Opening in the COVID-19 Pandemic Era.

Background:Since the beginning of the Sever Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, school closure as a mitigating measure was at the center of a public and professional debate. While the negative effects of school closure cannot be ignored, accumulating data suggested that it is necessary for reducing community transmission. Our study presents an optional strategy for safe school opening during a pandemic, implemented in selected Israeli high schools by a special task force constructed by the Sheba Medical Center (SMC).Methods:The study took place between November 2020 and April 2021. Three schools from different areas of Israel were enrolled. The participants were asked to undergo bi-weekly SARS-CoV-2 rapid diagnostic antigen tests (Ag-RDT). Those who tested positive were requested to self-isolate, whereas their school contacts were tested daily by Ag-RDT. Participants with a previously documented SARS-CoV-2 infection or who were found to be SARS-CoV-2 seropositive upon enrollment were exempted from screening.Results:Of a total of 361 participants who enrolled in the study, 12.3% were found to be seropositive. Fourteen SARS-CoV-2 cases were detected (3.5%), 12 of them in one single school located in an endemic area for SARS-CoV-2. The 14 cases resulted in 84 days of COVID-19-related absence from school, comparing with 1775 potential days of COVID-19-related absence under a strategy implementing self-isolation instead of testing.Conclusions:Safe continuation of academic routine during the pandemic is possible when using rapid Ag-RDT as a screening tool, while allowing swab collection by trained students and teachers.

Determinants of Quality of Life in Individuals With Spinal Cord Injury Using Structural Equation Modeling

ObjectiveThe objective of this study is to examine the interdependent associations between International Classification of Functioning, Disability and Health (ICF) domains and their relationship with environmental factors with regard to quality of life (QoL) in individuals with spinal cord injury (SCI). DesignSurvey, cross-sectional study, and model testing using structural equation modeling. SettingTwo inpatient and outpatient SCI rehabilitation units, Sheba Medical Center and Loewenstein Hospital, Israel. ParticipantsConvenience sample of 156 individuals with SCI (N=156). InterventionsNot applicable. Main Outcome MeasuresQoL assessed by the World Health Organization Quality of Life Assessment-BREF.Neurological impairment after SCI reflected by lesion completeness and neurologic level of injury as measured by the International Standards for Neurological Classification of Spinal Cord Injury.The Spinal Cord Independence Measure to assess SCI-related task performance.ICF Brief Core Sets composition scores to assess impairment in body structure and function domains, limitations in activities, restriction in participation constructs, and the effect of environmental factors within the ICF model. ResultsLevel of spinal cord injury and ICF Brief Core Sets composite score relating to activities and participation construct demonstrated a direct significant association with QoL. Moreover, a significant indirect association with QoL was found between the composite scores in ICF body structure and function and environmental factors, level of spinal cord injury, time since injury onset, and sex. Because the Spinal Cord Independence Measure was not related to QoL, we inferred that the categories related to instrumental activities of daily living and participation exert the most significant influence on QoL. ConclusionsIn order to optimize improvements in quality of life, current rehabilitation programs should target limitations specifically related to instrumental activities of daily living and participation restrictions. It may serve as a focal point for further development of current therapeutic models and analytical methods that optimize rehabilitation planning and decision making among both health care professionals and patients.

Incidentally Diagnosed Asymptomatic Crohn's Disease: A Retrospective Cohort Study of Long-Term Clinical Outcomes.

Crohn's disease (CD) is occasionally diagnosed in asymptomatic patients who have undergone colonoscopy or imaging for other reasons. The clinical outcome and optimal management of these patients remain poorly defined. This was a retrospective cohort study of asymptomatic patients with incidental diagnosis of CD from the electronic patient registry of the IBD Unit of Sheba Medical Center in Israel. The primary outcome was defined as the occurrence of a clinical flare. Of the 2700 CD patients in Sheba IBD registry, 60 asymptomatic patients with incidental diagnosis of CD were identified (31/60 males, median age 50.5, 25%-75% interquartile range [IQR] 43.5-57.25 years, median follow-up 4.5 years, 25-75% IQR 2.5-6.75, range 1-15 years). Most of the patients did not receive any treatment after diagnosis (53/60-88.33%). Of these, 5 patients (9.43%) experienced a flare during follow-up (median 4.5 years, IQR 2.5-6.75, range 1-15 years). Patients with subsequent flare had numerically higher CRP at diagnosis than patients who did not flare (2.2, IQR 2.0-3.0 vs 1.04, IQR 1.0-2.2, P = .09). When comparing the group of patients who received treatment immediately after diagnosis (n = 7) with the group who did not receive treatment (n = 53), there was no difference with respect to the survival time without a flare (P = .3). For other secondary outcomes, 3/40 progressed from B1 phenotype to B2, and 3/53 (6%) patients underwent surgery during the follow-up. The majority of patients with an incidental diagnosis of asymptomatic CD can probably be followed-up without immediate treatment. Although most remain asymptomatic and without complications during follow-up, close monitoring for disease progression is prudent.

