Eldad Dann - Academia.edu (original) (raw)

Papers by Eldad Dann

Hematological Oncology, Jun 1, 2023

Clinical Lymphoma, Myeloma & Leukemia, Sep 1, 2017

and overcoming some of PCR limitations. However, every NGS experiment is strictly dependent on co... more and overcoming some of PCR limitations. However, every NGS experiment is strictly dependent on computational analysis that manages the huge volume of deep sequencing data. Here, we present HashClone, a new easy-to-use bioinformatics tool that provides marker assessment at diagnosis and MRD monitoring over time. HashClone was tested in mantle cell lymphoma (MCL), with the aims to detect the major clone and monitor it over time during clinical follow-up. Methods: Five MCL patients, enrolled in a Fondazione Italiana Linfomi (FIL) prospective clinical trial, were studied for immunoglobulin heavy chain rearrangements (IGH) detection and MRD monitoring using both ASO-qPCR and a BIOMED II amplicon-based NGS approach. Overall, for each patient peripheral blood and bone marrow samples from diagnosis, 3 artificial follow-ups and samples collected during the clinical follow-up were analysed. HashClone analysis was focused, firstly, on the identification of a set of putative clones, independently from any biological knowledge. Then, IGH rearrangements identification was carried out thanks to the link to IMGT database. Finally, NGS MRD results were compared to data previously obtained by ASO qPCR. Results: Overall, the HashClone performances were tested on 39 MCL samples. For the 5 diagnostic samples, HashClone identified an average value of 1008 putative clones (range 540-1379). Of these, only 25 displayed a frequency higher than 5% and thus were considered representative of the disease. However, only 21 out of 25 clonotypes were recognized as B-cell clones after IMGT filtering. Finally, each of all the 5 diagnostic samples displayed only one predominant clone, with a median frequency of 98% (range 92%-99%). Compared to Sanger sequencing, all the major clones showed the same IGH rearrangement with a 100% of nucleotide homology in 4/5 cases. In one patient, 3 mismatches, not affecting the patient-specific insertions ("N regions"), decreased the homology to 98%. Overall, the correlation analysis showed a high concordance between ASO qPCR and NGS (r 2 = 0.85). Moreover, considering single patients, superimposable performances were observed (Figure 1). Conclusion: HashClone is a new bioinformatics tool for the identification of IGH clonality in NGS experiments, able to detect and monitor the major B-cell clone in MCL. It is not affected by biologic biases and is able to follow the temporal evolution of the IGH repertoire at several time points ("MRD monitoring"). Since this is the first HashClone application, the tool needs to be fine-tuned and validated on large samples series, before being used in prospective MRD-based clinical trials.

