Reprogrammed T Cells Effective for Relapsed or Refractory B-Cell Malignancies.


Six of eight patients with advanced, progressive B-cell lymphoma or chronic lymphocytic leukemia responded to molecularly reprogrammed targeted autologous T cells.

Dramatic progress has been made recently in generating and deploying redirected T cells for patients with refractory B-cell malignancies (JW Oncol Hematol Sep 13 2011). Now, investigators have transduced autologous T cells with a retroviral vector encoding a chimeric antigen receptor that targets the B-cell surface antigen CD19 and the T-cell activating molecule CD28. The modified T cells were expanded ex vivo and reinfused in eight patients with relapsed or refractory B-cell lymphoma or chronic lymphocytic leukemia (CLL) after a short course of chemotherapy (fludarabine plus cyclophosphamide). Patients received interleukin (IL)-2 after T-cell infusion to enhance in vivo expansion.

Of four patients with CLL, one achieved complete remission, two achieved partial remission (PR), and one achieved stable disease. Of four patients with follicular lymphoma, three achieved PR, and one died of influenza before evaluation for response. One patient with marginal zone lymphoma achieved PR. Of all eight patients, four experienced long-term depletion of normal B cells, consistent with known CD19 expression on circulating B cells and with persistence of the transduced T cells; serum immunoglobulin levels fell in these patients, necessitating regular prophylactic infusions of intravenous immunoglobulin. Four patients experienced severe toxicity in the first week after T-cell infusion, attributed to the release of inflammatory cytokines by the activated T cells, including tumor necrosis factor and interferon gamma. Because the exogenously administered IL-2 might have contributed to this toxicity, the investigators dropped IL-2 from the ongoing protocol.

Comment: These results extend the earlier promising reports of cellular immunotherapy with redirected autologous T cells for refractory B-cell malignancy. Further refinement of the methodology for generating therapeutic T-cell doses, better understanding and management of toxicities, and new insights into longer-term safety and efficacy should lead to the development of larger-scale clinical trials.

Source:  Journal Watch Oncology and Hematology

Kepler Explorer app puts distant planets at your fingertips.


Armchair explorers of the cosmos can now have at their fingertips the nearly 2,000 distant planetary systems discovered by NASA’s Kepler Mission. Kepler Explorer, an innovative app for iPads and iPhones developed by a team at the University of California, Santa Cruz, provides interactive displays of newly discovered planetary systems based on Kepler data.

 

Kepler Explorer was developed through the OpenLab initiative at UC Santa Cruz, which brought together faculty and students in astrophysics, art, and technology for a summer institute last year. The Kepler Explorer team includes astrophysicist Jonathan Fortney, a member of the Kepler science team; two of his graduate students, Eric Lopez and Caroline Morley; artist Kyle McKinley, a recent graduate of the Digital Arts and New Media program; and John Peters, a recent graduate of the computer game design program.

“I learned a lot about astrophysics from this project. It was a lot of fun,” said Peters, who wrote all of the software code for the app.

Fortney, an associate professor of astronomy and astrophysics at UCSC, said he enjoyed the opportunity to work on a project that could reach a wider audience than most of his research. The team quickly settled on the idea to create an app, and also developed it into an exhibit that provides additional information and shows the app’s output on a large screen. The exhibit was part of two OpenLab public exhibitions last year, one at the UCSC Digital Arts Research Center and another at the Tech Museum in San Jose. It is scheduled for long-term installation in the Lick Observatory visitors gallery later this month.

Kepler Explorer starts with drop-down menus listing all the Kepler-discovered planetary systems, plus our own solar system. The selected system is displayed in a view that shows the planet or planets in their orbits around the host star. Shown in real time the planets look motionless, but moving a slider increases the speed until the planets zip around their star. The touch screen lets users zoom in and move around the system, and tapping on an individual planet brings it up for further exploration. Another view shows the relative sizes of the individual planets compared to their host star.

