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Thursday, October 08, 2015




WASHINGTON—A new report released on Capitol Hill here shows that there has been a marked growth in hospital palliative care teams since 2011, but that major gaps in access to palliative care occur across the nation, especially in southern states.


The report—“America’s Care of Serious Illness: 2015 State-by-State Report Card on Access to Palliative Care in Our Nation’s Hospitals”--and a related study—“The Growth of Palliative Care in U.S. Hospitals: A Status Report,” published in the Journal of Palliative Medicine (doi:10.1089/jpm.2015.0351--were led by R. Sean Morrison, MD, Director of the National Palliative Care Research Center (NPCRC), and Diane E. Meier, MD, Director of the Center to Advance Palliative Care (CAPC). NPCRC and CAPC are part of the Icahn School of Medicine at Mount Sinai Health System in New York City. Other researchers were Tamara Dumanovsky, PhD (who was first author of the journal study); and Maggie Rogers, MPH, both of CAPC.

Overall, the new report gives the United States a B for access to palliative care in hospitals--access that depends on hospital size, geographic location, and tax status. The report follows previous similar report cards in 2008 and 2011; the B grade is unchanged from 2011. Data for the 2015 report card are drawn from the American Hospital Association’s Annual Survey Database from fiscal years 2012 and 2013 and the National Palliate Care Registry.


Key findings are as follows:

  • A major sign of progress is that 17 states received a grade of A (up from just three in the 2008 report and seven in the 2011 report): The states receiving an A are: Connecticut, Maryland, Massachusetts Minnesota, Montana, Nebraska, Nevada, New Hampshire, New Jersey, Ohio, Oregon, Rhode Island, South Dakota, Utah, Vermont, Washington, and Wisconsin;
  • 67 percent of U.S. hospitals with 50 or more beds report having palliative care teams--up from 63 percent in 2011 and 53 percent in 2008--but this means that one-third of U.S. hospitals with 50 or more beds report no palliative care services;
  • Southern states received a grade of C, reflecting the fact that 60 percent or fewer hospitals have palliative care teams, as compared with As and Bs (60% or more hospitals with palliative care teams) for all other regions;
  • The states receiving a D grade (having no more than 40% hospitals with palliative care teams) were Alabama, Arkansas, Mississippi, New Mexico, Oklahoma, and Wyoming; and
  • For the first time, no state received an F (defined as fewer than 20% of a state’s hospitals reporting a palliative care program).

What Would It Take to Have an A for the Country Overall?

Asked by OT what it would take for the nation to receive an A overall, Morrison said: “To ensure universal access to palliative care and bring the nation to an A, we need to promote regulatory and accreditation requirements that mandate the inclusion of palliative care in U.S. hospitals. Additionally, we need payment linked to value and quality measures that truly address the needs of the seriously ill and their families. These steps are critical to redress inconsistencies in access and quality of palliative care services associated with geographic location and ownership, among other factors.” 


The report recommends that as the Centers for Medicare & Medicaid Innovation of the Centers for Medicare & Medicaid Services pilots new care models, it should ensure that palliative care is a component of care, quality measurement, and payment for those with serious illness.


“I think we are past the point where we can rely on hospital administrators to start programs on their own initiative,” he continued. “We now need to actively address the barriers that are preventing universal access to high-quality palliative care.”


Good palliative services should be available in all hospitals and are a basic quality-of-care issue: “Whereas most Americans would not think about going to a hospital without an ICU in the setting of a serious illness, many Americans are still admitted to hospitals without a palliative care team--especially if they live in the south and their hospital is a for-profit hospital.”


Key Differentiator: Hospital Ownership

Indeed, the new report card found that hospital ownership is an important factor in whether the hospital has a palliative care team. Specifically, the data show that only 23 percent of for-profit hospitals offer their patients palliative care; in contrast, not-for-profit hospitals are seven times more likely to have a palliative care team than for-profits are.


The report also found that:

  • 90 percent of hospitals operated by the Catholic Church have palliative care;
  • 90 percent of hospitals with 300 or more beds have palliative care;
  • 78 percent of Medicare patients died near a hospital that had a palliative care team, suggesting that access to palliative care services is improving for this older population; and
  • 96 percent of teaching hospitals now have palliative care teams--increasing the likelihood that the next generation of clinicians will receive training in palliative care.

