Eosinophilic pleocytosis in the cerebrospinal fluid following CAR-T cell therapy for CNS lymphoma: A case for warning?

INTRODUCTION: CAR-T cell therapy, emerging as an efficient treatment option for patients with secondary central nervous system (CNS) lymphoma, is frequently complicated with immune effector cell-associated neurotoxicity syndrome (ICANS). CASE PRESENTATION: We report a case of a 64-year-old woman with transformed follicular lymphoma, developing high-grade ICANS with eosinophilic pleocytosis following third-line therapy with CAR-T cells (tisagenlecleucel). During bridging therapy, she declined neurologically and was diagnosed with secondary CNS lymphoma. She received methotrexate-cytarabine-thiotepa-rituximab regimen with clinical and radiological improvement. Post-CAR-T cell infusion she developed cytokine release syndrome grade II and ICANS grade III. Given the lack of response to steroids, anakinra was initiated with complete ICANS resolution. Cerebrospinal fluid (CSF) analysis, performed only on day +10 due to thrombocytopenia, revealed eosinophils, while infections were excluded. CONCLUSION: This report emphasizes the importance of CSF analysis in individuals with CAR-T-related neurotoxicity for elucidating the role of specific immune cells in such complications.

Assessment of Relative Energy Deficiency in Sport (REDs) Risk among Adolescent Acrobatic Gymnasts.

Energy imbalance exposes athletes to relative energy deficiency in sports (REDs) syndrome. Data on energy consumption, REDs, and bone mineral density (BMD) in adolescent acrobatic gymnasts, especially in males, are scarce. Our aim was to examine the eating habits, energy balance, body composition, and BMD of these athletes. In this study, 18 healthy adolescents participating in competitive acrobatic gymnastics completed a questionnaire, underwent a dual-energy X-ray absorptiometry scan (DXA), received a food log, and had their activities monitored for 3 days. Eighteen acrobats were enrolled (mean age: 14.3 ± 1.2 years; males: 6/18). The mean total body BMD Z-score was 0.4 ± 1.0. Top-position acrobats (7/18) had significantly lower total body BMD Z-scores than base-positioned acrobats (-0.2 ± 0.3 vs. 0.8 ± 0.3, p = 0.032), though their forearms were not significantly different (0.2 ± 0.5 vs. 0.8 ± 0.7, p = 0.331). No sex differences were found for BMD Z-scores, BMI, or energy availability. The BMD parameters of the acrobats were within the normal range for a healthy pediatric population, although three had low BMDs (<-1 SD) for healthy athletes. Total body and LS BMD Z-scores were significantly lower in top-position athletes compared to base-position athletes. These findings suggest personalized (top vs. base) training programs (high-impact training) that may achieve better health outcomes.

Reduction of the Vertebral Bone Mineral Density in Patients with Hodgkin Lymphoma Correlates with Their Age and the Treatment Regimen They Received.

Nowadays, Hodgkin lymphoma (HL) has become highly curable. The young age at diagnosis and long life expectancy emphasize the importance of preventing long-term treatment side effects, including bone mineral density (BMD) loss, in these patients. We aimed to evaluate the effects of first-line therapeutic modalities on BMD dynamics in HL patients, intending to identify individuals at risk for osteopenia. Demographics, HL risk factors, treatment, including cumulative steroid doses, and BMD of 213 newly-diagnosed HL patients (median age 29 years), treated at Rambam between 2008-2016, were analyzed. The main chemotherapy regimens applied were: ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP (EB; bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin, procarbazine, prednisone). BMD was measured using PET/CT scans. BMD loss >15% was revealed in 48% of patients at therapy completion, with osteopenia prevalence of 4% and 14% at baseline and post-therapy, respectively. Cumulative hydrocortisone equivalent doses >3400 mg/m2 correlated with significant BMD reduction. Multivariate analysis at 6 months post-therapy identified age ≥30 years and EB-regimens as significant risk factors for BMD decrease >15%. Therapy-related BMD loss is common in HL patients. Its persistence is associated with age ≥30 years and EB treatment. Reduction of cumulative steroid doses and switch to non-gonadotoxic drugs should be considered.

The Role of 18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) in Management of Nocardiosis: A Retrospective Study and Review of the Literature.