Surgical treatment on infective endocarditis: impact of diabetes on mortality

BackgroundType 2 diabetes mellitus (DM) is a frequent co-morbidity among patients suffering from infective endocarditis (IE). The aim of the study was to evaluate the impact of type 2 DM on the early-, intermediate- and long-term mortality of patients who underwent surgical treatment of endocarditis.MethodsWe performed an observational cohort study in the large tertiary center in Israel during 14 years. All data of patients who underwent surgical treatment of endocarditis, performed between 2006 and 2020 were extracted from the departmental database. Patients were divided into two groups: Group I (non-diabetic patients), and Group II (diabetic patients).ResultsThe study population includes 420 patients. Group I (non-diabetic patients), comprise 326 patients, and Group II (diabetic patients), comprise 94 patients. Mean follow-up duration was 39.3 ± 28.1 months. Short-term, 30-day and in-hospital mortality, also intermediate-term mortality (1- and 3-year) was higher in the DM group compared with the non-DM group, but did not reach statistical significance: 11.7% vs. 7.7%. (p = 0.215); 12.8% vs. 8.3% (p = 0.285); 20.2% vs. 13.2% (p = 0.1) and 23.4% vs. 15.6% (p = 0.09) respectively. Long-term, 5-year mortality was significantly higher in the DM group, compared to the non-DM group: 30.9% vs. 16.6% (p = 0.003). Furthermore, predictors for long-term mortality included diabetes (CI 1.056–2.785, p = 0.029), as demonstrated by regression analysis.ConclusionsDiabetic patients have trend to increasing mortality at the short- and intermediate period post-surgery for IE, but this is not statistically significant. Survival of diabetic patients deteriorates after more than three years follow surgery. Diabetes is an independent predictor for long-term, 5-year mortality after surgical treatment of endocarditis, regardless of the patients age and comorbidities.Trial registration Ethical Committee of Sheba Medical Centre, Israel on 02.12. 2014, Protocol 4257

Prognostic Value of Optical Coherence Tomography Characteristics in Anterior Visual Pathway Meningiomas.

Anterior visual pathway meningiomas (AVPM) represent 2.5%-18% of all meningiomas. They may affect visual function, including visual acuity (VA) and visual field (VF). The principal modes of treatment are surgery and radiotherapy. The prognostic value of macular ganglion cell complex count (GCC) thickness has not been assessed in the literature thus far. The purpose of this study was to evaluate the prognostic value of pre-treatment optical coherence tomography (OCT) parameters (retinal nerve fiber layer and GCC) for visual outcomes in patients with AVPM. We retrospectively reviewed the medical records of all patients with AVPM who were treated in the Sheba Medical Center between 2011 and 2020. Included were patients with valid data containing preintervention OCT findings on the CIRRUS device and a minimum follow-up of 6 months. Preintervention and postintervention data on comprehensive ophthalmic examinations and OCT parameters of the affected eyes were retrieved. The correlation between preintervention OCT parameters and the visual outcome was assessed. The patients were also divided into 2 groups according to preintervention GCC (thin vs normal), and the visual outcome was compared between groups. In total, 186 patients' medical records were analyzed, and 38 patients who met the inclusion criteria were included in the study (mean age at diagnosis 52.8 ± 12.2 years, 28 women). Twenty-nine patients had 1 affected eye, and 9 had bilateral insult. A higher preinterventional average GCC was associated with better VA at 6 months, 1 year, and 2 years after intervention (r = -0.5, P ≤ 0.004, 0.005, and 0.03, respectively). There was a significant correlation between preinterventional GCC and VF mean deviation 2 years after intervention (r = 0.7, P ≤ 0.001). The thinner the GCC, the more prominent was the change in VA from before intervention to 2 years after intervention ( P ≤ 0.008). Correction for multiple comparisons with the Benjamini-Hochberg procedure did not change the significance of our findings. OCT parameters (GCC) have a predictive value in AVPM. There is strong correlation between preinterventional GCC and VA shortly after the intervention. Although a thin GCC is generally considered a negative prognostic factor, improvement in clinical parameters was also evident in patients with thin GCC. The potential of improvement despite preinterventional GCC thinning can add to the clinical discussion of the prognosis, and therefore, we recommend the patients with AVPM to undergo OCT and to be advised that GCC thinning alone should not be used as a major criterion in deciding whether treatment should be pursued.