 

Kepler Explorer’s most innovative features are seen when viewing individual planets. The user can manipulate the composition of the planet and its atmosphere and see which mixtures of components (iron, rock, water, and hydrogen) are consistent with Kepler’s observations. This feature represents graphically the type of in-depth analysis that Fortney does for the Kepler Mission. “I have pretty good intuition for what the likely composition of a planet is based on its size, but the app allows anyone to explore the properties of many different planets very quickly,” he said.

Because Kepler detects planets as they pass in front of their host star, it only measures the radius of a planet, or how big it is. In most cases, the mass of the planet is unknown. When the mass is unconstrained, there may be different combinations of components that result in a planet of a given size. The app’s interactive graphics show how this works. There are sliders for different components and how they are partitioned in the core and the atmosphere, and as you move the sliders the image of the planet grows and shrinks, based on hundreds of calculations. As you change the settings, the app tells you when the size of your planet matches the observations. The calculations involved took hours of computer time, but the results are stored in tables so the app can use them on the fly.

“For a large-radius planet, you can very quickly tell that it can’t be a rocky planet, for example, and that in itself is pretty informative,” Lopez said.

So far, the Kepler Mission has detected a total of 2,321 planet candidates orbiting 1,790 host stars. Automatic updates for the Kepler Explorer app will add new planet candidates as they are discovered.

Source: University of California, Santa Cruz

 

Autism: 1 in 88 U.S. Kids Diagnosed


One in 88 children in the U.S. was diagnosed with an autism spectrum disorder in 2008, according to new CDC estimates published in MMWR. This represents an increase of 78% from 2002.

CDC researchers examined autism diagnoses among children aged 8 years in 14 areas of the country using education and health records. Among the reporting areas, Utah had the highest prevalence at 21.2 per 1000, and Alabama had the lowest at 4.8 per 1000.

The largest increases were seen among Hispanic and non-Hispanic black children and among those without intellectual disability. Boys were at greater risk for the disorder — 1 in 54 boys had autism, compared with 1 in 252 girls.

The authors say it is not known to what extent the observed increase is a true increase in autism symptoms versus better awareness and access to services.

Source: MMWR Surveillance Summaries

 

Coxsackievirus A6 Causing Severe Hand, Foot, and Mouth Disease in U.S.


Coxsackievirus serotype A6 — previously reported only outside the U.S. — is now causing severe cases of hand, foot, and mouth disease (HFMD) here, according to an MMWR article. HFMD in the U.S. is typically caused by serotype A16.

From November 2011 to February 2012, the CDC was contacted regarding 63 people with HFMD or with fever and unusual rash for whom diagnostic assistance was needed. The cases occurred in Alabama, California, Connecticut, and Nevada. Three-quarters of clinical specimens tested positive for coxsackievirus A6; the rest were negative for all enteroviruses.

Among the 63 patients, rash and fever were more severe and hospitalization was more frequent than with typical HFMD. Fever occurred in 76%. Rash was noted on the hands or feet or in the mouth (67%), on the arms or legs (46%), face (41%), buttocks (35%), and trunk (19%). Almost 20% of patients were hospitalized.

The CDC is continuing to receive reports of coxsackievirus A6–associated illness.

Source: MMWR

 

 

Depression Common After Stroke and TIA, but Widely Undertreated.


Depression is relatively common after both stroke and transient ischemic attack, but the condition is widely undertreated, according to a large U.S. study published in Stroke. (Clinical Conversations has an interview with the author at the link below.)

Researchers interviewed some 1800 patients participating in a multicenter cohort registry about symptoms of depression and antidepressant use at 3 and 12 months after stroke or TIA. They found that depression was more prevalent after stroke than TIA at 3 months, but was similar at 12 months — roughly 14%. Persistent depression (depression found at both the 3- and 12-month mark) was also similar for stroke and TIA — roughly 8%.

Two thirds or more of both stroke and TIA patients with persistent depression were not receiving antidepressants at either the 3- or the 12-month mark.

The authors call for depression screening in the first year after stroke or TIA, contrary to the hypothesis that the increased risk only spans the first months after the cerebrovascular event.