Morrison said that in addition to issues of hospital size, location, and ownership, the specific barriers need to be addressed to ensure that all Americans with serious illnesses have access to high-quality palliative care.


Workforce Demand

The first is workforce demand: “To address the workforce demand, we need to establish palliative care centers that would develop and disseminate curricula relating to palliative care, support the training and retraining of clinicians in palliative care skills, support continuing education, and provide students with clinical training in appropriate sites of care.”


Knowledge Gaps

A second barrier to universal access to palliative care is knowledge gaps in this relatively new but fast-growing medical specialty, Morrison continued: “To address the knowledge gaps, we need to support research by the Patient-Centered Outcomes Research Institute, the National Institutes of Health, and the Agency for Healthcare Research & Quality--research that focuses on symptom relief, communication with those with serious illness, and developing and evaluating models of care delivery. We also need to support the development of innovative palliative care delivery models.”


Meier and others have emphasized that palliative care can be provided at the same time as treatment to cure the disease. In fact, patients should have access to palliative care at any age and at any stage of a serious illness. Meier pointed to a groundbreaking study by Jennifer Temel, MD, et al published in the New England Journal of Medicine several years ago (2010;363:733-742), which found that patients newly diagnosed with metastatic lung cancer lived nearly three months longer than similar patients receiving the best cancer care but who did not receive palliative care. Those receiving palliative care also felt better and were less depressed, that team reported.


In 2009 the American Society of Clinical Oncology released an updated policy statement recommending the integration of palliative care into treatment as part of comprehensive cancer care for patients with metastatic disease and/or a high symptom burden. And at the 2015 Palliative Care in Oncology Symposium, starting tomorrow in Boston, ASCO plans to release a new joint guidance statement with the American Academy of Hospice and Palliative Medicine, which recommends primary palliative care services for medical oncology practices.


The statement is the first formal consensus-based set of recommendations on the types of palliative care services that constitute high-quality primary palliative care in oncology.



Still, despite the remaining gaps and barriers, the new report on U.S. palliative care takes an optimistic view of the future for increased access to palliative care services, stating: “The timing, demand, and opportunity to expand access to palliative care are unprecedented. The public and private heath care markets are under pressure to provide higher-quality care for the growing number of aging Americans who face serious and chronic disease.”

Thursday, October 08, 2015

Cutaneous T cell lymphoma (CTCL) is considered difficult to diagnose early in part because the mycosis fungoides that characterize the disease can resemble other skin lesions including such benign conditions as psoriasis and atopic dermatitis. But, researchers have now identified a potentially alternative method for diagnosing CTCL—high-throughput T-cell receptor (TCR) sequencing.


As noted in a study published online ahead of print in Science Translational Medicine (DOI: 10.1126/scitranslmed.aaa9122), the research—“co-first” authors were Ilan R. Kirsch, MD, of Adaptive Biotechnologies in Seattle and Rei Watanabe, MD, PhD, of Brigham and Women’s Hospital, Harvard Medical School—showed that high-throughput TCR sequencing accurately diagnosed CTCL in all stages, discriminated CTCL from benign inflammatory skin diseases, and provided insights into the cell of origin and location of malignant CTCL cells in skin.


Findings for Diagnosing CTCL

The team analyzed DNA from biopsies of 46 patients with CTCL skin lesions, 23 patients with psoriasis (with lesional skin), 11 patients with eczematous dermatitis, 12 patients with contact dermatitis, and 12 patients with pityriasis lichenoides et varioliformis acuta (PLEVA), as well as from the skin of six healthy donors using the high-throughput TCR sequencing technique.


By identifying and quantifying malignant T cells, the technique accurately distinguished CTCL from other skin diseases in all 46 patients. In contrast, polymerase chain reaction, the most commonly used diagnostic test for CTCL, correctly diagnosed only 70 percent of the cancer samples, and often missed earlier-stage tumors.


For a subset of patients, the researchers used high-throughput TCR sequencing to track malignant T cells over time, making it possible to detect early recurrence and monitor response to treatment. TCR sequencing also revealed new insights into the cell of origin for CTCL—that the cancer arises from mature, and not immature, T cells, which may help direct the design of more effective therapy, the researchers said.