Blood, Dec 3, 2015

Introduction: The treatment of hematological malignancies in older adults is an emerging and impo... more Introduction: The treatment of hematological malignancies in older adults is an emerging and important issue due to the aging population trend as well as drug-related toxicities in pts (pts) with comorbidities. Indolent lymphomas constitute a subgroup of incurable non-Hodgkin lymphomas characterized by multiple relapses. Anthracycline containing chemo-immunotherapy regimens (ACR) such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) are very active in indolent lymphomas, resulting in a long progression-free survival (PFS). Due to their high rate of associated toxicities, such regimens are less likely to be given to the elderly population. Currently, there is no consensus regarding the treatment of indolent lymphomas in older adults. The present study assessed overall survival (OS), time to next treatment (TNT) and treatment-associated toxicity in this distinctive subpopulation of pts with indolent lymphoma, aiming to develop an optimal approach to the management of such pts. Methods: This retrospective cohort analysis included pts with indolent lymphoma (histology diagnosis of follicular lymphoma, marginal zone lymphoma, Waldenstrom&#39;s macroglobulinaemia and indolent lymphoma not otherwise specified) aged ≥60 at therapy initiation (1st line) treated with either an ACR or a non-ACR at the Rambam Department of Hematology and Bone Marrow Transplantation between the years 2000 and 2012. All regimens included rituximab. OS, TNT and treatment-related toxicity (neutropenic fever and hospital admission due to noninfectious causes during the treatment period) were assessed. Results: Forty three pts treated with an ACR and 55 pts receiving a non-ACR were included in the analysis. Clinical characteristics, response to therapy and treatment modification data are presented in table 1. The median age was 67 years in the ACR group and 73 years in the non-ACR group; median duration of the follow-up was 4.3 years (range 0.1-11.9 years). No difference in terms of high risk co-morbidity score, defined as modified Charlson co-morbidity score ≥5 (Charlson et al, 1987), was found between the ACR group and the non-ACR group. Significantly more pts with follicular lymphoma were treated with ACR compared to non-follicular indolent lymphomas. There was no difference in CR rate between the ACR and non-ACR groups. In a univariate analysis, OS was found to be significantly higher in the ACR group, but in the multivariate analysis, OS appeared to be influenced only by age. The cause of death was disease-related in 8 pts (100% of deaths) in the ACR group and in 7 pts (64%) in the non-ACR group (data on the cause of death were available for 11 out of 18 pts from the non-ACR group). The median TNT was longer in the ACR cohort, but the difference did not reach statistical significance. No difference was found between the ACR and non-ACR groups in terms of major treatment-related toxicities assessed by the number of hospital admissions because of infection or other causes. Dose adjustments and treatment delays were far more frequent in the ACR cohort. This study is limited by its retrospective nature, the small number of patients and a significantly higher number of pts with follicular lymphoma treated in the ACR group. Conclusions: The present analysis of a cohort of older adults with indolent lymphoma treated with chemo-immunotherapy regimens in routine clinical practice has demonstrated that ACR was safe and efficacious. When approaching older adults suffering from indolent lymphoma, the considerations of quality of life (time without the need of further treatment, the minimal number of hospital admissions and minimal number of infections requiring hospitalization) should play a major role in treatment decision-making. In the current study, ACR was not inferior to non-ACR in terms of toxicity. A trend to an improved OS and longer TNT was demonstrated in the ACR group. The patient age should not deter physicians from using ACR in older adults. Table 1. Parameters ACR N=43 Non-ACR N=55 P value Age, median 67 73 0.05 Pts with modified Charlson comorbidity score ≥5 (%) 7 (17) 10 (19) 0.55 Pts with follicular lymphoma (%) 33 (77) 27 (49) 0.007 CR rate (%) 30 (70) 33 (60) 0.4 4-year OS, % 81 67 &amp;lt;0.04 Median time to next treatment, months 90 55 0.2 Dose adjustments 65 37 0.008 Treatment delays 57 37 0.06 Disclosures No relevant conflicts of interest to declare.

Blood, Nov 16, 2005

Rituximab has revolutionized the treatment outcome of non-Hodgkins lymphoma (NHL) patients but it... more Rituximab has revolutionized the treatment outcome of non-Hodgkins lymphoma (NHL) patients but its role in retreatment in all NHL patients is not yet established. Therefore, the Israel Rituximab Retreatment Study Group was organized in order to summarize retrospectively the treatment results of B-cell NHL patients who received ≥ 2 rituximab treatments. Eighty-eight NHL patients from 13 medical centers were enrolled, 39 males, 49 females with a mean age of 57.3 years (range 26–88). Sixty-four patients (73%) had indolent lymphoma (21- follicular grade I, 17 follicular grade II, 10-follicular grade III, 9-small lymphocytic, 6- MALT, 2- marginal zone, 1-lymphoplasmacytic). Eighteen patients (20%) had aggressive lymphoma [diffuse large B-cell lymphoma (DLBCL)] and 6 patients had mantle cell lymphoma. Fifty-nine patients received one regimen of chemotherapy and 23 patients received 2 chemotherapy regimens before the first treatment with rituximab. There was no significant difference in the median time to progression (TTP) after the first rituximab treatment whether the patient received no previous chemotherapy or 1 or 2 previous chemotherapy regimens (12 vs 12 vs 14 months, respectively). All patients received 2 courses of rituximab, 33 patients-3 courses, 6 patients -4 courses and 2 patients-5 courses, with a mean of 4.4 doses in each course (range 1–8). Only 45 patients received any treatment after the second course of rituximab. The first course of rituximab was administered alone in 46 patients and with chemotherapy in 42 (24 CHOP, 6 COP, 6 FC, 2 chlorambucil, 1 LMP, 1 DVIP, 1 ESHAP, 1 MACOP-B). There was no difference in the median time to next treatment (TTNT) whether the rituximab was given alone or with chemotherapy (16 and 14 months, respectively). The second course of rituximab was administered alone in 46 patients and with chemotherapy in 42 patients (13 CHOP, 11 FC, 6 COP, 5 ICE, 3 ESHAP, 2 HyperCVAD, 1 CNOP 1 VEEP). The addition of chemotherapy did not change the overall response (CR and PR) to the second rituximab treatment (72% in rituximab alone vs. 69% in rituximab with chemotherapy, in indolent lymphoma patients 76% vs. 72%, in aggressive lymphoma patients 70% vs. 62.5%, respectively). TTP after the second rituximab treatment was similar or possibly longer than after the first treatment (median 14 and 12 months, mean 23.4 and 16.2 months respectively). Conclusions: The response to a second rituximab treatment is the same whether the rituximab is given alone or combined with chemotherapy. TTP after retreatment with rituximab is as good as after the first treatment. Prospective studies should examine the treatment benefit of adding chemotherapy to a second treatment with rituximab.

