Efrat Ofek - Academia.edu (original) (raw)

Papers by Efrat Ofek

Supplementary Data from The Expression of Three Genes in Primary Non–Small Cell Lung Cancer Is As... more Supplementary Data from The Expression of Three Genes in Primary Non–Small Cell Lung Cancer Is Associated with Metastatic Spread to the Brain

Purpose: Brain metastases affect 25% of patients with non–small cell lung cancer (NSCLC). We hypo... more Purpose: Brain metastases affect 25% of patients with non–small cell lung cancer (NSCLC). We hypothesized that the expression of genes in primary NSCLC tumors could predict brain metastasis and be used for identification of high-risk patients, who may benefit from prophylactic therapy.Experimental Design: The expression of 12 genes was measured by real-time quantitative reverse transcriptase PCR in 142 frozen NSCLC tissue samples. Univariate and multivariate Cox regression analysis was used to analyze the correlation between gene expression and the occurrence of brain metastasis. Immunohistochemistry on independent samples was used to verify the findings.Results: A score based on the expression levels of three genes, CDH2 (N-cadherin), KIFC1, and FALZ, was highly predictive of brain metastasis in early and advanced lung cancer. The probability of remaining brain metastasis–free at 2 years after diagnosis was 90.0 ± 9.5% for patients with stage I/stage II tumors and low score compare...

Modern Pathology

Anaplastic lymphoma kinase (ALK) and ROS oncogene 1 (ROS1) gene fusions are well-established key ... more Anaplastic lymphoma kinase (ALK) and ROS oncogene 1 (ROS1) gene fusions are well-established key players in non-small cell lung cancer (NSCLC). Although their frequency is relatively low, their detection is important for patient care and guides therapeutic decisions. The accepted methods used for their detection are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assay, as well as DNA and RNA-based sequencing methodologies. These assays are expensive, time-consuming, and require technical expertise and specialized equipment as well as biological specimens that are not always available. Here we present an alternative detection method using a computer vision deep learning approach. An advanced convolutional neural network (CNN) was used to generate classifier models to detect ALK and ROS1-fusions directly from scanned hematoxylin and eosin (H&E) whole slide images prepared from NSCLC tumors of patients. A two-step training approach was applied, with an initial...

Journal of Clinical Oncology

9045 Background: Immune checkpoint inhibitors (ICI) have become the standard treatment for metast... more 9045 Background: Immune checkpoint inhibitors (ICI) have become the standard treatment for metastatic NSCLC, although only a small proportion of patients derive durable benefit. PDL1 expression is the only approved biomarker to select NSCLC patients for treatment with single-agent pembrolizumab, however its predictive value is limited and better predictive biomarkers are needed. The spatial arrangement of immune cells in the tumor microenvironment (TME), namely tumor infiltrating lymphocytes (TILs), emerges as a potential biomarker for ICI efficacy. In this work, we utilized deep-learning (DL) models to extract TME features from digitized H&E slides and evaluated their predictive and prognostic role in patients with mNSCLC treated with Pembrolizumab. Methods: NSCLC patients (n=90) treated with single-agent 1st line pembrolizumab in two centers were identified. 47 patients from one center were used to train the model, and 43 patients from another center were used for validating the m...

Cancer Research

Background Neoadjuvant immune checkpoint inhibitor treatment is a promising approach for resectab... more Background Neoadjuvant immune checkpoint inhibitor treatment is a promising approach for resectable cancer, including non-small cell lung cancer (NSCLC). The characteristics of potential responders to such treatments and the molecular underlying events are not known. Methods We have conducted a phase I, investigator-initiated single-center study (MK3457-223), to examine the safety of neoadjuvant pembrolizumab for stage I-II resectable NSCLC and to determine the recommended phase II dose/schedule (RP2D/S). FFPE biopsies and surgical specimens were subjected to correlative studies. NanoString’s GeoMx Digital Spatial Profiler (DSP) analysis was conducted on pre-treatment samples and post-treatment responder samples. Protein (72 proteins) and mRNA expression data (73 genes) analysis was conducted on regions of interest (ROIs), defined as mostly CD8 positive or mostly pan-cytokeratin positive (presumed cancer cells). Pathology assessment was done on the surgical specimen to identify majo...

Access Microbiology, 2022

Nontuberculous mycobacteria (NTM) may cause pulmonary and extra-pulmonary disease in both immunoc... more Nontuberculous mycobacteria (NTM) may cause pulmonary and extra-pulmonary disease in both immunocompetent and immunocompromised patients. Pleuritis is an uncommon manifestation on NTM disease, and pleuritis caused byMycobacterium xenopihas only been described once before. Because it is considered to be an environmental contaminant, isolation ofM. xenopifrom bronchopulmonary secretions or other sites is often dismissed. The disease caused byM. xenopiis usually a pulmonary infection and typically occurs in severely immunocompromised individuals or in immunocompetent patients with an underlying chronic lung disease. We describe an unusual case of pleuritis caused byM. xenopiin a patient without an underlying chronic lung disease and with no evidence of a concurrentM. xenopipulmonary infection.

