Early lymphocyte collection for anti-CD19 CART production improves T-cell fitness in patients with relapsed/refractory diffuse large B-cell lymphoma.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeted to the CD19 B-cell antigen form an approved treatment for patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). However, since this therapy is administered after multiple lines of treatment and exposure to lymphotoxic agents, there is an urgent need to optimize this modality of treatment. METHODS: To circumvent the difficulties of harvesting adequate and optimal T cells from DLBCL patients and improve CART therapy, we suggest an earlier lymphopheresis (i.e. at first relapse, before salvage treatment). We conducted a prospective study and evaluated the potential benefit of an earlier lymphopheresis (early group, n = 22) on the clinical outcome of CD19-CART infused DLBCL patients, in comparison with standard lymphopheresis (i.e. at second relapse and beyond; standard group, n = 23). RESULTS: An increased percentage of naïve T cells and increased in vitro T-cell functionality were observed in the early group. Additionally, these cells exhibit a lower exhaustion profile than T cells collected in the standard group. CONCLUSION: While improved T-cell phenotype and function in the lymphopheresis product did not translate into significantly improved clinical outcomes, a trend towards better overall survival (OS) and progression-free survival (PFS) was observed. Early lymphopheresis maximizes the potential of salvage therapies, without compromising CAR T-cell quality.

Justifying CT prior to MRI in cases of suspected occult hip fracture. A proposed diagnostic protocol.

INTRODUCTION: Patients with clinical suspicion of hip fracture, but negative radiographs are suspected of having an occult hip fracture (OHF). Different diagnostic modalities are available for investigating OHF and various protocols have been suggested. MRI has the highest sensitivity and specificity, however availability is limited in many institutes. CT is readily accessible in the large majority of hospitals throughout the world but has lower sensitivity and may miss some fractures. In this article we investigate a protocol that balances these issues providing a practical and cost-effective solution. METHODS: During a four-year period between 2012 and 2016 a strict diagnostic protocol was followed at our Medical Center for patients suspected of OHF. This MRI selective protocol consisted of CT initially being performed and only when negative for fracture, followed by an MRI. Retrospective analysis of all patients who followed the protocol was performed. The patients were divided into two groups: those diagnosed by CT alone and those diagnosed by MRI after having a negative CT scan. Diagnostic performance, time to diagnosis and the cost of this protocol were evaluated. RESULTS: 103 patients were treated under the protocol. In 50 patients (49%) hip fracture was diagnosed by CT alone. In the remaining 53 patients (51%) no definitive diagnosis was reached by CT and MRI was subsequently performed. 12 of these 53 patients (23%) were diagnosed with hip fracture necessitating surgery. In the CT only group mean time from admission to diagnosis was 3 hours, in the CT + MRI group this rose to 40 hours. Cost analysis showed that this protocol was more cost-effective than performing MRI in all patients, saving an estimated 66,805 Euro during the study period. CONCLUSION: The clinical challenge of diagnosing OHF can be minimised by implementing a diagnostic protocol. The protocol should take into consideration the diagnostic sensitivity, availability and cost of different imaging modalities. An MRI selective strategy with initial CT scanning is recommended, as it reduces time to diagnosis and lowers overall costs.

Reproducibility of geometric and flow-based echocardiographic measurements used for quantification of left ventricular total and forward stroke volume in healthy dogs.

BACKGROUND: Cardiac structure and function in dogs are commonly assessed using echocardiography. A variety of linear, area, and flow-based measurements can be used to calculate left ventricular (LV) total stroke volume (TSV) and forward stroke volume (FSV), but the reproducibility of many of these measurements has not been fully studied. We hypothesized that survey of echocardiographic variables would identify those with high reproducibility and inform future investigation of different methods to measure LV TSV and FSV. METHODS: The reproducibility of 25 geometric and flow-based echocardiographic measurements was prospectively evaluated in 23 healthy dogs by two experienced observers. Reproducibility (i.e., interobserver agreement) was described using intraclass correlation coefficients. The reproducibility of various methods to calculate LV TSV and FSV was explored. RESULTS: Reproducibility was generally good to excellent. Variables of LV width, length, and area and aortic and sinotubular junction diameter and velocity time integral were among measures with the highest reproducibility. Measurements of mitral annular diameter and mitral inflow velocity time integral possessed lower reproducibility. Calculation of LV TSV using measurements involved in the cube and bullet formulas demonstrated higher reproducibility than the Simpson's method of disks or mitral inflow methods. Calculation of LV FSV using LV outflow tract and aortic diameters from the right parasternal view generally demonstrated higher reproducibility compared with the left-sided view. CONCLUSIONS: The reproducibility of many simple geometric and flow-based echocardiographic measurements is high. Comparison of the reliability of different measurement informs future investigation of echocardiographic methods to determine LV TSV and FSV in dogs.