Current Oncology Reports, Jun 15, 2012

Current therapy of Hodgkin disease (HD) is based on risk assessment, taking into consideration bo... more Current therapy of Hodgkin disease (HD) is based on risk assessment, taking into consideration both staging and risk factors. Interim positron emission tomography/computerized tomography (PET/CT) has proven to distinguish between patients with advanced disease who have early response and good prognosis and those with interim positive response who have inferior progression free survival (PFS) with current therapy. Several issues need to be elucidated: (1) Which interim study should be defined as positive? (2) Should the same cutoff value be used for decision-making about escalation vs de-escalation of therapy? (3) Should it apply to different chemotherapy protocols? Currently, there are several ongoing studies where treatment is modified based on interim PET/CT. These studies may enable the medical community to establish whether bleomycin or radiation therapy could be omitted in early responders, whether chemotherapy could be shortened in these patients, and whether therapy escalation for patients with interim positive PET/CT could decrease disease progression rate.

Journal of Gastrointestinal Cancer, Sep 7, 2010

Malignancy is often associated with hematological disorders, but rarely is the diagnosis of malig... more Malignancy is often associated with hematological disorders, but rarely is the diagnosis of malignancy secondary to the diagnosis of microangiopathic hemolytic anemia and thrombocytopenia. We report hereby two patients with metastatic gastric carcinoma presenting with microangiopathic hemolytic anemia and thrombocytopenia. Despite chemotherapy and repeated plasmapheresis in one patient, both patients succumbed shortly after the diagnosis of cancer was made. A review of the literature regarding microangiopathic hemolytic anemia in cancer patients is discussed. In patients suffering from microangiopathic hemolytic anemia and thrombocytopenia, malignancy should be considered as a possible cause. Early diagnosis of malignancy may be critical for determining the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s prognosis and potentially avoiding unnecessary overtreatment.

Biomedical Optics Express, Oct 30, 2017

Measuring oxygen saturation in capillary vessels could provide valuable information on oxygen tra... more Measuring oxygen saturation in capillary vessels could provide valuable information on oxygen transport and tissue viability. Most spectroscopic measurement techniques, however, lack the spatial resolution to account for the small vessel dimensions within a scattering tissue and the steep gradients of oxygen saturation levels. Here, we developed a noninvasive technique for image-guided confocal measurement of the optical absorption spectrum from a small region that is comparable in size to the cross section of a single capillary vessel. A wide range of oxygen saturation levels were measured in a single capillary in a human volunteer, with blood deoxygenation rates of 7.1% per hundred microns. The technique could help in studying oxygen exchange dynamics in tissues and could play a key role in future clinical diagnosis and therapeutic applications that require localized functional tissue inspection.