Abstract 2148: Pre-clinical models recapitulating the spectrum of response of BRCA associated pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease, with the majority of patients diagnosed at an advanced stage. Comprehensive genomic analysis identified the homologous recombination deficiency (HRD) subgroup which is predominantly enriched in patients harboring germline BRCA1/2 mutations (glBRCA) and presents ~7% and up to 15% in selected high-risk populations. Tumors with HRD are susceptible to DNA-damaging agents and PARP inhibition. However, not all patients demonstrate a similar response, and a spectrum is observed. We analyzed the clinical outcome of ninety-one glBRCA PDAC patients treated at Sheba Medical Center. We identify three main subgroups of response spanning from ~25% patients refractory to first line platinum agents and ~9% patients with durable long-term response with no evidence of disease for over three years. The majority of the patients display a prolonged response to platinum and PARPi maintenance (&amp;gt;24 months) followed by acquired resistance. We generated patient derived xenograft (PDX) models and an ex-vivo culture system (EVOC) from naïve to treatment tissue and at clinical resistance. In vivo efficacy to platinum agents and PARPi demonstrates that these models recapitulate the specific clinical spectrum of response. We demonstrate the utility of both pre-clinical models in their ability to predict response to platinum-based agents and PARPi, with EVOC having a potential to assist in medical decisions while treating the patient. Whole genome sequencing of the tumors revealed that BRCA monoallelic tumors are associated with innate resistance while biallelic tumors reflect sensitivity to platinum agents and PARPi. In the acquired resistance models, the main identified mechanism of resistance was due to reversion mutations in 4/6 of samples. Whole genome analysis demonstrates high mutational and neo-antigen load in majority of the glBRCA tumors. In a preliminary study, we show the efficacy of anti PD1 in a novel humanized glBRCA PDAC PDX model. This extensive preclinical and clinical collection of BRCA associated PDAC, enables further understanding and investigation of this unique subtype in aim to develop alternative treatments to overcome resistance. Citation Format: Talia Golan, Chani Stossel, Maria Raitses-Gurevitch, Dikla Atias, Tamar Beller, Steven Gallinger, Raanan Berger. Pre-clinical models recapitulating the spectrum of response of BRCA associated pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2148.

BRAF-targeted therapy for locally advanced ameloblastoma of the mandible: A potential neoadjuvant strategy.

3149 Background: Ameloblastoma is a rare benign but locally aggressive odontogenic neoplasm, with 2% of cases representing ameloblastic carcinoma or metastatic ameloblastoma. It affects young adults with high recurrence rates after surgery. The standard therapy is radical bone resection with subsequent functional, aesthetic &amp; psychological impairments. Therefore, other therapeutic options, including neoadjuvant approach, should be considered. Sixty to 70% of mandible Ameloblastoma carry a BRAF mutation, usually V600E, and previous case reports have shown durable responses to treatment with BRAF inhibitors in these patients. We sought to explore the possibility of neoadjuvant BRAF or BRAF+MEK inhibition as neoadjuvant treatment in mandible Ameloblastoma. Here we present results of 12 patients with locally advanced disease who were treated with BRAF with or without MEK inhibitors. Methods: Patients who were unable to undergo jaw preservation surgery for locally advanced Ameloblastoma with a BRAF V600E mutation were treated with Dabrafenib or Dabrafenib-Tratmetinib in an EAP form. Patient records were analyzed for baseline parameters, treatment regimen, toxicity, response to therapy and the ability to convert to a mandible preservation surgery. Data were collected and analyzed in accordance with Sheba Medical Center IRB approval. Statistical analyses were done with STATA v.17. Results: Twelve patients were treated with Dabrafenib/ Dabrafenib-Tratmetinib between 2017-2021. Five patients received BRAF-MEK inhibitors and 7 BRAF inhibitor alone. Median age was 21. Ten patients(83%) showed excellent response to therapy and have successfully converted from planned radical bone resection to mandible preservation surgery. The other 2 patients are still on therapy and have also showed deep responses that enable conversion to mandible preservation. Median time to surgery was 10 months. With median follow up of 18 months, no cases of recurrence were documented. Rate of adverse events was as expected with only 1 case of G3-4 (hepatitis). Conclusions: Targeted therapy with BRAF with or without MEK inhibition may serve as an important therapeutic tool for locally advanced Ameloblastoma with the potential of organ preservation treatment, and is an important example of oncological therapy assisting in non-cancerous tumors.