[Treatment of pediatric femur fractures by immediate reduction and spica cast application--clinical and economical feasibility in the Israeli medical system].

BACKGROUND: Pediatric femur fractures are common injuries necessitating immediate application of spica cast or surgical stabilization. Currently, neither conservative nor operative fixation shows superior results; nevertheless, operative intervention has become more common lately. The current study retrospectively investigates short term results of immediate spica cast application, as well as the economic consequences of this treatment. METHODS: All cases of pediatric (6 months - 6 years) femur fractures treated in a single medium-sized hospital during 3 years were reviewed. Characteristics of fracture treatment and economical aspects were analyzed. RESULTS: Twenty four patients (17 boys and 7 girls, mean age 2.5 years, range 9 months to 5.5 years), were treated during the study period by immediate closed reduction and spica cast application. Eleven patients were also treated for medical reasons. All cases achieved acceptable alignment and shortening after cast removal. Two patients were re-admitted to the hospital Emergency Room but no changes in treatment were needed, one patient needed re-reduction. Mean hospital stay was 2.75 days. Calculated cost of such treatment is estimated to be almost equal to the compensation given by insurance companies (based on hospital stay in Israel). CONCLUSIONS: Immediate application of spica cast for pediatric femur fractures, achieves its goals of appropriate fracture-alignment and acceptable complication rates. The authors believe that the compensation should be procedure-based and not hospital-stay based, in a way that will encourage higher efficacy of medical treatment and shortened hospital stay.

Selective involvement of interleukin-6 in the transcriptional activation of the suppressor of cytokine signaling-3 in the brain during systemic immune challenges.

Cytokine-inducible proteins named as suppressors of cytokine signaling (SOCS) are rapidly induced by interleukin-6 (IL-6) and other members sharing the gp130 receptor subunit after activation of the Janus kinases (JAK) and the signal transducers and activators of transcription (STAT). These inhibitory proteins generally prevent tyrosine phosphorylation of IL-6 receptor signaling subunit gp130, specific JAK and STAT or in acting at steps distal to JAK activation. Expression of these inhibitory proteins is therefore a useful tool to investigate the signaling events occurring in the brain during immunogenic stimuli that involve cytokines of the IL-6 family. This study investigated the effect of ip lipopolysaccharide (LPS) administration on the expression of one key member of the SOCS family, SOCS-3, in both rats and mice. In rats, the endotoxin caused a profound transcriptional activation of the inhibitory factor in the circumventricular organs subfornical organ, organum vasculosum of the lamina terminalis, arcuate nucleus/median eminence, area postrema, choroid plexus, leptomeninges, ependymal lining cells, and along the endothelium of the brain blood vessels. The hybridization signal for SOCS-3 messenger RNA was low at 1 h, but robust at 3 and 6 h and declined to return to basal levels 12 h after the single ip LPS injection. The pattern of SOCS-3 expression was similar in the brain of wild-type mice, although induction of the inhibitory factor was no longer observed in the ependymal lining cells of the cerebral ventricles and the blood microvessels of IL-6-deficient animals at all the times evaluated, i.e. from 1-8 h post-LPS injection. The endothelium of the brain capillaries also exhibited up-regulation of both IL-6 receptor and gp130 subunits during systemic inflammation, which allowed SOCS-3 expression in response to circulating IL-6. The present data indicate that the JAK/STAT transduction pathways that lead to SOCS-3 transcription are activated within cells accessible from the blood circulation, but not within deep parenchymal elements of the brain during endotoxemia. Induction of SOCS-3 followed the cascade of events that take place during the acute phase response and the contribution of IL-6 in activating the inhibitory factor is site specific and not generalized throughout the central nervous system.

Radiochromium (chromium-51) evaluation of gastrointestinal blood loss associated with placebo, aspirin, and nabumetone.

Gastrointestinal blood loss is one of the most serious clinical events induced by drugs. To date, almost no nonsteroidal anti-inflammatory drug has been shown to be devoid of that side effect in a strictly controlled study. The objective of this study was to assess quantitatively, by use of radioactive chromium (chromium-51)-labeled red blood cells, gastrointestinal blood loss associated with nabumetone (1,000 mg daily), aspirin (3.6 g daily), and placebo. A total of 37 normal subjects, divided among the three treatment groups and a fourth group that received no treatment, were assessed clinically and quantitatively for gastrointestinal blood loss over a period of 28 days of "active" treatment. The results with chromium-51, analyzed on a logarithmic scale, revealed no statistically significant differences between the nabumetone, placebo, and control groups. Gastrointestinal blood loss in the aspirin group, however, was elevated when compared with all other groups at a high level of statistical significance (p less than 0.001). It is concluded that, under conditions in which aspirin causes substantial gastrointestinal microbleeding, nabumetone is not significantly different from placebo.