“Because of its ability to identify and quantify individual T cell clones, high-throughput TCR sequencing is a promising technique to apply to the diagnosis of CTCL,” the authors said. “T cell clones may be frequent within the total T cell population in benign inflammatory skin diseases, but the absolute number of these cells per unit of skin rarely exceeded a certain threshold (about 1:1000). In contrast, in CTCL clonal T cells accumulated not only in frequency but also in absolute numbers to levels that exceed those observed in benign inflammatory skin diseases.”


Accompanying Commentary

In an accompanying commentary article (STM DOI: 10.1126/scitranslmed.aad2518), Jason Weed and Michael Girardi, MD, both of the Department of Dermatology at Yale School of Medicine, note that high-throughput TCR sequencing could yield many advantages over current techniques for diagnosing CTCL: “The potential utility and advantages of high-throughput TCR sequencing analysis may go beyond early and accurate diagnosis.


“By sequencing and quantifying all rearranged TCRs present in a sample, high-throughput TCR sequencing captures and illuminates the presence of not only malignant T cells but also the local infiltrating lymphocytes (in skin) and the effector/memory and naïve T cells (in blood). Analysis of these nonmalignant T cell populations may one day improve prognostic accuracy by serving as an indicator of the antitumor response and, in later stages of disease, a measure of the compromised immune system’s capacity to generate and/or maintain T cell diversity.”

Wednesday, October 07, 2015




WASHINGTON—Federally funded research is indispensable to high-quality patient care, including cancer treatment. But inconsistent, duplicative, or unclear federal regulations on researchers in academic institutions constitute a growing burden that undercuts the effectiveness of the entire research enterprise, according to a new report requested by Congress from the National Academies of Sciences, Engineering, and Medicine (NAS).


The report, released at a news briefing here, charges that the continuing expansion of federal regulations draws investigators’ time away from research, stifles their innovation, forces them to spend an increasing amount of time on administrative matters and paperwork, and discourages the next generation of investigators.


New Entity: Research Policy Board

The report, “Optimizing the Nation’s Investment in Academic Research: A New Regulatory Framework for the 21st Century (Part 1), makes specific recommendations to establish a new regulatory framework and reduce the burden of federal regulations. A key recommendation is for Congress to establish a new entity, the Research Policy Board, which would streamline U.S. research policies.


“For nearly 70 years the partnership between universities and government has yielded great benefit; it behooves all of us to make sure that partnership continues to flourish,” said Larry Faulkner, PhD, Chair of the committee that wrote the report and President Emeritus of the University of Texas in Austin.


He said that while recognizing that effective oversight regulation is necessary for the integrity of the research enterprise, the government/university partnership is under stress, and federal regulations need to be “reexamined and recalibrated.” The committee’s recommendations are aimed at achieving a “more sensible” federal regulatory framework, he added. As used in the report, the term “research institutions” includes teaching hospitals.


Echoes Findings of NSF and FASEB

The National Science Foundation and the Federation of American Societies for Experimental Biology (FASEB) have also found that federal regulations on investigators are increasingly burdensome. A FASEB survey of its members showed that human subjects’ regulations and institutional review board policies are a major source of administrative burden for research institutions and investigators.


The multidisciplinary NAS committee plans to release an addendum to this first phase of the report next spring. Members of the NAS committee who wrote the new report include Lee M. Ellis, MD, Professor of Surgical Oncology and Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center, and David Korn, MD, Professor of Pathology at Massachusetts General Hospital and Harvard Medical School.


Dramatic Growth in Number of Regulations

“In recent decades the amount of regulations has grown dramatically,” said Harriet S. Rabb, JD, Vice Chair of the NAS committee and Vice President and General Counsel at Rockefeller University. “Our committee found that this growth diminishes the effectiveness of the nation’s investment in research.”


She noted that federal regulations are sometimes created when a research scientist behaves badly. But today, she said, the result of well-meaning regulations has meant that an investigator has varying obligations caused by multiple regulatory agencies, which may have little or no uniformity.


‘Steals from the Nation’s Investment in Research’

As the report puts it: “Throughout this study, the committee heard that the current volume of regulations steals from the nation’s investment in research and has become self-defeating.” The report also notes that the government/research partnership has mushroomed to more than 100,000 proposals annually with associated awards and reports, and that what “was once an investment of millions of dollars in the 1950s now involves over $65 billion of public, private, and institutional resources.”