European journal of applied physiology and occupational physiology, Sep 1, 1990

The effect of an imposed drinking discipline versus ad libitum drinking was studied on 21 healthy... more The effect of an imposed drinking discipline versus ad libitum drinking was studied on 21 healthy, well-trained volunteers, during a continuous 4.5-h march at an altitude of 1,700 m and an ambient temperature of 0 ° C, SD 1. Group I (n = 13) was instructed to drink 250 ml of warmed, artificially sweetened fluid every 30 rain, whereas group II (n = 8) drank plain water ad libitum. The median fluid intake in group I was significantly higher than in group II (P< 0.0002). Serum urea and osmolality decreased during the march in group I (P< 0.05; P< 0.002, respectively) with no significant change in group II. In both groups, a similar increase in haemoglobin concentration concomitant with a reduction in calculated blood and plasma volume was observed after exercise and did not correlate with the state of hydration. Total urine volume, creatinine clearance, urea clearance and potassium excretion were significantly higher and urinary osmolality was lower in group I than in group II (P< 0.05). These results reflect a state of extreme "voluntary dehydration" in the control group when no fluid intake was obligatory. Thus, during exercise in the cold, under conditions similar to those in this study, a fluid intake of 150 ml-h-1 should be maintained in order to keep a urinary flow of about 1 ml-kg-1, h-1 and to achieve a good state of hydration.

Biochemical Society Transactions, Oct 1, 2000

Small, Mar 19, 2012

numerous new approaches for treating malignant cells with minimal collateral damage are constantl... more numerous new approaches for treating malignant cells with minimal collateral damage are constantly being studied and developed. Owing to its low toxicity to native tissue, laser light in the visible and near-infrared wavelength range is particularly attractive for manipulating tissue through specifi c intermediate agents. The strong local interaction between light and a photosensitizer, combined with a negligible interaction with healthy nearby tissue, make photodynamic therapy a favorable approach for treating several types of cancer with relatively few side effects. [ 1 ] Recently, several approaches for targeting cancer with low toxicity have been proposed, utilizing gold nanoparticles which are relatively inert and biocompatible, and can mediate the effect of light without the need of a toxic photosensitizer. Gold nanoparticles of various sizes and shapes, including spheres, [ 2 ] rods, [ 3 , 4 ] shells, [ 5 , 6 ] hollow shells, [ 7 ] cages, [ 8 , 9 ] and branched particles [ 10 ] have been proven useful in generating signifi cant photothermal damage to cancer cells. Intense pulse lasers of pulses shorter than 10 ns [ 3 , 11-13 ] have been shown to induce different, more localized effects in tissues as compared to continuous-wave lasers, [ 14-17 ] either at the near-infrared wavelength range [ 4 , 18 ] or at the visible part of the spectrum. [ 2 , 15 ] Such effects, combined with specifi c localization of the mediating nanoparticles within the Specifi cally targeting and manipulating living cells is a key challenge in biomedicine and in cancer research in particular. Several studies have shown that nanoparticles irradiated by intense lasers are capable of conveying damage to nearby cells for various therapeutic and biological applications. In this work ultrashort laser pulses and gold nanospheres are used for the generation of localized, nanometric disruptions on the membranes of specifi cally targeted cells. The high structural stability of the nanospheres and the resonance pulse irradiation allow effective means for controlling the induced nanometric effects. The technique is demonstrated by inducing desired death mechanisms in epidermoid carcinoma and Burkitt lymphoma cells, and initiating effi cient cell fusion between various cell types. Main advantages of the presented approach include low toxicity, high specifi city, and high fl exibility in the regulation of cell damage and cell fusion, which would allow it to play an important role in various future clinical and scientifi c applications.

Natural disasters are unpredicted events that erupt abruptly and are characterized by mass casual... more Natural disasters are unpredicted events that erupt abruptly and are characterized by mass casualties and failure of infrastructure. The damage in such cases depends on two main factors, i.e., the magnitude of the natural event and human behavior. Collapse of houses and public facilities often results from non-adherence to building standards. Such a disaster is an ultimate test to executive capabilities of the community and authorities. Its successful management depends on efficient preemptive organization, including application of standard operating procedures (SOP) at both regional and state levels. Previous mega disasters have demonstrated that blood demand in such events increases only moderately, if at all, so that it may be easily covered by regional or central blood supply. Severely wounded patients require about 8 units of blood; however, these patients comprise about 5% of casualties that need blood transfusion. In cases when no electricity is available, most injured patients requiring emergency surgery would be airlifted to uninvolved areas and only minimal stock of blood products should be kept in the involved area. Fibrinogen and fresh frozen plasma are currently available as freeze-dried products which may be kept in the room temperature, not requiring refrigeration. The most important factor for maintaining adequate blood product supply is having a national or regional voluntary, non-remunerated blood donation system and appropriate SOP that are periodically tested. Collection of blood products beyond demand at time of such events is usually unnecessary and wasteful.