Single versus dual antiplatelet therapy following transcatheter left atrial appendage closure

Abstract Funding Acknowledgements Type of funding sources: None. Background Left atrial appendage occlusion (LAAO) had emerged as an alternative to anticoagulation in patients with non-valvular atrial fibrillation and a contraindication to long-term oral anticoagulants (OAC). LAAO implantation aims to reduce the risk of both systemic thromboembolism and the bleeding events associated with prolonged OAC. Post-procedural antithrombotic regimen varies among patients and may include antiaggregant (dual or single agents) or anticoagulation therapy in minority patients. The current study aims to compare the effectiveness and safety of post-procedural antithrombotic treatment with either dual antiplatelet therapy (DAPT) or single antiplatelet therapy (SAPT) in a real-world cohort. Methods The cohort consisted of 205 consecutive patients who had undergone LAAO at Sheba medical center between the years 2010-2020. We prospectively evaluated baseline characteristics and periprocedural clinical, laboratory, and imaging data. All patients were followed by scheduled in-clinic visits. After excluding patients prescribed OAC following the procedure or deceased in the index procedure, the study cohort was divided into two groups according to the antithrombotic regimen following the LAAO: SAPT (35 patients) versus DAPT (151 patients). A propensity analysis via the stabilized inverse-probability-of-treatment weighting (IPTW) was applied. Results The leading etiologies for transcatheter LAAO were previous gastrointestinal bleeding (41%) and previous intracranial bleeding (32%). The median CHADSVASC score is 5 [IQR:4-6]. Patients discharged with SAPT following LAAO were older (78±8 yrs vs.75±8 yrs), accompanied by an evident trend over the years of discharging more patients with SAPT instead of DAPT (Figure 1). No statistically significant differences were observed in other baseline characteristics, including gender, hypertension, diabetes mellitus, malignancy, chronic renal or heart failure. During two years of clinical follow-up, no differences in major adverse cardiovascular events were observed between the two groups (20% vs.19% for SAPT and DAPT, respectively). After applying an IPTW propensity analysis adjusting for several clinical and procedural relevant parameters, a K-M survival curve demonstrates no survival benefits of dual over single antiplatelet therapy (Figure 2). Conclusions Among patients undergoing LAAO, post-procedural DAPT provides no survival benefits over single antiplatelet therapy.

Human metapneumovirus prevalence during 2019-2021 in Israel is influenced by the COVID-19 pandemic

To compare infection rates and circulating subtypes of human metapneumovirus (hMPV) before (2019-2020) and after the emergence of coronavirus disease 2019 (COVID-19) (2021) in Israel. In total, 12,718 respiratory samples were collected from hospitalized patients of all ages during the years 2019 to 2021 at the Sheba Medical Center in Israel and subjected to reverse transcription-polymerase chain reaction analysis. In addition, whole-genome sequencing was performed to characterize the subtypes of hMPV circulating in Israel between 2019 and 2021. A total of 481 samples were found positive for hMPV. Before the emergence of COVID-19, hMPV peaked in winter months and declined thereafter. In sharp contrast, during the COVID-19 pandemic, we observed a delayed peak in hMPV infection cases and higher infection of young children. Viral sequencing showed a shift in the most prevalent circulating hMPV strain from A2b to B1 during the years 2019, 2020, and 2021. Compared with the years before the COVID-19 pandemic, in 2021, hMPV mostly affected young children, and the most prevalent circulating subtype shifted from A2b in 2019 to B1.