Comparative study of gastrointestinal microbleeding caused by aspirin, fenbufen, and placebo.

Fifty volunteers, randomly divided into five groups, received placebo, fenbufen, or aspirin at dosages used in treating osteoarthritis and rheumatoid arthritis (fenbufen, 600 or 900 mg daily; aspirin, 3.6 g daily) for 28 days. Following radioactive chromium labeling of red cells in each subject, stool specimens were collected weekly for determination of blood loss by radioisotope procedure. Statistical analyses demonstrated no significant differences in gastrointestinal microbleeding between subjects who received fenbufen (600 or 900 mg daily) and those who received placebo. Conversely, there were significant (p less than 0.01) differences in microbleeding between subjects given aspirin and those given either dosage of fenbufen or placebo.

Wedge-shaped scintillation crystals for positron emission tomography.

The use of wedge-shaped scintillation crystals for positron emission tomography is reevaluated with the aim of delimiting its range of benefit. A linear attenuation simulation model is used to generate the detector geometric aperture functions, and the investigation is carried out in terms of a newly introduced shape-independent definition of the spatial resolution, the "spectral resolution." Contrary to previous expectations, it is concluded that shaped crystals do not improve the performance of high resolution detection systems, either with or without intercrystal septa. However, wedges are found to be useful for lower resolution systems and the boundaries of applicability are estimated for NaI, BaF2, GSO, and BGO scintillators.

The use of a 51Cr technique to detect gastrointestinal microbleeding associated with nonsteroidal antiinflammatory drugs.

Of techniques used to evaluate gastrointestinal (GI) bleeding, use of radiochromium (51Cr)-tagged erythrocytes is the most quantitative and scientifically acceptable method. The value of this technique as well as systematic errors possible with its use are discussed. The medical literature concerning 51Cr evaluation of GI microbleeding with naproxen therapy is critically reviewed. We suggest that future studies using this technique be parallel, randomized, double-blind, and include a 1-week placebo baseline phase for all subjects. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) should last 3 to 4 weeks. A parallel group of subjects should receive placebo throughout the study. For valid statistical analyses, randomization must achieve baseline comparability of weight, height, age, and sex in the treatment groups. Data transformations may be necessary to satisfy the assumptions of the statistical model. Following these guidelines will enable investigators to better evaluate GI microbleeding during treatment with naproxen or other NSAIDs, and, hopefully, to establish the safety profiles of these drugs.

Gastrointestinal microbleeding in normal subjects receiving acetylsalicylic acid, placebo, and R-803, a new antiinflammatory agent, in a design balanced for residual effects.

This study was undertaken to compare the relative gastrointestinal toxicity of equipotent doses of acetylsalicylic acid (ASA), 900 MG q.i.d., and a new anti-inflammatory agent, R-803, 300 mg q.i.d., against placebo. Gastrointestinal micro-bleeding was quantitated with the 61Cr-labeled erythrocyte assay. The experimental design was balanced for residual effects in the first week following any treatment. An interesting relationship between stool weight and blood loss was found to influence the microbleeding independently of the treatments themselves. All observed blood loss values were corrected by regression to a reference stool weight of 100 Gm. Final analysis of corrected values was done on arithmetic and logarithmic scales. On both scales, R-803 induced much less blood loss than ASA. A difference of 1.3 ml/day between R-803 and placebo was not statistically significant on the arithmetic scale. On the log scale, a statistically significant difference was found; but since it corresponds to 0.4 ml/day, it was not considered to be clinically significant at this dosage.

Gastrointestinal blood loss of oxaprozin and aspirin with placebo control.

The objective of this study was to compare the effects of oxaprozin (4,5-diphenyl-2-oxazolepropionic acid), a nonsteroidal, antiinflammatory compound, and aspirin in a double-blind, placebo-controlled study to estimate gastrointestinal bleeding. The determination of fecal blood loss was made quantitatively by the use of the radioactive (51Cr) technique. During the first week, subjects were controlled with and without placebo. At the end of the second week, the subjects were divided and randomly assigned to one of three groups; 10 received 1200 mg oxaprozin (600 mg twice daily), 11 received 3900 mg aspirin (975 mg four times a day), and the remaining 8 subjects received placebo for two weeks. During the last two weeks, all received placebo again. A statistical analysis of variance showed that there were no statistical differences between the groups during the first and last two weeks of placebo therapy. During the active treatment period, weeks 3 and 4, there were statistically significant differences among the three groups. The mean blood loss during week 3 was significantly greater for the aspirin group, 8.8 ml/day, than the oxaprozin group, 3.3 ml/day (P less than 0.05), and the placebo group, 1.4 ml/day (P less than 0.001). The smaller difference between oxaprozin and placebo was also significant (P less than 0.05). During the fourth week, the mean daily blood loss among oxaprozin patients had decreased to 2.3 ml/day, and no statistically significant difference from placebo (1.1 ml/day) was found.