INTRODUCTION: 18-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is a well-established tool for managing metastatic infections. Nocardiosis, a primarily pulmonary infection, disseminates at high rates. Routine imaging includes chest CT and brain imaging. We examined the use of FDG-PET/CT in nocardiosis and assessed its contribution to diagnosis and management. METHODS: A retrospective study in two tertiary medical centers during 2011-2020. Individuals with nocardiosis for whom FDG-PET/CT was implemented for any reason were included and their medical records were reviewed. A board-certified nuclear medicine physician independently reviewed all scans. Additionally, a systematic review was conducted according to the PRISMA guidelines, to extract data from publications reporting FDG-PET/CT use for the management of nocardiosis. RESULTS: FDG-PET/CT contributed to the management of all seven patients who met inclusion criteria. It assisted in ruling out an underlying malignancy (29%, 2/7); establishing a wide infection extent (57%, 4/7); and affecting decisions regarding treatment (57%, 4/7), including drug regimen, oral step-down, and duration of therapy. We identified 20 published case reports on this topic. In 80% (16/20), FDG-PET/CT contributed to the management of nocardiosis similar to our study. In addition, in most of the literature cases, FDG-PET/CT guided the diagnostic biopsy. CONCLUSION: FDG-PET/CT is valuable in the diagnosis and management of individuals with nocardiosis. The contribution of incorporating FDG-PET/CT to the management of individuals with nocardiosis and its role in monitoring treatment response and shortening treatment duration should be evaluated in prospective studies.

Single agent oral selinexor as a key to potential cure in refractory diffuse large B-cell lymphoma: case report and literature review.

Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) portends a poor prognosis, with an estimated overall survival of less than 6 months. In the presented case, a female patient with DLBCL refractory to multiple lines of therapy, including chimeric antigen receptor T-cells, was treated with single-agent selinexor, achieving partial response following 5 months of treatment, which allowed the patient to proceed to potentially curative allogeneic stem cell transplantion. This approach enabled the patient, who would otherwise have been considered a candidate for palliative care, to achieve the most prolonged complete response since her first lymphoma-specific treatment. This outcome implies that early identification of relapsed/refractory patients who may benefit most from this drug - either as a single agent or in drug combinations - is imperative.

The presence of a bulky mediastinal mass of 7 cm or greater in diameter confers an adverse prognosis to patients with advanced Hodgkin lymphoma in case of negative interim PET/CT.

In the PET-adapted therapy era, a bulky mediastinal mass (BMM) is not considered a risk factor in patients with advanced-stage Hodgkin lymphoma (HL). The current retrospective study aimed to estimate the prognostic significance of BMM presence and size for disease-free survival (DFS) and determine the most accurate mass size cutoff (among 5 cm, 7 cm, 10 cm) to predict inferior DFS in such patients. The study included 196 advanced-HL patients treated at Rambam (n = 121) and Memorial Sloan Kettering Cancer Center (n = 75) between 2002 and 2016. At a median follow-up of 66.5 (1-222) months, 36 relapses occurred. In multivariate analysis, only the cutoff of 7 cm predicted inferior DFS and PFS (p < 0.007 and <0.038, respectively) in interim PET/CT (PET-2) negative (79%) patients. This study identifies the BMM size cutoff of 7 cm in any plane as most precise in predicting adverse prognosis in PET-2-negative patients with advanced-stage HL. More aggressive initial chemotherapy than ABVD improves such prognosis.

Head-to-Head Prospective Comparison of Quantitative Lung Scintigraphy and Segment Counting in Predicting Pulmonary Function in Lung Cancer Patients Undergoing Video-Assisted Thoracoscopic Lobectomy.

Prediction of postoperative pulmonary function in lung cancer patients before tumor resection is essential for patient selection for surgery and is conventionally done with a nonimaging segment counting method (SC) or 2-dimensional planar lung perfusion scintigraphy (PS). The purpose of this study was to compare quantitative analysis of PS to SPECT/CT and to estimate the accuracy of SC, PS, and SPECT/CT in predicting postoperative pulmonary function in patients undergoing lobectomy. Methods: Seventy-five non-small cell lung cancer patients planned for lobectomy were prospectively enrolled (68% male; average age, 68.1 ± 8 y). All patients completed tests of preoperative forced expiratory volume capacity in 1 s (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO), as well as 99mTc-macroaggregated albumin PS and SPECT/CT quantification. A subgroup of 60 patients underwent video-assisted thoracoscopic lobectomy and measurement of postoperative FEV1 and DLCO. Relative uptake of the lung lobes estimated by PS and SPECT/CT was compared. Predicted postoperative FEV1 and DLCO were derived from SC, PS, and SPECT/CT. Prediction results were compared between the different methods and the true postoperative measurements in patients who underwent lobectomy. Results: Relative uptake measurements differed significantly between PS and SPECT/CT in right lung lobes, with a mean difference of -8.2 ± 3.8, 18.0 ± 5.0, and -11.5 ± 6.1 for right upper, middle, and lower lobes, respectively (P < 0.001). The differences between the methods in the left lung lobes were minor, with a mean difference of -0.4 ± 4.4 (P > 0.05) and -2.0 ± 4.0 (P < 0.001) for left upper and lower lobes, respectively. No significant difference and a strong correlation (R = 0.6-0.76, P < 0.001) were found between predicted postoperative lung function values according to SC, PS, SPECT/CT, and the actual postoperative FEV1 and DLCO. Conclusion: Although lobar quantification parameters differed significantly between PS and SPECT/CT, no significant differences were found between the predicted postoperative lung function results derived from these methods and the actual postoperative results. The additional time and effort of SPECT/CT quantification may not have an added value in patient selection for surgery. SPECT/CT may be advantageous in patients planned for right lobectomy, but further research is warranted.