Source: Stroke

A Randomized Trial With Steroids and Antithymocyte Globulins Comparing Cyclosporine/Azathioprine Versus Tacrolimus/Mycophenolate Mofetil (CATM2) in Renal Transplantation.


The best immunosuppressive regimen in benefit-risk ratio in renal transplantation is debated. Nowadays, tacrolimus (Tac) and mycophenolate mofetil (MMF) are considered more efficient than cyclosporine A (CsA) and MMF, but recent studies have challenged this assumption.
METHODS: We conducted a monocentric, prospective, open-labeled, randomized, and controlled trial comparing CsA/azathioprine (Aza) versus Tac/MMF in 289 kidney transplant recipients treated with antithymocyte globulins and prednisone. Primary outcome was the number of patients with clinically suspected acute rejection at 1 year. Secondary outcomes were the number of patients with biopsy-proven acute rejection (BPAR), estimated glomerular filtration rate (eGFR), patient and graft survivals, and adverse events at 1 and 3 years.
RESULTS: During the first year, 21 patients had clinically suspected acute rejection with CsA/Aza (14.4%) vs. 11 (7.7%) with Tac/MMF (P=0.07). BPAR, including borderline, was more frequent in the CsA/Aza group (14.4%) than in the Tac/MMF group (5.6%; P=0.013). At 1 year, patient and graft survivals were not different, and eGFR was 48+/-1 in the CsA/Aza group and 53+/-1 mL/min/1.73 m in the Tac/MMF group (P=0.007). There was no significant difference in diabetes after transplantation (16.8% and 18.8%, respectively).
CONCLUSIONS: With antithymocyte globulins and steroids, clinically suspected acute rejections did not differ between CsA/Aza and Tac/MMF arms. Analysis of secondary endpoints showed a lower rate of BPAR, including border line, and a higher eGFR in the Tac/MMF group. CsA/Aza allowed a low acute rejection rate, but Tac/MMF seemed as a better regimen regarding severe secondary outcomes.

Source:Transplant

A randomized trial of tenecteplase versus alteplase for acute ischemic stroke.


Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent.
METHODS: In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits).
RESULTS: The three treatment groups each comprised 25 patients. The mean (+/-SD) NIHSS score at baseline for all patients was 14.4+/-2.6, and the time to treatment was 2.9+/-0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02).
CONCLUSIONS: Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging.

Source:NEJM

 

Can Immune Cell Function Assay Identify Patients at Risk of Infection or Rejection? A Meta-Analysis.


The Cylex ImmuKnow cell function assay (CICFA) is being considered as a possible tool for identification of infection and rejection in transplant recipients. However, the predictive capability of CICFA is still unclear.
METHODS: Herein, we performed a meta-analysis to assess the efficacy of CICFA in identifying risks of infection and rejection posttransplantation. After a careful review of eligible studies, sensitivity, specificity, and other measures of the accuracy of CICFA were pooled. Summary receiver operating characteristic curves were used to represent the overall test performance.
RESULTS: Nine studies met the inclusion criteria. The pooled estimates for CICFA in identification of infection risk were poor, with a sensitivity of 0.58 (95% confidence interval [CI]: 0.52-0.64), a specificity of 0.69 (95% CI: 0.66-0.70), a positive likelihood ratio of 2.37 (95% CI: 1.90-2.94), a negative likelihood ratio of 0.39 (95% CI: 0.16-0.70), and a diagnostic odds ratio of 7.41 (95% CI: 3.36-16.34). The pooled estimates for CICFA in identifying risk of rejection were also fairly poor with a sensitivity of 0.43 (95% CI: 0.34-0.52), a specificity of 0.75 (95% CI: 0.72-0.78), a positive likelihood ratio of 1.30 (95% CI: 0.74-2.28), a negative likelihood ratio of 0.96 (95% CI: 0.85-1.07), and a diagnostic odds ratio of 1.19 (95% CI: 0.65-2.20).
CONCLUSION: The current evidence suggests that CICFA is not able to identify individuals at risk of infection or rejection. Additional studies are still needed to clarify the usefulness of this test for identifying risks of infection and rejection in transplant recipients.

Source: Transplant.