Effect of naproxen on gastrointestinal microbleeding following acetylsalicylate medication.

This study was undertaken to determine if substitution of naproxen for ASA does influence salicylate-induced gastrointestinal bleeding. Twelve normal volunteers were selected and given increasing doses of salicylate until guaiac tests were consistently positive. Autologous labeling of their red blood cells with 51-Cr was used to quantitate the microbleeding. After two weeks on ASA, six subjects were double blindly switched to naproxen and six to placebo for another two weeks of observation. Two-way analysis of variance on the raw data shows a significant treatment effect associated with a significant interaction in both groups. Final analysis on a logarithmic scale permits orthogonal contrasts to be accurately made without any significant remaining interaction. It is concluded that substitution of naproxen for ASA at a dose of 500 mg daily is accompanied by a rapid reduction of microbleeding to "normal" levels.

Comparative gastrointestinal blood loss associated with placebo, aspirin, and nabumetone as assessed by radiochromium (51Cr).

Nabumetone differs from most other nonsteroidal anti-inflammatory drugs. It is presented to the gut as a nonacidic prodrug, and is metabolized to its active form after absorption. Studies in animals and humans suggest it is less irritating to the gastrointestinal mucosa. This study compared the gastrointestinal microbleeding induced by nabumetone to aspirin (acetylsalicylic acid, ASA), and placebo in a double blind parallel study using chromium 51Cr labelled red cells to quantitate fecal blood loss (FBL) in healthy volunteers. Thirty subjects were randomized to treatment with nabumetone (2000 mg), ASA (3.6 g) or placebo for 21 days following a 7 day placebo period. Six subjects served as untreated controls. FBL in nabumetone treated subjects was not significantly different to placebo or untreated subjects. In contrast, ASA-treated subjects exhibited significantly increased FBL than the other 3 groups (P less than .0001).

Fungal pulmonary abscess in an adult secondary to hyperimmunoglobulin E (Job's) syndrome.

Job's syndrome is characterized by recurring bacterial infections of the skin and sinopulmonary tract. Laboratory evaluation reveals consistent elevation of circulating immunoglobulin E levels. The syndrome has been reported as a rare cause of bacterial pulmonary abscess and pneumatocele formation in childhood; here we present a case of cavitating fungal abscess in an adult with Job's syndrome.

[Lymphoma of the knee joint simulating patellar fracture].

Fracture of the patella is not uncommon after direct anterior knee trauma. However, there are other medical situations that resemble it radiologically. We present a patient mistakenly diagnosed as having a patellar fracture who had primary, solitary, malignant B-cell lymphoma of the knee space eroding the lower pole of the patella. We have found no reports of such a lesion in the literature. Another common benign condition that might erode adjacent bone is chronic synovitis. Our patient was treated with chemo- and radiotherapy and the lesion fully regressed with no evidence of local or systemic recurrence 1.5 years after diagnosis.

[Syme amputation of the foot--is it appropriate for foot infections in diabetics?].

Syme ankle disarticulation for foot infections in diabetics with concomitant peripheral vascular disease is often unsuccessful. The need for re-amputation usually results from recurrent infection or ischemia of the posterior heel flap. We present 5 such cases of deep foot infections in diabetics who underwent Syme amputation after failure of local debridement. All patients needed reamputation in 4-18 days for ischemia of the flap.

Skeletal injuries sustained during the Haiti earthquake of 2010: a radiographic analysis of the casualties admitted to the Israel Defense Forces field hospital.

PURPOSE: To report the distribution and types of skeletal injuries demonstrated on the images taken at the field hospital following the Haiti 2010 earthquake. METHODS: Following the January 12, 2010, earthquake, the State of Israel dispatched a field hospital to Haiti, managing 1,111 patients from January 17, 2010, to January 26, 2010. Four hundred and seven patients (37 %) had 684 radiographic images, most of them (87 %) due to presumed skeletal injuries. RESULTS: There were 224 limb fractures (excluding the hands and feet), with 77 % of them in the lower limbs (30 % femur, 17 % tibial shaft, 16 % ankle). Out of 37 axial skeleton fractures, 30 involved the pelvis (21 anterior posterior, three vertical shear, three lateral compression, three combined). Nine traumatic dislocations (five hips, three shoulders, one knee) were reduced. After reviewing all the digital radiographs, on a PACS-compatible radiography screen, few false diagnoses (2 %) were encountered, with none of them affecting the management of these injuries. CONCLUSIONS: To the best of our knowledge, this is the first report of the radiological results emerging from a field hospital following a mass casualty event. Laptop personal computer-based workstations provide an adequate solution for radiographic image viewing in a field hospital setting. Recognition of the prevalence and distribution of skeletal injuries can improve the preparedness of such delegations before departure in the future.