Efficacy of posttreatment radioiodine scanning in patients with differentiated thyroid cancer.

BACKGROUND: Differentiated thyroid cancers often require radioiodine treatment followed by posttreatment scan. We aimed in this study to assess the utility of the posttreatment radioiodine scan in this population. METHODS: An analysis of patients who received radioiodine treatment at Rambam Campus, during 2006-2013. Scans showing remnant normal thyroid tissue were considered as normal. Positive uptake was defined as uptake in the lateral neck or distant sites. RESULTS: A total of 455 patients were analyzed, 68% had T1-T2 and 28% had positive lymph nodes. Positive uptake in the lateral neck was recorded in 52 (11.4%) and in distant sites in 41 (9%) patients. Tracheal invasion, esophageal invasion, nerve invasion, and N1b classification were associated with a positive scan (P < .05). A positive radioactive iodine scan was not related to poor prognosis. CONCLUSIONS: Posttreatment scans are positive in only 20% of patients. Locally invasive tumor and positive nodes are associated with positive scans.

Phosphaturic mesenchymal tumors among elderly patients: a case report and review of literature.

Phosphaturic mesenchymal tumor (PMT) represents a rare cause of osteomalacia. The clinical signs and symptoms are vague and these lead to diagnosis delay. In the presence of hypophosphatemia and relatively high urine phosphate excretion, this entity should be taken into consideration in the deferential diagnosis of osteomalacia. In the present article, we report 81-year-old man presented to our clinic for evaluation due to osteopenia. His laboratory results disclosed hypophosphatemia, relatively increased urine phosphate excretion and increased level of intact fibroblast growth factor 23 (FGF23). A 68Gallium DOTATATE PET/CT revealed pathological uptake in the upper aspect of the left shoulder adjacent to the coracoid process. For suspected PMT a wide resection of the tumor was performed and pathological findings were consistent for PMT. Laboratory tests were normalized postoperatively. Reviewing the literature, we had identified 33 reported cases of PMTs among elderly patients age ≥70 years. Unlike previously reported data, where tumors predominantly localized in the lower extremities and pelvis, our search disclosed a high rate of tumor localization (10 cases - 33.3%) in the head with equal number of tumors (14 cases - 42.4%) localized in the head and upper extremity as well as in pelvis and lower extremity. The present case describes unique tumor localization in an elderly patient and our literature search demonstrated for the first time a high rate of tumor localization in the head among this group of patients. Learning points: PMTs represent a rare entity that should be considered in the differential diagnosis of elderly patients presented with persistent hypophosphatemia. Unlike previously reported data, head and neck tumor localization is frequent among elderly patients. 68Gallium-conjugated somatostatin peptide analogs, such as 68Ga-DOTATATE PET/CT demonstrated the greatest sensitivity and specificity for tumor localization in patients with phosphaturic mesenchymal tumors (PMTs). Wide tumor resection using intraoperative ultrasound is of major importance in order to ensure long-term cure.

Post-translational Regulation of Radioactive Iodine Therapy Response in Papillary Thyroid Carcinoma.