Today, there is “enormous complexity” in complying with federal regulations, emphasized NAS committee member Barbara E. Bierer, MD, Professor of Medicine and Faculty Co-Chair of the Multi-Regional Clinical Trials Center at Harvard Medical School and Professor at Brigham and Women’s Hospital.


She cited a two-page chart in the report listing all the principles, statutes, agency policies, directives, and reference manuals relating to federal oversight of research involving animals: “We’re not trying to eliminate regulations,” Bierer said. Rather, the committee sought to simplify this ”extreme complexity” with one framework that would both be less burdensome for individual researchers and better for the health of the overall U.S. research enterprise.


Asked at the news briefing for a cost estimate on the committee’s proposed new regulatory framework, Faulkner replied that the committee had not done such an estimate.  But, he said, the committee believes that establishment of the new Research Policy Board “would in the end save more money than it costs.” 


Are the FCOI Regulations Really Helping?

The report delves into concerns relating to investigator financial conflict of interest (FCOI), which resulted in changes to U.S. Public Health Service regulations that were implemented in 2012. These changes, which grew out of episodes of scientific misconduct in the 1970s and 1980s, have the effect of making the regulations much stricter.


The committee found that surveys of members of the Association of American Medical Colleges and several other groups indicated that the new, changed FCOI regulations resulted in an increase in the number of significant financial interests that had be reviewed by institutions but without an increase in the number of FCOIs that warranted reporting to PHS funding agencies. Thus the report questions whether the stricter FCOI regulations, while well-intentioned, are really having their intended effect of protecting the integrity of the scientific process, or are just adding to the regulatory burden by creating “a substantially bigger haystack without significantly increasing the number of needles found.”




Specific Recommendations

In addition to recommending that Congress establish the new Research Policy Board, the committee also makes these specific recommendations:

1.  There should be a critical reexamination of the regulatory regime of laws, regulations, rules, policies, guidances, and requirements governing federally funded academic research, with Congress directing federal research-funding agencies to align and harmonize their regulations, especially those concerning protection of human subjects in research, among many other tasks;

2.   Federal agencies that follow the Common Rule, a federal policy for protection of human subjects in research, should institute a risk-stratified system of protections that substantially reduces regulatory burden on minimal-risk research while reserving more intensive regulatory oversight for higher-risk research;

3.  To maintain the integrity of the government/academic research enterprise, there should be a demand that research institutions meet the highest standards in institutional and individual behavior, with sanctioning of those that do not meet these standards;

4.  The responsibilities of inspectors general should be rebalanced so that appropriate consideration is given both to uncovering waste, fraud, and abuse and advising on economy, efficiency, and effectiveness, with the result that the relationship between research institutions and inspectors general is less adversarial and is based on a shared commitment to a dynamic and productive research enterprise.

5.  Congress should work with the White House Office of Management and Budget to conduct a review of agency research grant proposal documents in order to develop a uniform format to be used by all funding agencies;

6.   Congress should work with the Office of Science and Technology Policy and research institutions to develop a single FCOI policy to be used by all research funding agencies;

7.  Congress should direct federal agencies following the Common Rule to require, for multi-site research studies, that a single IRB with the necessary staff and infrastructure serve as the IRB of record for all domestic sites;

8.   Congress should instruct the Department of Health and Human Services to work with other agencies to ensure that research involving biospecimens is eligible for a waiver or modification of informed consent, so long as the proposed research meets the conditions for waiver or modification of informed consent specified in the Common Rule;

9.   Congress should task a single agency with overseeing and unifying efforts to develop a central database of investigators and their professional output;

10. Federal agencies should limit research proposals to the minimum information necessary to permit peer evaluation of the merit of the scientific questions being asked, the feasibility of answering those questions, and the ability of the investigator to carry out that research;

11. Federal agencies should reduce and streamline reporting, assurances, and verifications, and should also develop a central repository to house assurances; and

12. Research institutions should conduct a review of their policies developed to comply with federal regulations of research to determine whether the institution itself has created an excessive or unnecessary self-imposed burden.