Biomedical Optics Express, May 21, 2012

Optical microscopy of blood cells in vivo provides a unique opportunity for clinicians and resear... more Optical microscopy of blood cells in vivo provides a unique opportunity for clinicians and researchers to visualize the morphology and dynamics of circulating cells, but is usually limited by the imaging speed and by the need for exogenous labeling of the cells. Here we present a labelfree approach for in vivo flow cytometry of blood using a compact imaging probe that could be adapted for bedside real-time imaging of patients in clinical settings, and demonstrate subcellular resolution imaging of red and white blood cells flowing in the oral mucosa of a human volunteer. By analyzing the large data sets obtained by the system, valuable blood parameters could be extracted and used for direct, reliable assessment of patient physiology.

During a sickle cell crisis in sickle cell anemia patients, deoxygenated red blood cells may chan... more During a sickle cell crisis in sickle cell anemia patients, deoxygenated red blood cells may change their mechanical properties and block small blood vessels, causing pain, local tissue damage and even organ failure. Measuring these cellular structural and morphological changes is important for understanding the factors contributing to vessel blockage and developing an effective treatment. In this work, we use spectrally encoded flow cytometry for confocal, high-resolution imaging of flowing blood cells from sickle cell anemia patients. A wide variety of cell morphologies were observed by analyzing the interference patterns resulting from reflections from the front and back faces of the cells’ membrane. Using numerical simulation for calculating the two-dimensional reflection pattern from the cells, we propose an analytical expression for the three-dimensional shape of a characteristic sickle cell and compare it to a previous from the literature. In vitro spectrally encoded flow cytometry offers new means for analyzing the morphology of sickle cells in stress-free environment, and could provide an effective tool for studying the unique physiological properties of these cells.

Medical Oncology, Jun 1, 1996

We evaluated the effect of exogenously administered recombinant human granulocyte-macrophage colo... more We evaluated the effect of exogenously administered recombinant human granulocyte-macrophage colony stimulating factor (rHu GM-CSF) on plasma lipid and lipoprotein concentrations in 28 patients undergoing bone marrow transplantation (BMT). Twenty-one received rHu GM-CSF during the immediate post transplantation period (group 1) and seven did not (group 2). All patients received intravenous hyperalimentation starting at the immediate post-transplantation period until 3-5 days post engraftment. Plasma lipids and lipoproteins, liver and renal function tests and blood counts were determined prior to BMT (baseline levels) and during the immediate and late post transplantation periods. In both groups, marked changes of plasma total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) concentrations were observed. During the immediate post transplantation period, TC levels decreased by 22.2% and 26.2% in groups 1 and 2, respectively. During the same period, HDL-C levels decreased by 41.4% and 37.5% in these two groups. At the late recovery phase TC and HDL-C resumed pre-treatment levels. These changes were in parallel to the fluctuations in total WBC counts. We conclude, therefore, that BMT has a significant transient effect on plasma lipids and lipoproteins. Although this response is unrelated to the exogenous administration of rHu GM-CSF it may be causally related to endogenous cytokines or other, yet unidentified, factors.

Human Genetics, Nov 1, 1991

Segregation analyses were performed for plasma low density lipoprotein cholesterol (LDL-C), trigl... more Segregation analyses were performed for plasma low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) in five Christian Arab kindreds identified through probands with familial hypercholesterolemia. In this subset of the Christian Arab community, the results were consistent with major gene determination of LDL-C with allele frequency (q) of 0.042 (95% confidence interval 0.008-0.079) in addition to polygenic transmission (h 2 = 0.34). The "Lebanese" allele was identified directly by polymerase chain reaction and HinfI restriction analysis. Analysis of this mutation permits direct diagnosis of familial hypercholesterolemia in most affected individuals although our results indicated the possible existence of an additional independent factor leading to elevated LDL-C levels. The segregation results for TG indicated the presence of a major effect, although the existence of a major gene could not be demonstrated. There was also no evidence of a major locus effect on HDL-C levels.