Mediastinum, 2021

Circulating EBV (cEBV) and metabolic imaging monitoring during therapy for thymic lymphoepithelio... more Circulating EBV (cEBV) and metabolic imaging monitoring during therapy for thymic lymphoepithelioma-like carcinoma (tLELC): a case study. Mediastinum 2021;5:AB003.

Journal of Thoracic Oncology, 2021

Journal of Clinical Oncology, 2019

8534 Background: Resected NSCLC clinical stage I or II harbor a 5 year survival of only 30-50%. I... more 8534 Background: Resected NSCLC clinical stage I or II harbor a 5 year survival of only 30-50%. Immunotherapy might be more effective in low-burden disease. We hypothesized that neo-adjuvant immunotherapy is a feasible, safe and effective treatment (Tx) for early stage NSCLC. Methods: MK3475-223 is an ongoing phase I study of neoadjuvant pembrolizumab in stage I-II NSCLC. All Pembro Txs are 200mg q 3 weeks (wks). Objectives: determine safety; recommended phase 2 dose/schedule; pathological & radiological response. Doses-schedule limiting toxicities (DLT) were defined as significant surgical complications (bleeding, delayed wound healing, ARDS, prolonged air-leak) or a significant delay of surgery. The doses-schedule escalation cohorts were (i) single pembro dose 3 wk prior to surgery; (ii) 2 pembro doses, 2 wks later surgery; (iii) 2 pembro doses, 1 wk later surgery. Expansion cohort received the doses-schedule of cohort (iii). Percentages of remaining viable tumor in the post-Tx we...

Cancer Immunology, Immunotherapy, 2021

One of the major hurdles for the advancement of cancer immunotherapy is lack of robust, accessibl... more One of the major hurdles for the advancement of cancer immunotherapy is lack of robust, accessible experimental models. We aimed to produce an ex-vivo organ culture (EVOC) model of immunotherapy for non-small cell lung cancer (NSCLC). Freshly resected early stage tumors were collected from the operating room, fragmented to clusters < 450 µm and cultured with fetal calf serum and human autologous serum. The resulting EVOC includes cancer epithelial cells within tumor tissue clusters and immune cells. Original tissue features are reflected in the EVOCs. The response to immune checkpoint inhibitors (ICI) was assessed by IFNγ gene induction. Interestingly, IFNγ EVOC induction was numerically higher when anti-CTLA4 was added to anti-PD-L1 treatment, supporting the notion that anti-CTLA4 impacts cancer partly through tumor-resident immune cells. In parallel, immunohistochemistry (IHC) for key immune-related proteins was performed on the formalin-fixed paraffin embedded (FFPE) corresponding tumors. EVOC IFNγ induction by ICI correlated with basal non-induced IFNγ, CD8, CD4 and FOXP3 mRNA levels within EVOCs and with tumor-FFPE-IHC for CD8 and granzyme B. A weaker correlation was seen with tumor-FFPE-IHC for CD3, CD4, CD68, FOXP3 and tumor-PD-L1. Tertiary lymphoid structure density was also correlated with the ICI response. Our study provides novel data about biomarkers that correlate with ICI-induced response of early stage NSCLC. Retention of the microenvironment and minimal addition of exogenous factors suggest this model to reliably represent the original tumor. The cluster-based EVOC model we describe can provide a valuable, yet simple and widely applicable tool for the study of immunotherapy in NSCLC.

Journal of Clinical Pathology, 2020

AimsTo analyse microRNA (miR)-21 distribution and expression at the cellular level in non-small c... more AimsTo analyse microRNA (miR)-21 distribution and expression at the cellular level in non-small cell lung cancer (NSCLC). MiR-21 is an oncogenic microRNA overexpressed in NSCLC. In previous studies, overexpression of miR-21 was evaluated from the tumour bulk by quantitative reverse transcription PCR with results expressed on average across the entire cell population.MethodsWe used in situ hybridisation and immunohistochemistry to assess the correlation between miR-21 levels and the expression of markers that may be possible targets (epidermal growth factor reaction) or may be involved in its upregulation (phosphatase and tensin homolog (PTEN), p53). The Pearson’s χ2 tests was used to assess correlation with clinicopathological data and with miR-21 expression both in tumour and tumour stroma.ResultsCytoplasmic staining and expression of Mir-21 were detected in the tumours and in associated stromal cells. Expression was highest in the stroma immediately surrounding the tumour cells an...