Monday, October 05, 2015



The novel histone deacetylase (HDAC) inhibitor belinostat induced complete and durable responses with manageable toxicity as a single agent in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), according to a study led by Owen A. O’Connor, MD, PhD, Professor of Medicine and Experimental Therapeutics, Director of the Center for Lymphoid Malignancies, and Co-Program Director of the Lymphoid Development and Malignancy Program in the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center.


The drug’s safety profile suggests that it could be combined favorably with other regimens or agents to further improve outcomes for this hard-to-treat disease, the team wrote in the study—the pivotal Phase II BELIEF (CLN-19) trial--published in the Journal of Clinical Oncology (2015;33:2492-2499).


PTCLs represent a heterogeneous group of aggressive lymphoid malignancies constituting approximately 10 percent of non-Hodgkin lymphoma cases, with five-year survival rates of less than 32 percent, the article notes. Anthracycline-based regimens--predominantly cyclophosphamide, doxorubicin, vincristine, and prednisone, and sometimes including etoposide--are commonly used as first-line therapy but have not resulted in durable remissions across the subtypes of the disease.


None of the coauthors could be reached for further comment, but a researcher not affiliated with the study,   Amanda Cashen, MD, Associate Professor in Bone Marrow Transplantation & Leukemia Section of Washington University School of Medicine, said that although the response data had been presented in abstract form previously, the JCO publication for the first time provides full details about the study population and the spectrum and duration of responses.


“Belinostat thus joins the growing list of drugs that have activity in relapsed and refractory PTCL,” she said. “However, like other recently approved drugs in this space, the response rate is modest.”


Pralatrexate, Romidepsin, Brentuximab

Three drugs are currently FDA-approved in the United States for the treatment of relapsed or refractory PTCL—all of which received accelerated approval, with the decisions based on the results of nonrandomized Phase II studies:

  • Pralatrexate, a folate antagonist;
  • Romidepsin, another HDAC inhibitor; and
  • Brentuximab vedotin, an antibody-drug conjugate directed to the CD30 protein.

The researchers note that although all three represent advances in the treatment of patients with relapsed or refractory PTCL, most patients with continue to experience relapses. In addition, the drugs have unique toxicity profiles—for example, thrombocytopenia for pralatrexate and romidepsin and peripheral sensory neuropathy for brentuximab), limiting their use in select patients.


“Thus, durable, well-tolerated disease control is achieved in only a minority of patients, creating a need for additional effective treatment options,” the researchers wrote. “The recent emergence of several new drugs specifically active in T-cell lymphoma creates a unique opportunity to combine these agents and potentially generate novel first-line treatment platforms with superior outcomes.”


Belinostat is a hydroxamic acid–derived pan-HDAC inhibitor that broadly inhibits all zinc-dependent HDAC enzymes, with high affinity for class I HDACs 1, 2, and 3, but also class II HDACs 6, 9, and 10 and class IV HDAC 11.


Mechanism of Action

Cashen explained that HDAC inhibitors work through epigenetic changes: “After treatment with an HDAC inhibitor, changes in histone proteins attached to DNA will change the DNA structure, which affects the patterns of gene expression. Why T-cell lymphomas are susceptible to HDAC inhibitors and which specific genes affect the response are important research questions.”

In the study published in JCO, 129 patients with confirmed PTCL who had disease progression after one or more prior therapies received belinostat at a dose of 1,000 mg/m2 as daily 30-minute infusions on days 1 to 5 every 21 days. The patients had a median of two prior systemic therapies.


The overall response rate (ORR) in the 120 evaluable patients was 26 percent, including 13 complete responses (CR) (11%) and 18 partial responses (15%). The median duration of response was 13.6 months, with the longest at the time of the report still ongoing at 36+ months.


Median progression-free survival was 1.6 months and median overall survival was 7.9 months. Twelve of the enrolled patients underwent stem-cell transplantation after receiving belinostat.


The most common grade 3 to 4 adverse events were anemia (experienced by about 11% of patients), thrombocytopenia (7%), dyspnea (6%), and neutropenia (also 6%).


The results, although still modest, have “established that belinostat produces a meaningful ORR of approximately 26 percent, with CR rate of 11 percent, and has a favorable toxicity profile, producing substantially less myelosuppression and no mucositis compared with the adverse events reported with other approved agents,” the researchers said.