Background: Radioactive iodine (RAI) is the mainstay of treatment for differentiated thyroid carcinoma (DTC). Nevertheless, the mechanism of RAI resistance that occurs in many patients with DTC remains unknown. We aimed to elucidate the role of post-translational regulation of radioiodine uptake. Methods: We analyzed the expression pattern of the ribosomal glycosylphosphatidylinositol transamidase (GPIT) complex in freshly excised tumors from 10 patients with DTC. We used functional RAI uptake assays to assess the role of GPIT in iodine uptake both in vivo and in vitro. The effects of MEK inhibition on the GPIT subunit PIGU and the sodium iodide symporter (NIS) were assessed in three DTC cell lines and in four human DTC biopsies. We used a multivariable logistic regression model to study the role of PIGU in the response to RAI treatment in advanced DTC. All statistical tests were two-sided. Results: Expression profiling of different GPIT complex subunits revealed statistically significantly lower expression of PIGU in papillary carcinomas than in matched normal thyroid tissue (P < .001). Expression of PIGU in the K1 human papillary carcinoma cell line resulted in a robust increase in NIS glycosylation and trafficking to the cell membrane, accompanied by a robust increase in I125 uptake both in vitro (465 200 ± 56 343 vs 1236 ± 156 counts per million, P < .001) and in vivo (128 945 ± 28 556 vs 7963 ± 192 counts per million, P < .001, n = 5 mice per group). Treatment with the MEK inhibitors U0126 and PD302 rescued PIGU expression. Finally, the PIGU expression levels in tumors of 18 patients with recurrent DTC were associated with a biochemical response to RAI treatment (hazard ratio = 8.06, 95% confidence interval = 3.72 to 12.3, P = .001). Conclusions: We showed that downregulation of PIGU in DTC determines NIS function and RAI avidity. This represents a novel mechanism for RAI resistance.

Electron spin resonance microscopic imaging of oxygen concentration in cancer spheroids.

Oxygen (O2) plays a central role in most living organisms. The concentration of O2 is important in physiology and pathology. Despite the importance of accurate knowledge of the O2 levels, there is very limited capability to measure with high spatial resolution its distribution in millimeter-scale live biological samples. Many of the current oximetric methods, such as oxygen microelectrodes and fluorescence lifetime imaging, are compromised by O2 consumption, sample destruction, invasiveness, and difficulty to calibrate. Here, we present a new method, based on the use of the pulsed electron spin resonance (ESR) microimaging technique to obtain a 3D mapping of oxygen concentration in millimeter-scale biological samples. ESR imaging requires the incorporation of a suitable stable and inert paramagnetic spin probe into the desirable object. In this work, we use microcrystals of a paramagnetic spin probe in a new crystallographic packing form (denoted tg-LiNc-BuO). These paramagnetic species interact with paramagnetic oxygen molecules, causing a spectral line broadening that is linearly proportional to the oxygen concentration. Typical ESR results include 4D spatial-spectral images that give an indication about the oxygen concentration in different regions of the sample. This new oximetry microimaging method addresses all the problems mentioned above. It is noninvasive, sensitive to physiological oxygen levels, and easy to calibrate. Furthermore, in principle, it can be used for repetitive measurements without causing cell damage. The tissue model used in this research is spheroids of Human Colorectal carcinoma cell line (HCT-116) with a typical diameter of ∼600µm. Most studies of the microenvironmental O2 conditions inside such viable spheroids carried out in the past used microelectrodes, which require an invasive puncturing of the spheroid and are also not applicable to 3D O2 imaging. High resolution 3D oxygen maps could make it possible to evaluate the relationship between morphological and physiological alterations in the spheroids, which would help understand the oxygen metabolism in solid tumors and its correlation with the susceptibility of tumors to various oncologic treatments.

Characterizing bone marrow involvement in Hodgkin's lymphoma by FDG-PET/CT.

PURPOSE: Fluoro-deoxyglucose positron emmission tomography combined with computed tomography (FDG-PET/CT) is superior to iliac bone marrow biopsy (iBMB) for detection of bone marrow involvement (BMI) in staging of Hodgkin's lymphoma (HL). The present study aims to characterize the patterns and distribution of BMI in HL as determined by FDG-PET/CT. METHODS: Reports of FDG-PET/CT studies performed for staging of HL were reviewed. BMI was defined as positive iBMB and/or foci of pathological FDG uptake in the skeleton that behaved in concordance with other sites of lymphoma in studies following chemotherapy. Number of FDG uptake foci, their specific location in the skeleton and the presence of corresponding lesions in the CT component of the study, and stage according to the Ann Arbor staging system, were recorded. RESULTS: The study included 473 patients. iBMB was performed in 336 patients. Nine patients had positive iBMB (9/336, 3%). Seventy-three patients (73/473, 15%) had FDG-PET/CT-defined BMI. The BM was the only extranodal site of HL in 52/473 patients (11 %). Forty-five patients had three or more foci of pathological skeletal FDG uptake (45/73, 62 %). Sixty-four patients (64/73, 88%) had at least one uptake focus in the pelvis or vertebrae. In 60 patients (60/73, 82%), the number of skeletal FDG uptake foci without corresponding CT lesions was equal to or higher than the number of foci with morphological abnormalities. CONCLUSION: FDG-PET/CT demonstrated BMI in 15% of patients with newly diagnosed HL. Diagnosis of BMI in HL by FDG-PET/CT was more sensitive than iBMB with potential upstage in 11% of patients. The most common pattern of FDG-PET/CT BMI was multifocal (at least three foci) skeletal FDG uptake, with at least one focus in the pelvis or vertebrae and no corresponding CT lesions.