Journal of Thoracic Imaging, 2019

Purpose: The purpose of this article was to compare magnetic resonance imaging (MRI) depiction of... more Purpose: The purpose of this article was to compare magnetic resonance imaging (MRI) depiction of thymic malignancy progression/recurrence with that of computed tomography (CT). Methods: We retrospectively reviewed all surgically treated thymic epithelial malignancy (TEM) patients between 2011 and 2018 who were followed-up with chest CT and MRI. We compared the detection of recurrence and metastatic disease between the CT and MRI scans in each of these patients. Results: Of 187 patients treated in our institution for TEM, 22 were followed-up with both CT and MRI. TNM stage at diagnosis was as follows: I (n=14), II (n=1), IIIa (n=4), IIIb (n=2), IVa (n=1), and IVb (n=0). Patients were followed-up for a mean of 6.2 years, range 0.7 to 17.7 years. The mean interval between CT and MRI was 5.4 (range, 1 to 15) months. Most patients had no recurrence (n=16), 4 had recurrence after R0 or R1 resection, 1 had stable disease, and 1 had progression of disease after R2 resection. CT and MRI per...

Radiotherapy and Oncology, 2019

Journal of Thoracic Oncology, 2018

Respirology Case Reports, 2019

Angioleiomyomas are rare airway tumours with potential to cause central airway obstruction or hae... more Angioleiomyomas are rare airway tumours with potential to cause central airway obstruction or haemoptysis. Methods described to manage them include surgical resection, or rigid bronchoscopy and thermal ablation techniques. We describe a case presenting with central airway obstruction, safely and effectively treated with cryoextraction of the tumour using flexible bronchoscopy.

International Journal of Cardiology, 2018

Clinical Transplantation, 2017

Purpose: Autonomic cardiovascular control is crucial for maintaining cardiovascular homeostasis. ... more Purpose: Autonomic cardiovascular control is crucial for maintaining cardiovascular homeostasis. In healthy individuals the total peripheral resistance (TPR) maintains blood pressure during orthostatic challenge. The aim of this study was to explore the autonomic cardiovascular responses to gravity in heart transplanted recipients as compared with healthy controls. Methods: A total of 50 recently (3 months post-tx) heart transplanted recipients (18-69 years of age) and 50 healthy controls (18-69 years of age) underwent a head-up-tilt test (HUT) to 20 degrees/15minutes and 60 degrees/15 minutes. c recordings of heart rate (HR), stroke volume (SV) and blood pressures (BP) were obtained. Cardiac index (CI), stroke index (SI), total peripheral resistance (TPR), heart rate variability indices (HRV) and baroreceptor sensibility (BRS) were calculated from the primary recordings. Results: Baseline recordings at supine rest showed that heart transplant recipients had significantly higher HR (p<0.01), TPR (p<0.02), systolic (p<0.01), mean (p<0.01) and diastolic BP (p<0.01) whereas SI was significantly lower (p<0.01) than in healthy controls. Cardiac index was equal across groups. The response to 60 degrees HUT was characterized by stronger increase of HR (p<0.01), mean arterial pressure (p<0.01) and TPR (p<0.01) among healthy controls. SI response showed a significant decrease in healthy controls compare to the patients (p<0.01). Heart transplant recipients experienced no alteration in HR, BP and TPR at 60 degrees HUT. Regardless of this HR (p<0.01), SBP (p<0.04) and CI (p<0.04) were still significantly higher than in healthy controls and SI was lower (p<0.01). Conclusion: These results suggest that TPR at baseline is higher in heart transplant recipients than healthy controls at supine rest. During HUT to 60 degrees healthy controls show a rise in TPR while this response is not seen among patients. The BP remains unchanged at 60 degrees HUT in the patient group. Total peripheral resistance does not seem to contribute in maintaining BP during orthostatic challenge in recently heart transplanted recipients.

The Israel Medical Association journal : IMAJ, 2016

Circulation, Nov 22, 2011

Biomedical Papers, 2006

Background: hMLH1 and hMSH2 genes are both known to play a role in DNA mismatch repair. Nonethele... more Background: hMLH1 and hMSH2 genes are both known to play a role in DNA mismatch repair. Nonetheless, the clinical significance of hMLH1 and hMSH2 protein expression in lung cancers remains unclear. Aim: The aim of this study was to investigate the immunohistochemical expression of hMLH1 and hMSH2 proteins in tumor specimens from 179 non-small cell lung cancer (NSCLC) patients using a tissue microarray technique and to correlate these results with other clinicopathological variables, including the disease specific and overall survivals. Method: hMLH1 and hMSH2 protein expression was evaluated by immunohistochemistry using monoclonal antibodies G168-728 for hMLH1 and FE11 for hMSH2 protein expression analysis. The Pearson χ 2 test was used to compare the hMLH1 and hMSH2 alterations among the cases and between various clinical and laboratory variables. P < or = 0.05 was considered statistically significant. Results: Alteration of hMLH1 and hMSH2 protein expression was observed in 10 % of patients. No significant correlation was found between the protein expression and patient age, smoking status, tumor histology or disease stage and disease free and overall survival. Conclusions: Alterations in the expression of hMLH1 and hMSH2 proteins did not have any prognostic value in stage III. NSCLC patients.