Cashen said that brentuximab should be the first choice for patients with relapsed anaplastic large cell lymphoma, since that lymphoma expresses CD30, the target of brentuximab. “Otherwise, though, we do not know how to prioritize the other agents approved for relapsed or refractory T-cell lymphoma.”


Basis for New Treatment Paradigm?

O’Connor and colleagues wrote that they believe that HDAC inhibitor–based platforms could form the basis of new treatment paradigms for PTCL: “Although the precise mechanism of action of HDAC inhibitors is not defined, as a class, HDAC inhibitors have clear reproducible activity in this disease setting. In addition, the strategy of combining HDAC inhibitors with antitumor agents represents a promising opportunity to develop new treatment regimens for patients with PTCL.”


In addition, belinostat’s low incidence of grade 3 to 4 hematologic toxicities suggests that the drug could be combined safely with cytotoxic chemotherapies.


Cashen agreed: “Belinostat, romidepsin, and pralatrexate each have a single-agent response rate of 25 to 30 percent, and we may get better efficacy by combining these agents with each other or with other chemotherapy drugs.


“I wouldn't hesitate to enroll any eligible patient with relapsed PTCL in a clinical trial of novel combinations. But outside of a clinical trial, there is no combination that has proven to be more effective, with a good safety profile, than single-agent therapy.”


The researchers reported that in terms of toxicity, belinostat monotherapy was well tolerated in this heavily pretreated population, with few patients requiring dose reductions (12.4%). The drug was also tolerated by patients who would not have been candidates for treatment with the other approved treatments, such as those with low baseline platelet counts of less than 100,000/µL--with an overall response rate of 15 percent in this challenging patient population.


Future Directions

Looking toward the future, Cashen said: “We need more clinical trials of novel combination therapies in PTCL, and we need to improve the front-line therapy so fewer patients relapse.


“Also, since some patients do have dramatic and durable response to belinostat, we need biomarkers that can identify these patients.”

Monday, October 05, 2015

Of the nearly 1,000 current clinical trials devoted to lymphoma in the National Cancer Institute’s database, only seven are focused specifically on cutaneous T-cell lymphoma. They are the following (three Phase III, three Phase II, and one Phase I):


“A Phase 3 Trial of Brentuximab Vedotin(SGN-35) Versus Physician's Choice (Methotrexate or Bexarotene) in Patients with CD30-Positive Cutaneous T-Cell Lymphoma”

Phase: Phase III

Type: Treatment

Age: 18 and over

Trial IDs: C25001, NCI-2012-01066, 2010-024215-14, NCT01578499


“Study of KW-0761 Versus Vorinostat in Relapsed/Refractory CTCL”

Phase: Phase III

Type: Treatment

Age: 18 and over

Trial IDs: 0761-010, NCI-2012-02782, NCT01728805


“Topical SGX301 (Synthetic Hypericin) for the Treatment of Cutaneous T-Cell Lymphoma (Mycosis Fungoides)”

Phase: Phase III

Type: Treatment

Age: 18 and over

Trial IDs: HPN-CTCL-01, NCI-2015-00891, NCT02448381


“A-dmDT390-bisFv(UCHT1) Immunotoxin Therapy for Patients with Cutaneous T-Cell Lymphoma”

Phase: Phase II

Type: Treatment

Age: 18 and over

Trial IDs: FDA IND 100712, NCI-2014-00420, NCT00611208


“Donor Transplant, Total Lymphoid Irradiation, and Antithymocyte Globulin in Treating Patients with Cutaneous T Cell Lymphoma”

Phase: Phase II

Type: Treatment

Age: 18 to 75

Trial IDs: BMT206, NCI-2011-00855, SU-04062009-2138, NCT00896493


“Efficacy, Safety and Tolerability Study of SHAPE in IA, IB or IIA Cutaneous T-cell Lymphoma”

Phase: Phase II

Type: Treatment

Age: 18 and over

Trial IDs: SHP-141-003, NCI-2014-02164, NCT02213861


“Carfilzomib with or without Romidepsin in Treating Patients with Stage IA-IVB Cutaneous T-Cell Lymphoma”

Phase: Phase I

Type: Biomarker/Laboratory analysis, Treatment

Age: 18 and over

Trial IDs: NU 12H06, NCI-2012-01952, IST-CAR-532, SP0021927, STU00071042, NCT01738594