Methods for human embryonic stem cells derived cardiomyocytes cultivation, genetic manipulation, and transplantation.

A decade has passed since the initial derivation of human embryonic stem cells (hESC). The ensuing years have witnessed a significant progress in the development of methodologies allowing cell cultivation, differentiation, genetic manipulation, and in vivo transplantation. Specifically, the potential to derive human cardiomyocytes from the hESC lines, which can be used for several basic and applied cardiovascular research areas including in the emerging field of cardiac regenerative medicine, attracted significant attention from the scientific community. This resulted in the development of protocols for the cultivation of hESC and their successful differentiation toward the cardiomyocyte lineage fate. In this chapter, we will describe in detail methods related to the cultivation, genetic manipulation, selection, and in vivo transplantation of hESC-derived cardiomyocytes.

(18)F-FDG avidity in lymphoma readdressed: a study of 766 patients.

UNLABELLED: PET/CT with (18)F-FDG is an important noninvasive diagnostic tool for management of patients with lymphoma, and its use may surpass current guideline recommendations. The aim of the present study is to enlarge the growing body of evidence concerning (18)F-FDG avidity of lymphoma to provide a basis for future guidelines. METHODS: The reports from (18)F-FDG PET/CT studies performed in a single center for staging of 1,093 patients with newly diagnosed Hodgkin disease and non-Hodgkin lymphoma between 2001 and 2008 were reviewed for the presence of (18)F-FDG avidity. Of these patients, 766 patients with a histopathologic diagnosis verified according to the World Health Organization classification were included in the final analysis. (18)F-FDG avidity was defined as the presence of at least 1 focus of (18)F-FDG uptake reported as a disease site. Nonavidity was defined as disease proven by clinical examination, conventional imaging modalities, and histopathology with no (18)F-FDG uptake in any of the involved sites. RESULTS: At least one (18)F-FDG-avid lymphoma site was reported for 718 patient studies (94%). Forty-eight patients (6%) had lymphoma not avid for (18)F-FDG. (18)F-FDG avidity was found in all patients (100%) with Hodgkin disease (n = 233), Burkitt lymphoma (n = 18), mantle cell lymphoma (n = 14), nodal marginal zone lymphoma (n = 8), and lymphoblastic lymphoma (n = 6). An (18)F-FDG avidity of 97% was found in patients with diffuse large B-cell lymphoma (216/222), 95% for follicular lymphoma (133/140), 85% for T-cell lymphoma (34/40), 83% for small lymphocytic lymphoma (24/29), and 55% for extranodal marginal zone lymphoma (29/53). CONCLUSION: The present study indicated that with the exception of extranodal marginal zone lymphoma and small lymphocytic lymphoma, most lymphoma subtypes have high (18)F-FDG avidity. The cumulating evidence consistently showing high (18)F-FDG avidity in the potentially curable Burkitt, natural killer/T-cell, and anaplastic large T-cell lymphoma subtypes justifies further investigations of the utility of (18)F-FDG PET in these diseases at presentation.

PET/CT quantitation of the effect of patient-related factors on cardiac 18F-FDG uptake.

UNLABELLED: The effect of multiple patient-related factors on the degree of cardiac 18F-FDG uptake was assessed. METHODS: Five hundred four consecutive patients undergoing routine 18F-FDG PET/CT studies completed a clinical questionnaire. 18F-FDG uptake was measured as the mean standardized uptake value within the heart delineated on the CT component of the study. Univariate and multivariate analyses assessed the influence of 51 clinical factors on cardiac 18F-FDG uptake. RESULTS: On both multivariate and univariate analyses, cardiac 18F-FDG uptake was significantly lower in diabetics and in patients receiving bezafibrate or levothyroxine. Cardiac 18F-FDG uptake was significantly higher in men, patients younger than 30 y old, fasting duration of <5 h, patients with heart failure, and those receiving benzodiazepines. CONCLUSION: Cardiac 18F-FDG uptake was lower in patients receiving bezafibrate and levothyroxine and higher in patients receiving benzodiazepines. If further confirmed by prospectively designed studies, manipulation of these drugs may represent tools for optimized PET/CT imaging.